Molybdenum and cancer

Molybdenum trioxide has been reported to be weakly carcinogenic in mice in a short-term (30 week) lung adenoma assay at high doses (4 750 mg/kg total) but not at lower doses [Stoner et al., 1976]. The reported carcinogenicity of molybdenum orange pigment (a mixture of lead chromate and lead molybdate) injected subcutaneously injection to rats is likely due to the lead and chromium rather than the molybdenum since lead chromate is a carcinogen [Maltoni (a), 1976; Maltoni (b), 1976].

Stoner, G. D., Shimkin, M. B., Troxell, M. C., Thompson, T. L. and Terry, L. S., Cancer Res., 1976, 36, 1744.
Maltoni, C., Ann. N.Y. Acad. Sci., 1976, 271, 431.
Maltoni, C., Ann. N.Y. Acad. Sci., 1976, 271, 444.

In the rat azoxymethane induced aberrant crypt foci have been suggested to be biological precursors to colon cancers. The effects of 41 potential chemopreventive agents in the F344 rat using the inhibition of carcinogen-induced aberrant crypt foci in the colon as the measure of efficacy were assessed [Wargovich et al., 1996]. Aberrant crypt foci were induced by the carcinogen azoxymethane. Twenty-three agents did not inhibit aberrant crypt foci; among these were several agents, including sodium molybdate, that promoted the development of aberrant crypt foci at one or both doses tested. The average yield of aberrant crypts for the azoxymethane-only group was 88 8 aberrant crypt foci/colon. When the diet included sodium molybdate (0.05 g/kg diet) the yield of aberrant crypts was 103 8 significantly greater than control group.

Wargovich, M.J., Chen, C.D., Jimenez, A., Steele, V.E., Velasco, M., Stephens, L.C., Price, R., Gray, K., Kelloff, G.J., Aberrant Crypts As A Biomarker For Colon-Cancer - Evaluation Of Potential Chemopreventive Agents In The Rat, Cancer Epidemiology Biomarkers & Prevention, 1996, 5, 355-360.

The potential toxicities of organic and some inorganic compounds have been predicted by a computer program which correlates toxicity with molecular properties [Lewis et al.,1996]. The program is called COMPACT (Computer Optimised Molecular Parametric Analysis for Chemical Toxicity: CYP1A and CYP2E1). Evaluations were also made by Hazard expert, and for metal ion redox potentials; and these, together with COMPACT, were compared with results from the Ames test for mutagenicity in Salmonella, the micronucleus test and 90-day subchronic rodent pathology. According to the abstract, molybdenum trioxide is a metal compound with a redox potential of the metal/metal ion indicative of possible carcinogenicity and the prediction for carcinogenicity was positive for molybdenum trioxide. However, it is clear from the body of the paper that this statement is most misleading. The programs gave no prediction for molybdenum trioxide. The reference to the redox potential is to the Mo(III)/Mo(IV) couple allegedly 0.32 V oxidising and so having carcinogenic potential. This potential is hardly relevant since MoO3 is Mo(VI) and the relevant potential is Mo(VI)/Mo(V), 0.4 V.

Lewis, D.F.V., Ioannides, C., Parke, D.V., Compact And Molecular-Structure In Toxicity Assessment - A Prospective Evaluation Of 30 Chemicals Currently Being Tested For Rodent Carcinogenicity, Environmental Health Perspectives, 1996, 104, 1011-1016.

Cobalt sulfate hydrate, gallium arsenide, molybdenum trioxide, vanadium pentoxide, and nickel sulfate heptahydrate were tested in the Syrian hamster embryo (SHE) assay in order to increase the SHE assay database for heavy metals [Kerckaert et al., 1996]. All five compounds produced significant morphological transformation {MT) at one or more doses in a dose-responsive manner. Cobalt sulfate hydrate, gallium arsenide, molybdenum trioxide, and nickel (II) sulfate heptahydrate were all positive with a 24-h exposure, suggesting direct DNA perturbation. Vanadium pentoxide was negative with a 24-h exposure, but positive with a 7-day exposure. This pattern of response (24-h SHE negative/7-day SHE positive) has been seen with other chemicals which have tumour promotion-like characteristics. MoO3 in a 24 h exposure to SHE cells with culture medium as the solvent gave a significant increase in SHE cell MT in four doses =/> 75 microg/ml and 67% cytotoxicity at the top dose of 200 microg/ml. The Mo value compares with Ni 5 microg/ml and Co 1 microg/l.

Kerckaert, G.A., Leboeuf, R.A., Isfort, R.J., Use Of The Syrian-Hamster Embryo Cell-Transformation Assay For Determining The Carcinogenic Potential Of Heavy-Metal Compounds, Fundamental And Applied Toxicology, 1996, 34, 67-72.

Chronic exposure of animals to molybdenum oxide fumes (53 mg/m3 for 1 h daily) produced pulmonary irritation and fatty changes in the liver and the kidney, but no deaths occurred [Smyth, 1956.]

Smyth, H.E., Hygienic standard for daily inhalation. Ind Hyg Q, 1956,17,129-185.

The results of a study of the respiratory effects of inhalation of air-borne MoO3dust during two years are summarised in Table 7.2 [Chan et al., 1998]. Although the blood concentration of Mo increased as a consequence of the Mo exposure toxic symptoms were not observed. Prolonged inhalation of MoO3 dusts was harmful to the respiratory system of the mice and rats. The effect of MoO3 is similar to that of talc, nickel oxide and nickel subsulfide and irritants generally in inhalation studies. There is, however, a species dependence and some of the effects are marginal. Whether inhalation of MoO3 induces carcinomas is of particular interest. The number of animals experiencing adenoma or carcinoma at the highest MoO3 exposures were: male mice 9/50 and 10/50, female mice 9/49 and 6/49; male rats 3/50 and 1/50, female rats 2/50 and 0/50. The exposure (100 mg m-3) is ten times the US workplace threshold limit value. The authors comment that MoO3 is not mutagenic.

Chan, P.C., Herbert, R.A., Roycroft, J.H., Haseman, J.K., Grumbein, S.L.,Miller, R.A., Chou, B.J., Lung tumor induction by inhalation exposure to molybdenum trioxide in rats and mice, Toxicological Sciences, 1998, 45, 58-65.

Anti-cancer properties of molybdenum

Sodium molybdate administered in drinking water has a protective action against the induction of cancer in rats by organic N-nitroso compounds [Luo , X.-M.et al.,1983]. Inhibitory effects of molybdenum on oesophageal and forestomach carcinogenesis in rats have been reported [Komada, H. et al., 1990] and the effect of dietary molybdenum on oesophageal carcinogenesis in rats induced by N-methyl-N-benzylnitrosamine [Wei, H.-J et al., 1985]. Effects of molybdenum and tungsten on mammary carcinogenesis are found in SD rats.[ Seaborn and Yang, 1993]. Molybdenum supplementation affects N-nitroso- N-methylurea-induced mammary carcinogenesis and molybdenum excretion in rats [Kopf-Meyer, 1979].

Luo, X. M., Wei, H. J. and Yang, S. P., J.Nat.Cancer Inst.,1983, 71, 75.
Komada, H., Nakagawa, M., Yamamura, M., Hioki, K. and Yamamoto, Cancer Res., 1990, 50, 2418.
Wei, H. J., Luo, X. M. and Yang, S. P., J.Nat.Cancer Inst., 1985, 74, 469.
Seaborn, C. D. and Yang, S. P., Biol. Trace Elem. Res., 1993, 39, 245.
Kopf-Meyer, P., Naturforsch., 1979, 34, 1174.

Molybdenum dichloride has anti-tumour agent properties [Koizumi et al., 1995]. Suppressive effects of molybdenum on hepatotoxicity of N-nitrosodiethylamine in rats have been reported.

Koizumi, T., Tajima, K., Emi, N., Hara, A., Suzuki, K.T., Suppressive Effect Of Molybdenum On Hepatotoxicity Of N-Nitrosodimethylamine In Rats, Biological & Pharmaceutical Bulletin, 1995, 18, 460-462.

The beneficial effect of the molybdenum is due to the denitrosation of the nitroso compound. Molybdenum is also a biological antagonist of cancer-producing copper [Nederbragt, 1982].

Nederbragt, H., Br. J. Nutr., 1982, 48, 353.

Molybdenum prevents the carcinogenesis of N-nitroso compounds [Koizumi et al., 1995]. Male Wistar rats weighing 170-190 g were pretreated with sodium molybdate, Na2MoO4(1.24 mmol/kg body weight, i.p., once a day) for 3 d and on day 4, they were exposed to N-nitrosodimethylamine (50 mg/kg body weight, once, i.p.). Na2MoO4-pretreatment prevented both nitrosodimethylamine-induced DNA damage and disruption of the metabolism of K and Ca but rather enhanced lipid peroxidation.Mo prevented N nitrosodimethylamine-induced DNA damage by preventing disruption of intracellular Ca metabolism while stimulating the metabolism of the nitroso compound via a nontoxic pathway.

Koizumi, T., Tajima, K., Emi, N., Hara, A. and Suzuki, K.T., Biol. Pharm. Bull., 1995, 18, 460.

 Protective effect of sodium molybdate against hepatotoxicity in rat

The hepatoprotective potential of sodium molybdate was investigated against liver damage in rats induced by carbon tetrachloride.

Carbon tetrachloride increased the serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels in rats and reduced levels of the antioxidant enzymes superoxide dismutase and catalase in the liver.

Treatment with sodium molybdate attenuated these changes to nearly undetectable levels.

The histopathological changes induced by carbon tetrachloride were also significantly attenuated by sodium molybdate treatment.

Sodium molybdate can protect the liver against carbon tetrachloride-induced oxidative damage in rats. This hepatoprotective effect might be attributable to modulation of detoxification enzymes and/or its antioxidant and free radical scavenger effects.

Eidi, A., Eidi, M., Al Ebrahim, M., Rohani, A. H., and Mortazavi, P., Protective effects of sodium molybdate on carbon tetrachloride-induced hepatotoxicity in rats, Journal of Trace Elements in Medicine and Biology, 2011, 25, 67-71.

Bioaccumulation of Zn, Mn and Mo in healthy and cancerous mammary glands in dogs

The investigation was to find the dependence among Zn, Mn and Mo in healthy (no pathological lesions) mammary glands in bitches and in mammary gland neoplastic tumors of bitches to confirm a hypothesis which that neoplastic tissues accumulate higher amounts of some elements as compared to tissues at the state of homeostasis.

The research material comprised mammary gland tumors obtained from bitches collected during routine surgical procedures and mammary glands obtained during post mortem examination from bitches which comprised the control group.

Due to great morphological variability of the bitch mammary gland tumors, the investigations were performed on certain groups of neoplasms of epithelial origin (carcinomas and adenocarcinomas) which were separated on the basis of histopathological examinations.

In the control group a lower content of particular elements was observed as compared to tissues undergoing the neoplastic process. There were also highly significant differences observed (p <= 0.01) between the investigated groups. For neoplastic tissues more zinc and molybdenum were observed in the group of carcinomas and a lower content in the group of adenocarcinomas. For manganese the dependence was reversed.

Skibniewska, Ewa M.; Kosla, Tadeusz; Skibniewski, MihalBioaccumulation of Zn, Mn and Mo in healthy and cancerous mammary glands in dogsTrace Elements and Electrolytes,2012, 29, 1, 42-47.

Molybdate and cancer

Antiproliferative activity of vanadate, tungstate, and molybdate in the PC-3 human prostate cancer cell line.

The differential antiproliferative effects of vanadate, tungstate, and molybdate on human prostate cancer cell line PC-3 were compared.

The three oxoanions can cause G2-M cell cycle arrest as evidenced by the increase in the level of phosphorylated Cdc2 [cell division control protein 2, a key player in cell cycle regulation] at its inactive Tyr-15 site.

Even if the difference in cellular uptake among the three oxoanions is excluded from the possible factors affecting their antiproliferative activity, vanadate exerted a much more potent effect in PC-3 cells than the other two oxoanions. Reactive oxygen species (ROS)-mediated degradation of Cdc25C rather than Cdc25A or Cdc25B is responsible for vanadate-induced G2-M cell cycle arrest.

A mechanism is proposed to account for the different effects of the three oxoanions in biological systems beyond just considering that they are structural analogs of phosphate. It is suggest that ROS formation is unlikely to be involved in the biological function of tungstate and molybdate, whereas the redox properties of vanadium may be important for its pharmacological effects.

Liu, Tong-Tong; Liu, Yan-Jun; Wang, Qin; Yang, Xiao-Gai; Wang, Kui Reactive-oxygen-species-mediated Cdc25C degradation results in differential antiproliferative activities of vanadate, tungstate, and molybdate in the PC-3 human prostate cancer cell line.Journal of Biological Inorganic Chemistry 2012, 172, 311-20.

[Antiproliferative: inhibiting cell growth, e.g antiproliferative effects on tumor cells;a substance used to prevent or retard the spread of cells, especially malignant cells, into surroundingtissues.]

[Entry into each phase of the cell-cycle is regulated by receptor collectives, cell-cycle checkpoints. One theme emerging in drug discovery is to develop agents that target the cell-cycle checkpoints that are responsible for the control of cell-cycle phase progression. It is clear that the cell-cycle checkpoints can regulate the quality and rate of cell division; These checkpoints allow progression through the cell-cycle or arrest in response to DNA damage to allow time for DNA repair.The G2 checkpoint allows the cell to repair DNA damage before entering mitosis DiPaola,R.S., Clin. Cancer Res., 2002, 8: 3512–3519.]

Molybdenum(VI) glutathione complex binding to DNA

The complex [Mo(VI)(GS)(Cl)(H2O)]Cl2 (= MoG) was synthesized in aqueous solution and characterised analytically and spectroscopically.It is diamagnetic, hence molybdenum(VI), and a 1:2 electrolyte.

The binding of MoG with calf thymus DNA was studied by spectroscopic titration,monitoring the DNA 260 nm band and the S -> Mo LMCT band of the complex at 225 nm. The interaction ratio was 1:0.70 (DNA:MoG) and the binding constant of DNA-MoG was 4.8 x 105 M-1, a value indicative of intercalative binding.

Glutathione

Glutathione

Selim, M., Saha, A., Mukherjea, K. Synthesis, characterization, and DNA binding of the biologically relevant novel cationic molybdenum(VI)-glutathione complex [Mo(GS)(Cl)(H(2)O)]Cl(2), Monatshefte fur Chemie, 2012, 143,2, 227-233.

Oxometallate interactionswith Sarcoplasmic reticulum calcium ATPase

Interest in oxometalate and polyoxometalate applications to medicine and pharmacology is due to their anti-cancer, anti-diabetic properties and treatment of neurodegenerative diseases.

Sarcoplasmic reticulum (SR) vesicles, containing a large amount of Ca2+-ATPase, an enzyme that accumulates calcium by active transport using ATP, are a useful model to study the effects of oxometalates on calcium homeostasis.

Molybdate is an inhibitor of the Ca2+-ATPase enzyme but much less so than are polyoxovanadate and polyoxoniobate which are strong inhibitors. IC50 values [half maximal inhibitory concentrations/microM, measuring the effectiveness of the compounds in inhibiting SR Ca Ca2+ATPase] were:decavanadate, 15; decaniobate, 50; vanadate, 35; tungstate, 400; molybdate, 45000.

The inhibition affects,inter alia, calcium homeostasis, cell signalling and cell bioenergetics. An oxometalate may act as a phosphate analogue, as a transition-state analogue in enzyme-catalysed phosphoryl group transfer processes, or as a potentially nucleotide-dependent enzyme modulator or inhibitor.

The inhibition of specific enzymes by decameric species of V and Nb may contribute to their anti-cancer, anti-viral and anti-diabetic activities.

Overall, these results indicate a need to understand the impact of groups V and VI metals on health and in particular, the effect of these metals on different types of biological tissue, such as membrane proteins as these are one of the first potential cellular targets upon metal exposure. The potential impact on the ion pumps will affect, for instance, the modulation of calcium homeostasis, and thus also the regulation and bioenergetics of muscle contraction/relaxation in muscle cells, as well as others processes in non-muscle cells, such as cytoskeleton dynamics, apoptosis/necrosis, oxidative-stress alterations and mitochondrial activity.

Fraqueza, G., Ohlin, C. A., Casey, W.H., Aureliano, M. Sarcoplasmic reticulum calcium ATPase interactions with decaniobate, decavanadate, vanadate, Journal of Inorganic Biochemistry, 2012, 107, 82-89.