[(boron OR boric acid) AND (neoplasm or cancer) NOT neutron NOT proteasome]
________________________________________________________________

Boric acid as a promising agent in the treatment 
of ovarian cancer: Molecular mechanisms.

Cabus U, Secme M, Kabukcu C, Cil N, Dodurga Y, Mete G, Fenkci IV 

Gene. 2021 Sep 5;796-797:145799 

PURPOSE: The aim of this study is to determine the therapeutic effects of boric 
acid cell proliferation, invasion, migration, colony formation, cell cycle and 
apoptosis mechanisms in ovarian cancer cell line under in vitro conditions.
METHODS: MDAH-2774 ovarian cancer cells were employed. Real-time PCR test was 
used to investigate changes in genes and proteins of cell cycle and apoptosis 
and identified miRNAs under the addition of boric acid. The apoptosis rates were 
calculated by TUNEL assay. Matrigel invasion, colony formation and Wound healing 
tests were used to determine invasion and migration. Oxidative stress index 
value was calculated for oxidative stress.
RESULTS: Boric acid inhibited cell proliferation, invasion, migration and colony 
formation, but induces apoptosis and oxidative stress. Also, the expression of 
miRNA-21, miRNA-200a, miRNA-130a and mi-RNA-224 (which are indicators of poor 
prognosis of ovarian cancer) decreased significantly.
CONCLUSION: The potential of boric acid as a natural molecule may supports its 
effectiveness in reducing adverse effects arising from conventional ovarian 
cancer treatments.
________________________________________________________________

Boronic acid/boronate prodrugs for cancer treatment: 
current status and perspectives.

Maslah H, Pethe S, Labruère R 

Future Med Chem. 2021 May;13(10):859-861 
________________________________________________________________

Boron-containing compounds as preventive 
and chemotherapeutic agents for cancer.

Scorei RI, Popa R Jr 

Anticancer Agents Med Chem. 2010 May;10(4):346-51 

In the last few years boron (B) compounds became increasingly frequent in the 
chemotherapy of some forms of cancer with high malignancy and of inoperable 
cancers. As more B-based therapy chemicals are developed it is necessary to 
review the correlation between B and the incidence of different forms of cancer, 
the biochemical and molecular mechanisms influenced by B and to explore the 
relevance of B in the chemoprevention of cancer. This minireview analyzes 
dietary and therapeutic principles based on the chemistry of B compounds. We 
summarize studies correlating B-rich diets or B-rich environments with regional 
risks of specific forms of cancers, and studies about the utilization of natural 
and synthetic B-containing compounds as anticancer agents. We review mechanisms 
where B-containing compounds interfere with the physiology and reproduction of 
cancer cells. Types of cancers most frequently impacted by B-containing 
compounds include prostate, breast, cervical and lung cancer. Mechanisms 
involving B activity on cancer cells are based on the inhibition of a variety of 
enzymatic activities, including serine proteases, NAD-dehydrogenases, mRNA 
splicing and cell division, but also receptor binding mimicry, and the induction 
of apoptosis. Boron-enriched diets resulted in significant decrease in the risk 
for prostate and cervical cancer, and decrease in lung cancer in smoking women. 
Boron-based compounds show promising effects for the chemotherapy of specific 
forms of cancer, but due to specific benefits should also be included in cancer 
chemopreventive strategies.
________________________________________________________________

Boron clusters as breast cancer therapeutics.

Murphy N, McCarthy E, Dwyer R, Farràs P

J Inorg Biochem. 2021 May;218:111412 

Since the foundation of small molecule-based therapeutics over 100 years ago, 
their design has been dominated by organic based components. This has also been 
apparent in anti-cancer therapeutics in a broad range of strategies; from the 
older DNA chelating drugs, to the more recent molecular-targeted therapies. The 
main challenges facing current treatments; multidrug resistance and low 
therapeutic index, can potentially be alleviated by the incorporation of boron 
clusters. While retaining the versatility of their organic counterparts, these 
compounds offer a unique set of molecular interactions, which are a useful tool 
in targeted therapies and can improve many organic formulations with their 
incorporation. This review will discuss the potential of boron clusters in 
medicine while focusing on their activity in the breast cancer setting.
________________________________________________________________

Anti-cancer effect of boron derivatives on small-cell lung cancer.

Cebeci E, Yüksel B, Şahin F 

J Trace Elem Med Biol. 2022 Mar;70:126923 

BACKGROUND: Anti-cancer activity of boron has been reported. Although many boron 
derivatives such as boric acid (BA) have been discovered to have anticancer 
effects, there are many boron derivatives whose anticancer effects have not yet 
been discovered. Some of these include sodium pentaborate pentahydrate (NaB), 
which has had limited research on its anticancer effects, and sodium perborate 
tetrahydrate (SPT), whose anticancer effect has yet to be discovered. The aim of 
this study was to investigate the anti-cancer effects of boric acid (BA), sodium 
pentaborate pentahydrate (NaB), and sodium perborate tetrahydrate (SPT) against 
small-cell lung cancer (SCLC) cell line DMS-114 cells in vitro.
METHODS: EC50 concentrations and effects of BA, NaB, and SPT on cell survival 
were detected with an MTS assay. The colony-forming unit (CFU) assay was used to 
assess their effects on cell colony formation capability. Their effects on 
apoptosis were determined by an Annexin-V assay. A cell cycle analysis was 
performed to understand at what phase the cell cycle is arrested. Real-Time PCR 
(RT-PCR) was used to evaluate the mRNA levels of apoptotic, anti-apoptotic, and 
tumor suppressor genes. Western blotting was used to determine the protein 
levels of p53 and Caspase 3.
RESULTS: The survival rates of DMS-114 cells decreased with BA, NaB and SPT 
after 72 h of treatment and the EC50 concentrations ​​of DMS-114 and MRC-5 cells 
differed 5.5-fold in BA treatment, 5,2-fold in NaB treatment and 10-fold in SPT 
treatment. Colony unit numbers were decreased from 350 to 128, from 320 to 95, 
and from 430 to 96 in the BA, NaB, and SPT treatment groups, respectively. The 
apoptosis increased by 10, 19, and 42 percent after treatment with BA, NaB, and 
SPT for 72 h, respectively. Following 72 h of treatment with BA, NaB, and SPT, 
some pro-apoptotic and tumor suppressor genes were upregulated and some 
anti-apoptotic genes were downregulated. Cell cycle arrests were detected at the 
G2/M phase in the BA, and NaB treatment groups and at the Sub-G1 phase in the 
SPT treatment group. The protein levels of P53 and Caspase 3 increased with BA, 
NaB and SPT treatment for 72 h.
CONCLUSIONS: BA, NaB and SPT show anti-cancer activity in the DMS-114 cell line 
without damaging MRC-5 cells, and some of the molecular mechanisms are involved 
in apoptosis and cell cycle arrest.
________________________________________________________________

Boron- and phosphorus-containing molecular/nano platforms: 
exploiting pathological redox imbalance to fight cancer.

Wolfram A, Fuentes-Soriano P, Herold-Mende C, Romero-Nieto C 

Nanoscale. 2022 Dec 8;14(47):17500-17513 

Cancer is currently the second leading cause of death globally. Despite 
multidisciplinary efforts, therapies to fight various types of cancer still 
remain inefficient. Reducing high recurrence rates and mortality is thus a major 
challenge to tackle. In this context, redox imbalance is an undervalued 
characteristic of cancer. However, it may be targeted by boron- and 
phosphorus-containing materials to selectively or systemically fight cancer. In 
particular, boron and phosphorus derivatives are attractive building blocks for 
rational drug discovery due to their unique and wide regioselective chemistry, 
high degree of tuneability and chemical stability. Thus, they can be 
meticulously employed to access tunable molecular platforms to selectively 
exploit the redox imbalance of cancer cells towards necrosis/apoptosis. This 
field of research holds a remarkable potential; nevertheless, it is still in its 
infancy. In this mini-review, we underline recent advances in the development of 
boron- or phosphorus-derivatives as molecular/nano platforms for rational 
anticancer drug design. Our goal is to provide comprehensive information on 
different methodologies that bear an outstanding potential to further develop 
this very promising field of research.
________________________________________________________________

Boric acid exert anti-cancer effect in poorly differentiated hepatocellular 
carcinoma cells via inhibition of AKT signaling pathway.

Kahraman E, Göker E 

J Trace Elem Med Biol. 2022 Sep;73:127043 

BACKGROUND: The possible anti-cancer properties of boron, a trace element for 
humans, have been demonstrated in various experimental and epidemiological 
studies, although the effects of boron on liver cancer are unclear. In the 
present study we evaluate the effects of boric acid on the cell lines of 
hepatocellular carcinoma (HCC) of the liver, as the leading form of liver 
cancer, for which a poorly-differentiated HCC cell line (Mahlavu cell line) was 
used.
METHODS: The anti-cancer effect of boric acid was investigated with a cell 
viability assay, apoptosis analysis, cell migration analysis, cell morphology 
analysis, colony formation assay and 3D cell culture techniques. Also, the 
effect of boric acid on the AKT signaling pathway was determined through a 
western blot analysis.
RESULTS: Boric acid was found to reduce cell viability in a dose- and 
time-dependent manner, and decreased survival, colony formation ability, 
migration capability and HCC cell tumor spheroid growth in HCC cell lines, while 
also inducing apoptosis, autophagy and morphological alteration. Furthermore, 
boric acid inhibited AKT phosphorylation, and anticancer biological responses in 
HCC cells were observed only in cells in which AKT phosphorylation was 
suppressed by boric acid.
CONCLUSION: Our results suggest that boric acid might be a promising therapeutic 
candidate in hepatocellular carcinoma via the inhibition of AKT signaling 
pathway.
________________________________________________________________

Boron intake and prostate cancer risk.

Gonzalez A, Peters U, Lampe JW, White E.

Cancer Causes Control. 2007 Dec;18(10):1131-40 

INTRODUCTION: Experimental studies suggest that boron may prevent prostate 
cancer. Only one small epidemiological study has been conducted of boron, which 
found that those in the highest quartile of boron intake had less than half the 
risk of prostate cancer versus those in the lowest quartile.
METHODS: We evaluated the association between boron intake and prostate cancer 
within the VITamins And Lifestyle (VITAL) cohort. A total of 35,244 men 
completed the baseline supplement and food frequency questionnaire (FFQ) in 
2000-2002. A boron database was constructed from published sources to estimate 
boron intake from the FFQ and from multivitamins. A total of 832 men developed 
prostate cancer from baseline to 31 December 2004.
RESULTS: Dietary boron intake and total boron intake from diet plus 
multivitamins were not associated with prostate cancer risk. The hazard ratio of 
prostate cancer for those in the highest versus lowest quartile of total boron 
intake was 1.17 (95% CI 0.85, 1.61). This risk did not vary by prostate cancer 
stage or Gleason score. Furthermore, none of the foods high in boron content was 
associated with a decreased risk of prostate cancer.
DISCUSSION: This cohort study provides no evidence for a preventive role of 
boron intake on prostate cancer. Since few studies exist on this topic, future 
research is needed to better elucidate any role that boron may play in the 
prevention of prostate cancer.
________________________________________________________________

Anticancer boron-containing prodrugs responsive to oxidative 
stress from the tumor microenvironment.

Maslah H, Skarbek C, Pethe S, Labruère R

Eur J Med Chem. 2020 Dec 1;207:112670 

Boronic acid (and ester) prodrugs targeting the overexpressed level of reactive 
oxygen species within tumor microenvironment represent a promising area for the 
discovery of new selective anticancer chemotherapy. This strategy that emerged 
only ten years ago is exponentially growing and could demonstrate its clinical 
usefulness in the near future. Herein, the previously described small-molecule 
and macromolecular anticancer prodrugs activated by carbon-boron oxidation are 
gathered. This review reports on the most interesting derivatives mentioned in 
the literature based on the in vitro and in vivo activity when available. 
Eventually, the pharmacological applicability of this strategy is discussed, in 
particular, the kinetic aspect of the prodrug oxidation and the selectivity of 
this reaction towards certain ROS from the tumor microenvironment are specified.
________________________________________________________________

Comparative effects of boric acid and calcium fructoborate 
on breast cancer cells.

Scorei R, Ciubar R, Ciofrangeanu CM, Mitran V, Cimpean A, Iordachescu D.

Biol Trace Elem Res. 2008 Jun;122(3):197-205 

Recent studies suggested that boron has a chemo-preventive role in prostate 
cancer. In the present report, we investigated the effects of calcium 
fructoborate (CF) and boric acid (BA) on activation of the apoptotic pathway in 
MDA-MB-231 human breast cancer cells. Exposure to BA and CF inhibited the 
proliferation of breast cancer cells in a dose-dependent manner. Treatment with 
CF but not BA resulted in a decrease in p53 and bcl-2 protein levels. 
Furthermore, after the treatment with CF, augmentation of pro-caspase-3 protein 
expression, cytosolic cytochrome c level, and caspase-3 activity were observed, 
indicating apoptotic cell death induction. This was also demonstrated by 
terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate 
nick-end-labeling assay. In conclusion, our data provide arguments to the fact 
that both BA and CF inhibited the growth of breast cancer cells, while only CF 
induced apoptosis. Additional studies will be needed to identify the underlying 
mechanism responsible for the observed cellular responses to these compounds and 
to determine if BA and CF may be further evaluated as chemotherapeutic agents 
for human cancer.
________________________________________________________________

Boric Acid Activation of eIF2α and Nrf2 Is PERK Dependent: a Mechanism that 
Explains How Boron Prevents DNA Damage and Enhances Antioxidant Status.

Yamada KE, Eckhert CD 

Biol Trace Elem Res. 2019 Mar;188(1):2-10 

Boron is abundant in vegetables, nuts, legumes, and fruit and intake is 
associated with reduced risk of cancer and DNA damage and increased antioxidant 
status. Blood boric acid (BA) levels are approximately 10 μM BA in men at the 
mean US boron intake. Treatment of DU-145 human prostate cancer cells with 10 μM 
BA stimulates phosphorylation of elongation initiation factor 2α (eIF2α) at 
Ser51 leading to activation of the eIF2α/ATF4 pathway which activates the DNA 
damage-inducible protein GADD34. In the present study, we used MEF WT and MEF 
PERK (±) cells to test the hypothesis that BA-activated eIF2α phosphorylation 
requires protein kinase RNA-like endoplasmic reticulum kinase (PERK) and 
activates Nrf2 and the antioxidant response element (ARE). BA (10 μM) increased 
phosphorylation of eIF2α Ser51 in MEF WT cells at 1 h, but not in MEF Perk -/- 
cells exposed for as long as 6 h. GCN2 kinase-dependent phosphorylation of eIF2α 
Ser51 was activated in MEF PERK -/- cells by amino acid starvation. Nrf2 
phosphorylation is PERK dependent and when activated is translocated from the 
cytoplasm to the nucleus where it acts as a transcription factor for ARE. DU-145 
cells were treated with 10 μM BA and Nrf2 measured by immunofluorescence. 
Cytoplasmic Nrf2 was translocated to the nucleus at 1.5-2 h in DU-145 and MEF WT 
cells, but not MEF PERK -/- cells. Real-time PCR was used to measure mRNA levels 
of three ARE genes (HMOX-1, NQO1, and GCLC). Treatment with 10 μM BA increased 
the mRNA levels of all three genes at 1-4 h in DU-145 cells and HMOX1 and GCLC 
in MEF WT cells. These results extend the known boric acid signaling pathway to 
ARE-regulated genes. The BA signaling pathway can be expressed using the 
schematic [BA + cADPR → cADPR-BA → [[ER]i Ca2+↓] → 3 pathways: 
PERK/eIF2αP → pathways ATF4 and Nrf2; and [[ER]i Ca2+↓] → ER stress → ATF6 
pathway. This signaling pathway provides a framework that links many of the 
molecular changes that underpin the biological effects of boron intake.
________________________________________________________________

Toxicity and carcinogenicity studies of boric acid 
in male and female B6C3F1 mice.

Dieter MP 

Environ Health Perspect. 1994 Nov;102 Suppl 7(Suppl 7):93-7 

Toxicity and potential carcinogenicity studies of boric acid were investigated 
in mice to verify in a second rodent species that this was a noncarcinogenic 
chemical. Earlier chronic studies in rats indicated boric acid was not a 
carcinogen. The chemical is nominated for testing because over 200 tons are 
produced annually, there are multiple uses for the product, and there is 
potential for widespread human exposure, both orally and dermally. Both sexes of 
B6C3F1 mice were offered diets mixed with boric acid for 14 days, 13 weeks, or 2 
years. Dietary doses used in the acute, 14-day study were 0, 0.62, 1.25, 2.5, 5, 
and 10%; those in the subchronic, 13-week study were 0, 0.12, 0.25, 0.50, 1, and 
2%; and doses in the 2-year, chronic study were 0, 0.25, and 0.50% in the diet. 
Mortality, clinical signs of toxicity, estimates of food consumption, body 
weight gain, and histopathologic examination of selected tissues constituted the 
variables measured. In the 14-day study mortality was proportional to dose and 
time of exposure in both sexes, occurring in dose groups as low as 2.5% and as 
early as 7 days of exposure. Body weights were depressed more than 10% below 
controls in the higher dose groups of both sexes. Mortality in the 13-week study 
was confined to the two highest dose groups in male mice and to the 2%-dose 
group in females. Body weight depression from 8 to 23% below those of controls 
occurred in the 0.50% and higher dose groups of both sexes. 
(ABSTRACT TRUNCATED AT 250 WORDS)
________________________________________________________________

Dietary boron and hormone replacement therapy 
as risk factors for lung cancer in women.

Mahabir S, Spitz MR, Barrera SL, Dong YQ, Eastham C, Forman MR.

Am J Epidemiol. 2008 May 1;167(9):1070-80 

Hormone replacement therapy (HRT) may reduce lung cancer risk. Dietary boron may 
have actions similar to those of HRT; however, no previous study has reported 
the associations between dietary boron intake and lung cancer risk or the joint 
effects of boron intake and HRT use on lung cancer risk. The authors examined 
the associations between boron intake and the joint effects of boron intake and 
HRT on lung cancer risk in women. In an ongoing case-control study in Houston, 
Texas (July 1995 through April 2005, end date for this analysis), 763 women were 
diagnosed with lung cancer, and 838 were matched healthy controls with data on 
both diet and HRT. Multiple logistic regression analyses were conducted to 
assess the associations between dietary boron and HRT with lung cancer risk. 
After adjustment for potential confounders, the odds ratios for lung cancer with 
decreasing quartiles of dietary boron intake were 1.0, 1.39 (95% confidence 
interval (CI): 1.02, 1.90), 1.64 (95% CI: 1.20, 2.24), and 1.95 (95% CI: 1.42, 
2.68) mg/day, respectively, for all women (p(trend) < 0.0001). In joint-effects 
analyses, compared with women with high dietary boron intake who used HRT, the 
odds ratio for lung cancer for low dietary boron intake and no HRT use was 2.07 
(95% CI: 1.53, 2.81). Boron intake was inversely associated with lung cancer in 
women, whereas women who consumed low boron and did not use HRT were at 
substantial increased odds.
________________________________________________________________

Boric acid induces cytoplasmic stress granule formation, 
eIF2α phosphorylation, and ATF4 in prostate DU-145 cells.

Henderson KA, Kobylewski SE, Yamada KE, Eckhert CD.

Biometals. 2015 Feb;28(1):133-41 

Dietary boron intake is associated with reduced prostate and lung cancer risk 
and increased bone mass. Boron is absorbed and circulated as boric acid (BA) and 
at physiological concentrations is a reversible competitive inhibitor of cyclic 
ADP ribose, the endogenous agonist of the ryanodine receptor calcium (Ca(+2)) 
channel, and lowers endoplasmic reticulum (ER) [Ca(2+)]. Low ER [Ca(2+)] has 
been reported to induce ER stress and activate the eIF2α/ATF4 pathway. Here we 
report that treatment of DU-145 prostate cells with physiological levels of BA 
induces ER stress with the formation of stress granules and mild activation of 
eIF2α, GRP78/BiP, and ATF4. Mild activation of eIF2α and its downstream 
transcription factor, ATF4, enables cells to reconfigure gene expression to 
manage stress conditions and mild activation of ATF4 is also required for the 
differentiation of osteoblast cells. Our results using physiological levels of 
boric acid identify the eIF2α/ATF pathway as a plausible mode of action that 
underpins the reported health effects of dietary boron.
________________________________________________________________

Evaluation of ecological and in vitro effects 
of boron on prostate cancer risk (United States).

Barranco WT, Hudak PF, Eckhert CD.

Cancer Causes Control. 2007 Feb;18(1):71-7 
Erratum in
    Cancer Causes Control. 2007 Jun;18(5):583-4.

OBJECTIVE: To determine: (1) the correlation of prostate cancer incidence and 
mortality with groundwater boron and selenium concentrations; and (2) the impact 
of boron on prostate cancer cell proliferation during co-treatment with 
alternative chemo-preventative agents, along with boron pre-treatment effects on 
cell sensitivity to ionizing radiation.
METHODS: For regression analysis, data on prostate cancer incidence and 
mortality were obtained from the Texas Cancer Registry, while groundwater boron 
and selenium concentrations were derived from the Texas Water Development Board. 
Cultured DU-145 prostate cancer cells were used to assess the impact of boric 
acid on cell proliferation when applied in combination with selenomethionine and 
genistein, or preceding radiation exposure.
RESULTS: Groundwater boron levels correlated with a decrease in prostate cancer 
incidence (R = 0.6) and mortality (R = 0.6) in state planning regions, whereas 
selenium did not (R = 0.1; R = 0.2). Growth inhibition was greater during 
combined treatments of boric acid and selenomethionine, or boric acid and 
genistein, versus singular treatments. 8-day boric acid pre-exposure enhanced 
the toxicity of ionizing radiation treatment, while dose-dependently decreasing 
the expression of anti-apoptotic protein Bcl-2.
CONCLUSIONS: Increased groundwater boron concentrations, across the state of 
Texas, correlate with reduced risk of prostate cancer incidence and mortality. 
Also, boric acid improves the anti-proliferative effectiveness of 
chemo-preventative agents, selenomethionine and genistein, while enhancing 
ionizing radiation cell kill.
________________________________________________________________

Dietary boron intake and prostate cancer risk.

Cui Y, Winton MI, Zhang ZF, Rainey C, Marshall J, De Kernion JB, Eckhert CD.

Oncol Rep. 2004 Apr;11(4):887-92.

Boron affects human steroid hormone levels. Circulating testosterone and 
estradiol levels have been proposed to modify prostate cancer risk. However, the 
association between dietary boron intake and the risk of prostate cancer has not 
been evaluated by any epidemiological study. We explored the association between 
dietary boron intake and the risk of prostate cancer in the USA. Our analysis 
was based on data from the third National Health and Nutrition Examination 
Survey (NHANES III). Cross-sectional case-control study design was employed by 
comparing boron intake of 95 prostate cancer cases with that of 8,720 male 
controls. After controlling for age, race, education, smoking, body mass index, 
dietary caloric intake, and alcohol consumption, increased dietary boron intake 
was associated with a decreased risk of prostate cancer with a dose-response 
pattern. The adjusted odds ratio was 0.46 (95% confidence interval: 0.21-0.98) 
for the highest quartile of boron intake comparing to the lowest quartile (P for 
trend = 0.0525). The observed association should be interpreted with caution 
because of the small case sample size and the nature of the cross-sectional 
study design, but deserve further investigation.
________________________________________________________________

High Concentrations of Boric Acid Trigger Concentration-Dependent Oxidative 
Stress, Apoptotic Pathways and Morphological Alterations in DU-145 Human 
Prostate Cancer Cell Line.

Hacioglu C, Kar F, Kacar S, Sahinturk V, Kanbak G 

Biol Trace Elem Res. 2020 Feb;193(2):400-409 

Boric acid is known to regulate the proliferation of cancer cells. Prostate 
cancer is among the types of cancer with high mortality in men. There are a few 
numbers of studies investigating the effects of boric acid on prostate cancer 
cells. The objective of the present study was to assess the effects of boric 
acid at concentrations higher than that can be achieved in blood by dietary 
intake on DU-145 human prostate cancer cells for 24 h. Firstly, we determined 
the cytotoxic activity of boric acid (0 to 12.5 mM) on DU-145 human prostate 
cancer cells by using 3-(4, 5-dimethylthiazol, 2-yl)-2, 5-diphenyl tetrazolium 
bromide (MTT) and defined the IC50 concentration of boric acid. Then, by 
employing the doses found in MTT, the levels of antioxidant-oxidant molecules 
and apoptotic proteins were measured and morphological changes were evaluated. 
We have concluded that boric acid caused oxidative stress, inhibition of cell 
growth, apoptosis, and morphological alterations in a concentration-dependent 
manner in DU-145 cells. Furthermore, treatments with increasing boric acid 
concentrations decreased the antioxidant levels in cells. We actually revealed 
that boric acid, known as an antioxidant, may prevent cell proliferation by 
acting as an oxidant in certain doses. Although the high IC50 concentration of 
boric acid is perceived to be negative, we think it provides important 
background for subsequent studies.
________________________________________________________________

Brain Boron Level, DNA Content, and Myeloperoxidase Activity 
of Metformin-Treated Rats in Diabetes and Prostate Cancer Model.

Ozel AB, Dagsuyu E, Aydın PK, Bugan I, 
Bulan OK, Yanardag R, Yarat A

Biol Trace Elem Res. 2022 Mar;200(3):1164-1170 

In this study, the effect of metformin on boron levels and oxidative brain 
damage in rats due to diabetes and prostate cancer was investigated for the 
first time. Myeloperoxidase (MPO) activity and the amount of DNA were 
investigated as tissue oxidative and toxic damage parameters. In Copenhagen 
rats, Dunning prostate cancer was induced using high metastatic MAT-Lylu cells 
and diabetes was induced by single dose of streptozotocin (STZ) injection. 
Metformin was administered for 14 days after diabetes and prostate cancer 
induced. The rats were divided into six groups as follows: control group, 
diabetic group (D), cancer group (C), diabetic + cancer (DC) group, cancer + 
metformin (CM) group, diabetic + cancer + metformin (DCM) group. At the end of 
the experiment, brains were removed. Significant decrease of brain boron levels 
and significant elevation of MPO activity and DNA levels were observed in D, C, 
and DC groups as compared to control group. The effect of diabetes induction on 
the brain boron levels was much more than prostate cancer induction. The 
administration of metformin with CM and DCM obviously declined MPO activity and 
increased brain boron levels almost near to control group level. In conclusion, 
this study shows that the protective effect of metformin against brain damage in 
STZ-induced diabetic rats with Dunning prostate cancer may also be related to 
increased boron levels. The boron levels may be a novel indicator of reduced 
toxic and oxidative stress. Furthermore, the distribution and mechanism of 
action of boron should be clarified.
________________________________________________________________

Phenylboronic acid selectively inhibits human prostate 
and breast cancer cell migration and decreases viability.

Bradke TM, Hall C, Carper SW, Plopper GE.

Cell Adh Migr. 2008 Jul-Sep;2(3):153-60 

We compared the in vitro effect of boric acid (BA) versus phenylboronic acid 
(PBA) on the migration of prostate and breast cancer cell lines and 
non-tumorigenic cells from the same tissues. Treatment at 24 hours with BA (< or 
=500 microM) did not inhibit chemotaxis on fibronectin in any cell line. 
However, treatment over the same time course with concentrations of PBA as low 
as 1 muM significantly inhibited cancer cell migration without effecting 
non-tumorigenic cell lines. The compounds did not affect cell adhesion or 
viability at 24 hours but did alter morphology; both decreased cancer cell 
viability at eight days. These results suggest that PBA is more potent than BA 
in targeting the metastatic and proliferative properties of cancer cells.
________________________________________________________________

Boric acid inhibits human prostate cancer cell proliferation.

Barranco WT, Eckhert CD.

Cancer Lett. 2004 Dec 8;216(1):21-9 

The role of boron in biology includes coordinated regulation of gene expression 
in mixed bacterial populations and the growth and proliferation of higher plants 
and lower animals. Here we report that boric acid, the dominant form of boron in 
plasma, inhibits the proliferation of prostate cancer cell lines, DU-145 and 
LNCaP, in a dose-dependent manner. Non-tumorigenic prostate cell lines, PWR-1E 
and RWPE-1, and the cancer line PC-3 were also inhibited, but required 
concentrations higher than observed human blood levels. Studies using DU-145 
cells showed that boric acid induced a cell death-independent proliferative 
inhibition, with little effect on cell cycle stage distribution and 
mitochondrial function.
________________________________________________________________

Cellular changes in boric acid-treated DU-145 prostate cancer cells.

Barranco WT, Eckhert CD.

Br J Cancer. 2006 Mar 27;94(6):884-90 

Epidemiological, animal, and cell culture studies have identified boron as a 
chemopreventative agent in prostate cancer. The present objective was to 
identify boron-induced changes in the DU-145 human prostate cancer cell line. We 
show that prolonged exposure to pharmacologically-relevant levels of boric acid, 
the naturally occurring form of boron circulating in human plasma, induces the 
following morphological changes in cells: increases in granularity and 
intracellular vesicle content, enhanced cell spreading and decreased cell 
volume. Documented increases in beta-galactosidase activity suggest that boric 
acid induces conversion to a senescent-like cellular phenotype. Boric acid also 
causes a dose-dependent reduction in cyclins A-E, as well as MAPK proteins, 
suggesting their contribution to proliferative inhibition. Furthermore, treated 
cells display reduced adhesion, migration and invasion potential, along with 
F-actin changes indicative of reduced metastatic potential. Finally, the 
observation of media acidosis in treated cells correlated with an accumulation 
of lysosome-associated membrane protein type 2 (LAMP-2)-negative acidic 
compartments. The challenge of future studies will be to identify the underlying 
mechanism responsible for the observed cellular responses to this natural blood 
constituent.
________________________________________________________________

Receptor activated Ca(2+) release is inhibited 
by boric acid in prostate cancer cells.

Henderson K, Stella SL, Kobylewski S, Eckhert CD.

PLoS One. 2009 Jun 23;4(6):e6009 

BACKGROUND: The global disparity in cancer incidence remains a major public 
health problem. We focused on prostate cancer since microscopic disease in men 
is common, but the incidence of clinical disease varies more than 100 fold 
worldwide. Ca(2+) signaling is a central regulator of cell proliferation, but 
has received little attention in cancer prevention. We and others have reported 
a strong dose-dependent reduction in the incidence of prostate and lung cancer 
within populations exposed to boron (B) in drinking water and food; and in tumor 
and cell proliferation in animal and cell culture models.
METHODS/PRINCIPAL FINDINGS: We examined the impact of B on Ca(2+) stores using 
cancer and non-cancer human prostate cell lines, Ca(2+) indicators Rhod-2 AM and 
Indo-1 AM and confocal microscopy. In DU-145 cells, inhibition of Ca(2+) release 
was apparent following treatment with Ringers containing RyR agonists cADPR, 
4CmC or caffeine and respective levels of BA (50 microM), (1, 10 microM) or (10, 
20, 50,150 microM). Less aggressive LNCaP cancer cells required 20 microM BA and 
the non-tumor cell line PWR1E required 150 microM BA to significantly inhibit 
caffeine stimulated Ca(2+) release. BA (10 microM) and the RyR antagonist 
dantroline (10 microM) were equivalent in their ability to inhibit ER Ca(2+) 
loss. Flow cytometry and confocal microscopy analysis showed exposure of DU-145 
cells to 50 microM BA for 1 hr decreased stored [Ca(2+)] by 32%.
CONCLUSION/SIGNIFICANCE: We show B causes a dose dependent decrease of Ca(2+) 
release from ryanodine receptor sensitive stores. This occurred at BA 
concentrations present in blood of geographically disparate populations. Our 
results suggest higher BA blood levels lower the risk of prostate cancer by 
reducing intracellular Ca(2+) signals and storage.
________________________________________________________________

Inhibition of the enzymatic activity of prostate-specific antigen 
by boric acid and 3-nitrophenyl boronic acid.

Gallardo-Williams MT, Maronpot RR, Wine RN, Brunssen SH, Chapin RE.

Prostate. 2003 Jan 1;54(1):44-9 

BACKGROUND: Prostate specific antigen (PSA) is a well-established marker of 
prostate cancer, but it can also degrade extracellular matrix proteins such as 
fibronectin and could be involved in tumor progression and metastasis. In this 
study, we have addressed the use of boric acid and 3-nitrophenyl boronic acid 
(NPBA) as PSA inhibitors in vitro.
METHODS: The inhibition of PSA by boric acid was studied by using specific 
fluorogenic substrates. Fibronectin, a biologically relevant substrate for PSA, 
was used as a substrate in a zymographic assay, and the degradation of 
fibronectin by PSA in the presence of boric acid and NPBA was followed by 
Western Blot.
RESULTS: Low concentrations of boric acid partially inhibited the proteolytic 
activity of PSA toward a synthetic fluorogenic substrate. Also, by Western blot, 
we have found significant inhibition in the proteolysis of fibronectin by PSA in 
the presence of boric acid as well as NPBA. Results indicate that the boronated 
compounds used in this study can be used for the modulation of PSA activity.
CONCLUSION: PSA activity is inhibited in vitro by boric acid and NPBA. If 
degradation of fibronectin by PSA were, in fact, an important step in the 
progression of prostate cancer, then borate-induced inhibition of PSA activity 
should help reduce the development and proliferation of prostate carcinomas.
________________________________________________________________

Promising potential of boron compounds against Glioblastoma: 
In Vitro antioxidant, anti-inflammatory and anticancer studies.

Turkez H, Arslan ME, Tatar A, Mardinoglu A 

Neurochem Int. 2021 Oct;149:105137 

Glioblastoma (GB) is the most common and aggressive primary malignant 
astrocytoma correlated with poor patient survival. There are no curative 
treatments for GB, and it becomes resistant to chemotherapy, radiation therapy, 
and immunotherapy. Resistance in GB cells is closely related to their states of 
redox imbalance, and the role of reactive oxygen species and its impact on 
cancer cell survival is still far from elucidation. Boron-containing compounds, 
especially boric acid (BA) and borax (BX) exhibited interesting biological 
effects involving antibacterial, antiviral, anti-cancerogenic, anti-mutagenic, 
anti-inflammatory as well as anti-oxidative features. Recent studies indicated 
that certain boron compounds could be cytotoxic on human GB. Nevertheless, there 
is gap of knowledge in the literature on exploring the underlying mechanisms of 
anti-GB action by boron compounds. Here, we identified and compared the 
potential anti-GB effect of both BA and BX, and revealed their underlying 
anti-GB mechanism. We performed cell viability, oxidative alterations, oxidative 
DNA damage potential assays, and explored the inflammatory responses and gene 
expression changes by real-time PCR using U-87MG cells. We found that BA and BX 
led to a remarkable reduction in U-87MG cell viability in a 
concentration-dependent manner. We also found that boron compounds increased the 
total oxidative status and MDA levels along with the SOD and CAT enzyme 
activities and decreased total antioxidant capacity and GSH levels in U-87MG 
cells without inducing DNA damage. The cytokine levels of cancer cells were also 
altered. We verified the selectivity of the compounds using a normal cell line, 
HaCaT and found an exact opposite condition after treating HaCaT cells with BA 
and BX. BA applications were more effective than BX on U-87MG cell line in terms 
of increasing MDA levels, SOD and CAT enzyme activities, and decreasing 
Interleukin-1α, Interleukin-6 and Tumor necrosis factor- α (TNF- α) levels. We 
finally observed that anticancer effect of BA and BX were associated with the 
BRAF/MAPK, PTEN and PI3K/AKT signaling pathways in respect of downregulatory 
manner. Especially, BA application was found more favorable because of its 
inhibitory effect on PIK3CA, PIK3R1, PTEN and RAF1 genes. In conclusion, our 
analysis indicated that boron compounds may be safe and promising for effective 
treatment of GB.
________________________________________________________________

A Study on the Anticarcinogenic Effects of Calcium Fructoborate.

Tepedelen BE, Korkmaz M, Tatlisumak E, Uluer ET, 
Ölmez E, Değerli İ, Soya E, İnan S 

Biol Trace Elem Res. 2017 Aug;178(2):210-217 

Evidences about the preventive and therapeutic effects of boron compounds on 
cancer have been increasing in the last years. Although calcium fructoborate 
(CaFB) is used as a nutritional supplement, data about its preventive and 
therapeutic effects on neoplastic transformations are limited. In the present 
study, the various concentrations of CaFB were applied to the MDA-MB-231 
metastatic breast cancer cell line. First, we examined the cytotoxic effect and 
IC50 value of CaFB by MTT assay. For the evaluation of the DNA damage, apoptosis 
and metastatic potential, expression levels of ATM, pATM, PARP, p53, p-p53, 
caspase-3, caspase-9, and VEGF were investigated by using immunoblotting and 
immunohistochemical methods. Cell viability was significantly reduced at 50 μM 
CaFB treatment. pATM, p-p53, and caspase-9 levels increased significantly in all 
groups; furthermore, there was approximately 12.5-, 2.4-, and 10.7-fold 
increase, respectively, for 100 μM CaFB treatment. ATM and p53 levels did not 
change with CaFB treatment, but PARP levels significantly 2.5-fold decreased. 
While VEGF immunoreactivity decreased in all groups, significant increase in 
caspase-3 immunoreactivity was observed only in the group treated with 50 μM 
CaFB (p < 0,001). Our results imply that CaFB may have therapeutic potential as 
well as preventive benefits in cancer.
________________________________________________________________

Prevalence of prostate cancer in high boron-exposed population: 
a community-based study.

Müezzinoğlu T, Korkmaz M, Neşe N, Bakırdere S, Arslan Y, Ataman OY, Lekili M.

Biol Trace Elem Res. 2011 Dec;144(1-3):49-57. 

We investigated the possible relationship between boron exposure and prostate 
cancer (PCa) for men living and being employed at boron mines in villages with 
rich boron minerals. Out of 456 men studied, 159 were from villages with rich 
boron sources and boron levels in drinking water of >1 mg L(-1) and these men 
formed the study group, while 63 from villages with rich boron sources and boron 
levels in drinking water of <1 mg L(-1) were enrolled into control group 1. A 
further 234 subjects from other villages with no boron mines were considered as 
control group 2. Prostate specific antigen (PSA) levels could be obtained from a 
total of 423 men. Urinary boron concentration as an indicator of boron exposure 
in 63 subjects, prostatic volumes by transrectal ultrasonography in 39 subjects, 
and prostatic biopsies in 36 subjects were obtained for study and control 
groups. The daily boron exposure was calculated according to urinary boron 
levels. Although there was no significant difference among the groups in terms 
of total PSA levels, the number of subjects with tPSA ≥2.5 and tPSA 
≥10.0 ng dL(-1) prostatic volumes in men whose prostates were biopsied 
(p < 0.012) was significantly lower in the study group as compared with those in 
the control group 2. These results suggested that high exposure to boron might 
have an implication within the prostatic cellular processes related to 
hyperplasia and carcinogenesis, even though we did not find a statistically 
significant association between PCa and boron exposure.
________________________________________________________________

Investigation of the biochemical and apoptotic changes 
in breast cancer cells treated with leaf extract from tea 
(Camellia sinensis L.) grown with added boric acid. 

Sezekler I, Ersoz M, Turan MA, Coskun ZM 

Pak J Pharm Sci. 2020 Sep;33(5):1927-1932.

Tea obtained from the leaves of Camellia sinensis L., a medicinal plant, is a 
widely popular beverage. Deficiency in boron, a micronutrient for C. sinensis, 
affects the growth as well as the quality of tea. The aim of this study was to 
explore whether boric acid at various concentrations added to soil improves the 
quality of C. sinensis and also whether it changes the apoptotic, 
anti-proliferative, and anti-oxidative effects of C. sinensis leaf extract on 
breast cancer (MCF-7) cells. C. sinensis was grown in Rize-Turkey. Boric acid at 
concentrations of 100 (group B), 300 (group C), and 500 (group D) mg/m2 in 
sodium tetraborate buffer was administered as a single dose to the soil; group A 
(no boric acid) was the control. Boron, glutathione (GSH), malondialdehyde and 
protein carbonyl levels in the C. sinensis leaves were measured. C. sinensis 
leaf extracts at different concentrations was applied to MCF-7 cells for 24 and 
48h. Cytotoxicity, proliferation, and apoptosis were examined. The highest 
TUNEL+ cell percentage was in MCF-7 cells treated with D group leaf extract 
compared to the control group (p<0.001 at concentrations of 2.3, 2.6 and 
3mg/mL). Moreover, the GSH level increased in the MCF-7 cells under the same 
conditions (p<0.001 for each concentration). Leaf extracts from C. sinensis 
grown in soil with boric acid have more anti-proliferative, apoptotic and 
anti-oxidative effects on the MCF 7 cells.
________________________________________________________________

Boron Induces Lymphocyte Proliferation and Modulates the 
Priming Effects of Lipopolysaccharide on Macrophages.

Routray I, Ali S 

PLoS One. 2016 Mar 2;11(3):e0150607 

Chemical mediators of inflammation (CMI) are important in host defense against 
infection. The reduced capacity of host to induce the secretion of these 
mediators following infection is one of the factors in host susceptibility to 
infection. Boron, which has been suggested for its role in infection, is 
reported in this study to increase lymphocyte proliferation and the secretion of 
CMI by the lipopolysaccharide (LPS)-stimulated peritoneal macrophages in BALB/c 
mice. Boron was administered to mice orally as borax at different doses for 10 
consecutive days, followed by the stimulation of animals with ovalbumin and 
isolation of splenocytes for proliferation assay. The lymphocyte subsets were 
determined by flow cytometry in spleen cell suspension. The mediators of 
inflammation, TNF-α, IL-6, IL-1β and nitric oxide (NO), were measured in culture 
supernatant of LPS-primed macrophages isolated from borax treated mice. TNF and 
ILs were measured by ELISA. NO was determined by Griess test. The expression of 
inducible nitric oxide synthase (iNOS) in macrophages was studied by confocal 
microscopy. Results showed a significant increase in T and B cell populations, 
as indicated by an increase in CD4 and CD19, but not CD8, cells. Boron further 
stimulated the secretion of TNF-α, IL-6, IL-1β, NO and the expression of iNOS by 
the LPS-primed macrophages. The effect was dose dependent and most significant 
at a dose level of 4.6 mg/kg b. wt. Taken together, the study concludes that 
boron at physiological concentration induces lymphocyte proliferation and 
increases the synthesis and secretion of pro-inflammatory mediators by the 
LPS-primed macrophages, more specifically the M1 macrophages, possibly acting 
through Toll-like receptor. The study implicates boron as a regulator of the 
immune and inflammatory reactions and macrophage polarization, thus playing an 
important role in augmenting host defense against infection, with possible role 
in cancer and other diseases.
________________________________________________________________

Phenylboronic acid is a more potent inhibitor than boric acid 
of key signaling networks involved in cancer cell migration.

McAuley EM, Bradke TA, Plopper GE.

Cell Adh Migr. 2011 Sep-Oct;5(5):382-6 

Previous studies from our lab have shown that both boric (BA) and phenylboronic- 
acid (PBA) inhibit the migration of prostate cancer cell lines, as well as 
non-tumorigenic prostate cells. Our results indicate that PBA is more potent 
than BA in targeting metastatic and proliferative properties of cancer cells. 
Here we focus on the impact of BA and PBA on Rho family of GTP-binding proteins 
and their downstream targets. Treatment with 1mM PBA and BA decreases activities 
of RhoA, Rac1, and Cdc42 in DU-145 metastatic prostate cancer cells, but not in 
normal RWPE-1 prostate cells. Furthermore, ROCKII activity and phosphorylation 
of myosin light chain kinase decrease as a result of either PBA or BA treatment 
in DU-145 cells, suggesting these compounds target actomyosin-based 
contractility.
________________________________________________________________

The inhibitory effect of boric acid on hypoxia-regulated 
tumour-associated carbonic anhydrase IX.

Yusuf ZS, Uysal TK, Simsek E, Nocentini A, 
Osman SM, Supuran CT, Özensoy Güler Ö 

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1340-1345 

Carbonic anhydrases (EC 4.2.1.1) catalyse the reversible hydration of CO2 into 
bicarbonate and protons. As a hypoxia-sensitive and tumour-associated isoform, 
isoform CA IX, is significantly overexpressed in various malignancies, being a 
validated target for new anticancer/antimetastatic drugs. A multitude of studies 
has shown that CA IX inhibition decreases cancer cell proliferation and 
metastasis through pHe/pHi modulation and enhancement of ferroptosis among 
others. Numerous studies demonstrated increased efficacy of cytotoxic drugs 
combined with CA inhibitors (CAIs) in various cancer types. We tested the 
inhibitory effect of boric acid (BA), an inorganic Lewis acid, on CA IX as well 
as other isoforms (CA I, II, and XII). BA acted as a millimolar in vitro CAI, 
decreased proliferation of two cancer cell lines, although not strong 
correlations between the in vitro inhibition and in vivo effects were observed. 
The mechanism of antiproliferative action of BA should be investigated in more 
detail.
________________________________________________________________

High levels of boron promote anchorage-independent growth 
of nontumorigenic cells.

Xu H, Hashimoto K, Maeda M, Azimi MD, Fayaz SH, 
Chen W, Hamajima N, Kato M 

Environ Pollut. 2020 Nov;266(Pt 3):115094 

WHO has presented a health-based guideline value for boron in drinking water. 
That fact indicates that a high level of boron is toxic for humans. However, 
there is no direct evidence of boron-mediated malignant transformation. In this 
study, human lung epithelial nontumorigenic BEAS-2B cells and tumorigenic 
A549 cells were used to investigate the tumorigenic toxicity of boron in vitro. 
Anchorage-independent growth, a hallmark of malignant transformation, was 
increased by boron at concentrations of 50, 250 and 500 μM in BEAS-2B cells, 
though the same concentrations of boron had no influence on 
anchorage-independent growth of A549 cells. Moreover, boron at concentrations of 
250 and 500 μM activated the c-SRC/PI3K/AKT pathway of BEAS-2B cells. The 
results of our in vitro study suggest that exposure to high levels of boron 
promotes transforming activity of nontumorigenic cells.
________________________________________________________________

Effects of dietary boron on cervical cytopathology and on micronucleus frequency 
in exfoliated buccal cells.

Korkmaz M, Uzgören E, Bakirdere S, Aydin F, Ataman OY.

Environ Toxicol. 2007 Feb;22(1):17-25 

Recent evidence indicates that boron and borates may have anticarcinogenic 
properties. In this study, we have investigated the incidence of adverse 
cytological findings in cervical smears and the micronucleus (MN) frequency in 
women living in boron-rich and boron-poor regions. Cervical smears were prepared 
from 1059 women with low socioeconomic status; 472 of the women lived in 
relatively boron-rich rural areas, while 587 lived in relatively boron-poor 
regions. The average and standard deviation values for the age of the women 
screened with the cervical Pap smear test were 41.55 +/- 8.38. The mean dietary 
intake of boron was 8.41 mg/day for women from the boron-rich regions, and 1.26 
mg/day for women living in the boron-poor regions (P < 0.0001). Women from the 
boron-rich regions had no cytopathological indications of cervical cancer, while 
there were cytopathological findings for 15 women from the boron-poor areas 
(chi(2) = 10.473, P < 0.05). Sixty women, 30 from each region, were chosen for 
evaluating MN frequencies in exfoliated buccal cells. MN frequencies for women 
from the boron-rich and boron-poor regions were not significantly different (t = 
-0.294, P > 0.05). Also, there were no significant correlations between age and 
MN frequency for women from both the boron-rich (r = 0.133, P = 0.48, P > 0.05) 
and boron-poor (r = -0.033, P = 0.861, P > 0.05) regions. The results suggest 
that ingestion of boron in the drinking water decreases the incidence of 
cervical cancer-related histopathological findings. There was no correlation 
between the pathological findings from the cervical smears and buccal cell MN 
frequency suggesting that the two study populations were exposed equally to 
gentotoxic agents. Nonetheless, cervical cancer-related histopathological 
findings should be validated by other researchers.
________________________________________________________________

Boron supplementation inhibits the growth and local expression 
of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice.

Gallardo-Williams MT, Chapin RE, King PE, Moser GJ, Goldsworthy TL, 
Morrison JP, Maronpot RR.

Toxicol Pathol. 2004 Jan-Feb;32(1):73-8

Prostate-specific antigen (PSA) is a serine protease and one of the most 
abundant proteins secreted by the human prostate epithelium. PSA is used as a 
well-established marker of prostate cancer. The involvement of PSA in several 
early events leading to the development of malignant prostate tumors has made it 
a target for prevention and intervention. It is thought that PSA cleaves 
insulin-like growth factor binding protein-3 (IGFBP-3), providing increased 
local levels of IGF-1, leading to tumor growth. Separately, there are data that 
suggest an enzymatic regulatory role for dietary boron, which is a serine 
protease inhibitor. In this study we have addressed the use of boric acid as a 
PSA inhibitor in an animal study. We have previously reported that low 
concentrations (6 ug/mL) of boric acid can partially inhibit the proteolytic 
activity of purified PSA towards a synthetic fluorogenic substrate. Also, by 
Western blot we have followed the degradation of fibronectin by enzymatically 
active PSA and have found significant inhibition in the presence of boric acid. 
We proposed that dietary supplementation with boric acid would inhibit PSA and 
reduce the development and proliferation of prostate carcinomas in an animal 
model. We tested this hypothesis using nude mice implanted subcutaneously with 
LNCaP cells in Matrigel. Two groups (10 animals/group) were dosed with boric 
acid solutions (1.7, 9.0 mgB/kg/day) by gavage. Control group received only 
water. Tumor sizes were measured weekly for 8 weeks. Serum PSA and IGF-1 levels 
were determined at terminal sacrifice. The size of tumors was decreased in mice 
exposed to the low and high dose of boric acid by 38% and 25%, respectively. 
Serum PSA levels decreased by 88.6% and 86.4%, respectively, as compared to the 
control group. There were morphological differences between the tumors in 
control and boron-dosed animals, including a significantly lower incidence of 
mitotic figures in the boron-supplemented groups. Circulating IGF-1 levels were 
not different among groups, though expression of IGF-1 in the tumors was 
markedly reduced by boron treatment, which we have shown by 
immunohistochemistry. These data indicate that low-level dietary boron 
supplementation reduced tumor size and content of a tumor trophic factor, IGF-1. 
This promising model is being evaluated in further studies.
________________________________________________________________

Boron-based inhibitors of acyl protein thioesterases 1 and 2.

Zimmermann TJ, Bürger M, Tashiro E, Kondoh Y, Martinez NE, Görmer K, 
Rosin-Steiner S, Shimizu T, Ozaki S, Mikoshiba K, Watanabe N, Hall D, 
Vetter IR, Osada H, Hedberg C, Waldmann H.

Chembiochem. 2013 Jan 2;14(1):115-22 

Ras proteins are of importance in cell proliferation, and hence their mutated 
forms play causative roles in many kinds of cancer in different tissues. 
Inhibition of the Ras-depalmitoylating enzyme acyl protein thioesterases APT1 
and -2 is a new approach to modulating the Ras cycle. Here we present boronic 
and borinic acid derivatives as a new class of potent and nontoxic APT 
inhibitors. These compounds were detected by extensive library screening using 
chemical arrays and turned out to inhibit human APT1 and -2 in a competitive 
mode. Furthermore, one of the molecules was demonstrated to inhibit Erk1/2 
phosphorylation significantly.
________________________________________________________________

ROS-activated anticancer prodrugs: a new strategy for tumor-specific damage.

Peng X, Gandhi V.

Ther Deliv. 2012 Jul;3(7):823-33 

Targeting tumor cells is an important strategy to improve the selectivity of 
cancer therapies. With the advanced studies in cancer biology, we know that 
cancer cells are usually under increased oxidative stress. The high level of 
reactive oxygen species in cancer cells has been exploited for developing novel 
therapeutic strategies to preferentially kill cancer cells. Our group, amongst 
others, have used boronic acids/esters as triggers for developing ROS-activated 
anticancer prodrugs that target cancer cells. The selectivity was achieved by 
combining a specific reaction between boronates and H2O2, with the efficient 
masking of drug toxicity in the prodrug via boronates. Prodrugs activated via 
ferrocene-mediated oxidation have also been developed to improve the selectivity 
of anticancer drugs. We describe how the strategies of ROS-activation can be 
used for further development of new ROS-targeting prodrugs, eventually leading 
to novel approaches and/or combined technology for more efficient and selective 
treatment of cancers.
________________________________________________________________

Boron inhibits the proliferating cell nuclear antigen index, 
molybdenum containing proteins and ameliorates oxidative 
stress in hepatocellular carcinoma.

Zafar H, Ali S.

Arch Biochem Biophys. 2013 Jan 15;529(2):66-74 

Hepatocellular carcinoma (HCC) is a common malignancy and the main cause of 
mortality in patients with chronic liver diseases. This study reports the 
inhibitory effect of boron on HCC induced in rats by administering thioacetamide 
(TAA) (0.03%) in drinking water for 400days. Boron (4mg/kg body weight) was 
administered orally after induction of carcinoma. Treatment was continued for 
122days, and cell proliferation, histology and biochemistry of treated and 
control group of rats were studied. Proliferating cell nuclear antigen (PCNA), 
and [(3)H]-thymidine incorporation, which increased in rats exposed to 
carcinogen, significantly decreased after boron treatment. PCNA index decreased 
from 80 in HCC rats to 32 after boron treatment. In the control group, it was 
20. Boron caused a dose-dependent decrease in carcinogen-induced 
[(3)H]-thymidine uptake by the rat hepatocyte. It could partially reverse the 
activity of selected biochemical indicators of hepatic damage, oxidative stress, 
selenium and serum retinol, which are depleted in liver cancer, and improved 
overall health of animal. The study implicates the elevated levels of mammalian 
molybdenum Fe-S containing flavin hydroxylases, which increase the free radical 
production and oxidative stress, consequently causing increased hepatic cell 
proliferation in HCC, and reports boron to ameliorate these changes in liver 
cancer.
________________________________________________________________

The dual role of boron in vitro neurotoxication of glioblastoma 
cells via SEMA3F/NRP2 and ferroptosis signaling pathways.

Kar F, Hacioğlu C, Kaçar S 

Environ Toxicol. 2023 Jan;38(1):70-77 

Glioblastoma multiform (GBM) is a malignant tumor cancer that originates from 
the star-shaped glial support tissues, namely astrocytes, and it is associated 
with a poor prognosis in the brain. The GBM has no cure, and chemotherapy, 
radiation therapy, and immunotherapy are all ineffective. A certain dose of 
Boric acid (BA) has many biochemical effects, conspicuously over 
antioxidant/oxidant rates. This article sought to investigate the modifies of 
various doses of BA on the glioblastoma concerning cytotoxicity, ferroptosis, 
apoptosis, and semaphorin-neuropilin signaling pathway. The Cytotoxic activity 
and cell viability of BA (0.39-25 mM) in C6 cells were tested at 24, 48, and 
72 h using 3-(4,5-dimethylthiazol, 2-yl)-2,5-diphenyl tetrazolium bromide (MTT). 
The IC50 concentration of BA at 1.56 mM was found and cell lysate used for 
biochemical analysis. Glutathione peroxidase 4 (GPx4) and ACLS4 levels of 
ferroptosis, levels of total antioxidant (TAS) and oxidant (TAS) parameters, 
malondialdehyde (MDA), apoptotic proteins as caspase 3 (CASP3) and caspase 7 
(CASP7) were measured. The ferroptosis, semaphoring-neuropilin, apoptotic 
pathway markers and cell counts were analyzed with flow cytometry, Q-PCR, 
Western and Elisa technique in the C6 cell lysate. BA triggered ferroptosis in 
the C6 cells dose-dependently, affecting the semaphorin pathway, so reducing 
proliferation with apoptotic compared with untreated cell as control group 
(p < .05). This study revealed that BA, defined as trace element and natural 
compound, incubated ferroptosis, total oxidant molecules, and caspase protein in 
a dose-dependently by disrupting SEMA3F in tumor cells.
________________________________________________________________

FOXP3-miR-146-NF-κB Axis and Therapy for Precancerous Lesions in Prostate.

Liu R, Yi B, Wei S, Yang WH, Hart KM, Chauhan P, Zhang W, 
Mao X, Liu X, Liu CG, Wang L 

Cancer Res. 2015 Apr 15;75(8):1714-24 

The tumor-suppressive activity of FOXP3 has been observed in tumor initiation, 
but the underlying mechanism still remains largely unknown. Here, we identified 
a FOXP3-microRNA-146 (miR-146)-NF-κB axis in vitro and in vivo in prostate 
cancer cells. We observed that FOXP3 dramatically induced the expression of 
miR-146a/b, which contributed to transcriptional inhibition of IRAK1 and TRAF6, 
in prostate cancer cell lines. Tissue-specific deletion of Foxp3 in mouse 
prostate caused a significant reduction of miR-146a and upregulation of NF-κB 
activation. In addition, prostatic intraepithelial neoplasia lesions were 
observed in miR-146a-mutant mice as well as in Foxp3-mutant mice. Notably, the 
NF-κB inhibitor bortezomib inhibited cell proliferation and induced apoptosis in 
prostate epithelial cells, attenuating prostatic intraepithelial neoplasia 
formation in Foxp3-mutant mice. Our data suggest that the FOXP3-miR-146-NF-κB 
axis has a functional role during tumor initiation in prostate cancer. Targeting 
the miR-146-NF-κB axis may provide a new therapeutic approach for prostate 
cancers with FOXP3 defects.
________________________________________________________________

Assessment of the chemical changes induced in human melanoma cells 
by boric acid treatment using infrared imaging.

Acerbo AS, Miller LM.

Analyst. 2009 Aug;134(8):1669-74. 

Boron is found in everyday foods and drinking water in trace quantities. Boron 
exists as boric acid (BA) within plants and animals, where low levels have been 
linked to cancer incidence. However, this correlation is not well characterized. 
In this study, we examined the chemical and morphological effects of BA on human 
skin melanoma cells (SK-MEL28) using Fourier Transform InfraRed Imaging (FTIRI) 
with a Focal Plane Array (FPA) detector. Cells were grown under concentrations 
of BA ranging from 0 to 50 mM. Cell viability was determined after 1, 2, 3, 5, 7 
and 10 days using trypan blue staining. With FTIRI, images of approximately 
twenty cells per time point per condition were collected. Principal components 
analysis (PCA) was used to evaluate changes in cell composition, with particular 
focus on the lipid, protein, and nucleic acid spectral components. Results from 
trypan blue staining revealed decreased cell viability as BA concentration 
increased. FTIRI data indicated that the protein and lipid contents (as 
indicated by the lipid/protein ratio) did not undergo substantial changes due to 
BA treatment. In contrast, the nucleic acid/protein ratio significantly 
decreased with BA treatment. PCA results showed an increase in beta-sheet 
protein at higher concentrations of BA (12.5, 25, and 50 mM). Together, these 
results suggest that high concentrations of BA have an anti-proliferative effect 
and show signs consistent with apoptosis.
________________________________________________________________

Phenylboronate 160Tb complexes for molecular recognition 
of glycoproteins expressed on tumor cells.

Djanashvili K, Koning GA, van der Meer AJ, Wolterbeek HT, Peters JA.

Contrast Media Mol Imaging. 2007 Jan-Feb;2(1):35-41 

The over-expression of sialic acid on the surface of cancer cells compared with 
normal ones makes this nine-carbon sugar an attractive biomarker for molecular 
diagnosis and therapy. Here, we describe a study on the molecular recognition of 
sialic acid end groups on the surface of human glioma cells by 
(160)Tb-DTPA-EN(2), (160)Tb-DTPA-(ENPBA)(2) and (160)Tb-DTPA-(PBA)(2) complexes. 
The results show Tb-DTPA-(ENPBA)(2) to be the most efficient targeting agent, 
due to the electrostatic interaction between its two positively charged ammonium 
groups and the negatively charged cell surface, which provides an additional 
stabilization of the covalent binding through the PBA moieties and the sialic 
acid diol functions. Up to 5.5 nmol Tb/mg protein is taken up by the cells. ICP 
analysis after incubation experiments with non-radioactive Tb-DTPA-(ENPBA)(2) 
suggests that dissociation of Tb from this complex occurs after its binding to 
the cell surface. Most likely, most of the free Tb remains adsorbed on the 
surface of the cells, although internalization of a small amount cannot be 
excluded.
________________________________________________________________

Boron betaine analogs: antitumor activity and effects 
on Ehrlich ascites tumor cell metabolism.

Hall IH, Starnes CO, Spielvogel BF, Wisian-Neilson P, Das MK, Wojnowich L.

J Pharm Sci. 1979 Jun;68(6):685-8 

Several newly synthesized boron betaine analogs had antitumor activity in 
Ehrlich ascites, Walker 256 ascites carcinosarcoma, and Lewis lung screens and 
marginal activity in the B-16 melanotic melanoma screen. In vivo testing 
demonstrated that trimethylamine-cyanoborane inhibied Ehrlich ascites cell DNA 
and protein syntheses as well as gene modulation by chromatin protein 
phosphorylation and methylation. Trimethylamine-cyanoborane increased cyclic-AMP 
levels. In vitro testing showed that nuclear DNA polymerase, thymidylate 
synthetase, S-adenosylmethyltransferase, nonhistone chromatin methylation, 
deoxyribonuclease, ribonuclease, and cathepsin were inhibited by the boron 
analogs. These compounds did not demonstrate high antitumor activity at the 
doses employed, but blockage of methyl transfer from S-adenosylmethionine was 
established as a feasible method for controlling cell proliferation.
________________________________________________________________

Integrative treatment of gliomas.

Sano K.

Clin Neurosurg. 1983;30:93-124. 
________________________________________________________________

Boron uptake in mouse brain neoplasm.

KRUGER PG.

Radiat Res. 1955 Sep;3(1):1-17.
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Penetration of brain and brain tumor. 
VII. Tumor-binding sulfhydryl boron compounds.

Soloway AH, Hatanaka H, Davis MA.

J Med Chem. 1967 Jul;10(4):714-7 
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Boron substituted deoxyribonucleosides as cytotoxic agents.

Hall IH, Elkins A, Sood A, Tomasz J, SpielVogel BF.

Anticancer Res. 1996 Nov-Dec;16(6B):3709-14.

Base substituted boronated nucleosides and phosphate modified nucleotides were 
examined for their cytotoxic activity in both murine and human tissue cultured 
cancer cells. These derivatives demonstrated better activity against the growth 
of single cell suspensions than solid cell tumor cell growth. A detailed mode of 
action study showed that 2'deoxyriboadenosine-N7-cyanoborane 6 suppressed Tmolt3 
DNA synthesis preferentially with the major target of the agent being the purine 
de novo pathway. The activities of one of the regulatory enzymes of the pathway 
were reduced by the agents, i.e. PRPP-amido transferase. Other sites in the cell 
which were moderately affected by the agent were nucleoside kinase activities. 
DNA polymerase alpha and dihydrofolate reductase activities. The DNA molecule 
itself did not appear to be a target of the compound.
________________________________________________________________

The localization of boronic acids in mouse neoplasm.

FRIGERIO NA, BINK N.

ANL Rep. 1960 Aug;ANL-6200:60-2.
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Evaluation of selective boron absorption in liver tumors.

Chiaraviglio D, De Grazia F, Zonta A, Altieri S, Braghieri A, Fossati F, 
Pedroni P, Pinelli T, Perotti A, Specchariello M, et al.

Strahlenther Onkol. 1989 Feb-Mar;165(2-3):170-2.
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Trans-resveratrol boronic acid exhibits enhanced anti-proliferative 
activity on estrogen-dependent MCF-7 breast cancer cells.

Yenugonda VM, Kong Y, Deb TB, Yang Y, Riggins RB, Brown ML.

Cancer Biol Ther. 2012 Aug;13(10):925-34 

Resveratrol (RSV), a natural compound present in the skin and seeds of red 
grapes, is considered a phytoestrogen and has structural similarity to the 
synthetic estrogen diethylstilbestrol. RSV inhibits tumor cell growth in 
estrogen receptor-positive (ER+) and negative (ER-) breast cancer cell lines 
resulting in cell specific regulation of the G1/S and G2/M stages of the cell 
cycle. However apoptotic cell death was only observed in ER+ MCF-7 cells. In 
this study, we designed and synthesized boronic acid derivative of RSV and 
evaluated their biological effects on ER+ MCF-7 breast cancer cells. The trans-4 
analog inhibited the growth of MCF-7 cells and is not a substrate for 
p-glycoprotein. The trans-4 analog induces G1 cell cycle arrest, which coincides 
with marked inhibition of G1 cell cycle proteins and a greater pro-apoptotic 
effect. Finally, the trans-4 analog had no effect on the estrogen-stimulated 
growth of MCF-7 cells. Our results demonstrate that the trans-4 analog inhibits 
MCF-7 breast cancer cells by a different mechanism of action than that of RSV 
(S-phase arrest), and provides a new class of novel boronic acids of RSV that 
inhibit breast cancer cell growth.
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Green tea and lung cancer: a systematic review. 
[green tea may bind to and reduce the effectiveness of bortezomib]

Fritz H, Seely D, Kennedy DA, Fernandes R, Cooley K, Fergusson D.

Integr Cancer Ther. 2013 Jan;12(1):7-24 

BACKGROUND: Green tea is a beverage widely used by lung cancer patients and the 
public for its purported anticancer properties. The authors conducted a 
systematic review of green tea for the treatment and prevention of lung cancer.
METHODOLOGY: Six electronic databases were searched from inception until 
November 2011 for human interventional and preclinical evidence pertaining to 
the safety and efficacy of green tea for lung cancer.
RESULTS: A total of 84 articles met inclusion criteria: two Phase I trials, 
three reports of one surrogate study, and 79 preclinical studies. There is a 
lack of controlled trials investigating green tea for lung cancer. Two Phase I 
studies showed no objective tumor responses at the maximum tolerated dose, 
ranging from 3 to 4.2 g/m(2) green tea extract (GTE) per day. Four cups of green 
tea daily decreased DNA damage (8OH-dG) in smokers. Human studies indicate that 
800mg of green tea catechins daily does not alter activity of the CYP2D6, 
CYP1A2, CYP3A4 and CYP2C9 enzymes, however in vitro evidence suggests that green 
tea may bind to and reduce the effectiveness of bortezomib. Green tea applied 
topically may improve the healing time of radiation burns.
CONCLUSIONS: Although some evidence suggests that chemopreventative benefits can 
be accrued from green tea, there is currently insufficient evidence to support 
green tea as a treatment or preventative agent for lung cancer. Green tea should 
not be used by patients on bortezomib therapy. Further research is warranted to 
explore this natural agent for lung cancer treatment and prevention.
________________________________________________________________

Curcumin in combination with bortezomib synergistically 
induced apoptosis in human multiple myeloma U266 cells.

Park J, Ayyappan V, Bae EK, Lee C, Kim BS, Kim BK, Lee YY, Ahn KS, Yoon SS.

Mol Oncol. 2008 Dec;2(4):317-26 

Growth of multiple myeloma cells is controlled by various factors derived from 
host bone marrow microenvironments. Interaction between multiple myeloma cells 
and bone marrow stromal cells (BMSCs) plays an important role in the expression 
of adhesive molecules and secretion of growth factors involved in multiple 
myeloma (MM) cell growth, survival, and resistance to anticancer drugs. 
Recently, the possibility of developing novel anti-cancer therapeutic strategies 
targeting both MM cells and MM cell-BMSC interactions has been discussed. Here 
we present data showing that curcumin, a major constituent of turmeric compounds 
extracted from the rhizomes of the plant Curcuma longa, effectively reduced the 
growth of MM cells and BMSCs. Upon treatment with curcumin, IL-6/sIL-6R-induced 
STAT3 and Erk phosphorylation was dramatically reduced in the co-cultured cells. 
In addition, curcumin inhibited the production of pro-inflammatory cytokines and 
VEGF, factors that are associated with the progression of multiple myeloma, from 
both MM cells and BMSCs. In a combination treatment with curcumin and 
bortezomib, IL-6/sIL-6R-induced STAT3 and Erk phosphorylation was effectively 
inhibited. Moreover, this combination treatment synergistically inhibited the 
growth of MM cells co-cultured with BMSCs as compared to controls. Taken 
together, these results indicate that curcumin potentiates the therapeutic 
efficacy of bortezomib in MM suggesting this combination therapy to be of value 
in the clinical management of MM.
________________________________________________________________

Gene expression alterations of human liver cancer cells 
following borax exposure.

Wu L, Wei Y, Zhou WB, Zhang YS, Chen QH, Liu MX, Zhu ZP, 
Zhou J, Yang LH, Wang HM, Wei GM, Wang S, Tang ZG

Oncol Rep. 2019 Jul;42(1):115-130 

Borax is a boron compound that is becoming widely recognized for its biological 
effects, including lipid peroxidation, cytotoxicity, genotoxicity, antioxidant 
activity and potential therapeutic benefits. However, it remains unknown whether 
exposure of human liver cancer (HepG2) cells to borax affects the gene 
expression of these cells. HepG2 cells were treated with 4 mM borax for either 2 
or 24 h. Gene expression analysis was performed using Affymetrix GeneChip Human 
Gene 2.0 ST Arrays, which was followed by gene ontology analysis and pathway 
analysis. The clustering result was validated using reverse 
transcription‑quantitative polymerase chain reaction. A cell proliferation assay 
was performed using Celigo Image Cytometer Instrumentation. Following this, 2‑ 
or 24‑h exposure to borax significantly altered the expression level of a number 
of genes in HepG2 cells, specifically 530 genes (384 upregulated and 146 
downregulated) or 1,763 genes (1,044 upregulated and 719 downregulated) compared 
with the control group, respectively (≥2‑fold; P<0.05). Twenty downregulated 
genes were abundantly expressed in HepG2 cells under normal conditions. 
Furthermore, the growth of HepG2 cells was inhibited through the downregulation 
of PRUNE1, NBPF1, PPcaspase‑1, UPF2 and MBTPS1 (≥1.5‑fold, P<0.05). The 
dysregulated genes potentially serve important roles in various biological 
processes, including the inflammation response, stress response, cellular 
growth, proliferation, apoptosis and tumorigenesis/oncolysis.