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
The differential antiproliferative effects of vanadate, tungstate, and molybdate on human prostate cancer cell line PC-3 were compared and the underlying mechanisms were investigated.
The results demonstrate that all of the three oxoanions can cause G2/M cell cycle arrest, which is evidenced by the increase in the level of phosphorylated Cdc2 at its inactive Tyr-15 site. Moreover, 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.
Our results also reveal that reactive oxygen species (ROS)-mediated degradation of Cdc25C rather than Cdc25A or Cdc25B is responsible for vanadate-induced G2/M cell cycle arrest.
We propose a possible mechanism to clarify the differential effect of the three oxoanions in biological systems beyond just considering that they are structural analogs of phosphate. We 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 factors for it to exert pharmacological effects. Further, given the evidence from epidemiology studies of the association between diabetes and prostate cancer, the possibility of vanadate as a good candidate as both an antidiabetic and an anticancer agent or a chemopreventive agent is indicated
Liu, T. T., Liu, Y. J., Wang, Q., Yang, X. G., and Wang, K., 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, 17, 311-320.
[Cdc25C: a gene which plays a key role in the regulation of cell division. The encoded protein is a tyrosine phosphatase. It directs dephosphorylation of cyclin B-bound CDC2 (CDK1) and triggers entry into mitosis [cell (nucleus) division].
Antiproliferative: a substance used to prevent or retard the spreadof cells, especially malignant cells, into surrounding tissues.]
Two epidemiological surveys conducted in 1971 in Colorado, USA, revealed differences in the molybdenum intake but no evidence that these differences were related to cancer incidence [Breise, 1976]. The comparatively high tolerance of non-ruminants for molybdenum and the interrelationship between copper, sulfate and molybdenum has been well demonstrated in ruminants. Studies on carcinogenic effects provided suggestive evidence that neither very low or very high intakes of molybdenum presented mutagenic, carcinogenic, or teratogenic hazards.
Breise. F. W., , in: Molybdenum in the Environment ,Chappell, W. R., and Petersen, K. K. (eds.), Vol. 1, Chap. 19. Marcel Dekker, New York.
The relation between lung cancer and exposure to industrial carcinogens in the Antwerp region of Belgium was investigated by questionnaires to male lung cancer patients and controls [Droste et al., 1999.]..Exposure was assessed by self report and by job-task exposure matrix. There was an excess risk of lung cancer among workers in manufacturing metal goods (e.g., welders), transport equipment (other than automobiles) (e.g., shipyard workers) and transport support services (e.g., dockers). Assessment of exposure to specific carcinogens resulted in associations of chromium, mineral oils and molybdenum with lung cancer. The authors comment that theirs is the first study reporting a significant association between occupational exposure to molybdenum and lung cancer. There are methodological problems in this type of study, which are fully discussed in the paper, in particular job descriptions and self assessment. We have also the familiar problem of attempting to equate a (not very strong) statistical correlation with a causal relationship. More work is needed, for example, to demonstrate (or not) that the lung cancer patients allegedly exposed to molybdenum do in fact have higher molybdenum lung levels than normal and display other symptoms of exposure to molybdenum.
Droste, J.H.J., Weyler, J.J., Van Meerbeeck, J.P., Vermeire, P.A., Van Sprundel, M.P., Occupational risk factors of lung cancer: a hospital based case-control-study, Occup. Environ. Med., 1999, 56, 322 - 327.
Potential chemical mutagens may be screened by the rec-assay method [Nishioka, 1975]. Differential growth sensitivities to drugs in wild and recombination-deficient strains of Bacillus subtilis are measured. When a compound is more inhibitory for Rec- than for Rec+ cells (described as a positive rec-assay or rec-effect) mutagenicity based on its DNA-damaging capacity is suspected. Cells deficient in the repair capacity of DNA lesions are usually killed much more by any DNA-damaging agent than wild cells. The difference between the inhibition zones for Rec+ and Rec- cells may be due to the magnitude of the cellular repair. The compounds potassim dichromate, K2CrO7, ammonium heptamolybdate, (NH4)6Mo7O24.4H2O, and sodium arsenite (NaAsO2) were rec-assay positive and so reported as possible mutagens. Each culture (2.5*107colony-forming cells) was treated with metal solution (0.05M, 0.05 ml) and growth inhibition determined in an agar gelled nutrient broth. Mutation induction experiments used 3 strains of E. Coli possessing different DNA repair capacities. The abilities of the compounds to induce reversions in E. Coli Trp- strains possessing different DNA repair pathways were determined. The strain (CM571) carrying the recA- was hardly mutable by any of the sodium arsenate, potassium dichromate and ammonium heptamolybdate. It is difficult to conclude from this paper that ammonium heptamolybdate is mutagenic. There are a number of inconsistencies. The suggestion that the apparent mutagenicity of dichromate and heptamolybdate is due to their common 6+ oxidation state and their oxidising ability is not tenable. Cr(VI) is strongly oxidising and is reduced to Cr(III) by sulfite; Mo(VI) is not strongly oxidising.The paper reports a decrease of Bacillus subtilis growth inhibition of dichromate after reduction with sodium sulfite. The observation that chromium(III) chloride is not inhibitory is consistent with this result (Cr(III) is formed by reduction of Cr(VI)). Similarly MoCl5 is not inhibitory. However, potassium permanganate, a stronger oxidising agent that dichromate, is not inhibitory whereas Mn(II) compounds are. Sodium arsenite (As(III) is more inhibitory than sodium arsenate (As(V)).
The effect of sulfite on dichromate inhibition is difficult to understand. Stoichiometric reduction requires 3SO32-/Cr2O72-. In this experiment where this ratio is only 0.3 (Table II) the rec-effect is the same as for a ratio of 3. We would expect the effect at the 0.3 ratio to be little different from the effect with no sulfite. It should also be noted that reduction of dichromate by sulfite requires acidic conditions, not apparently used according to the description in the paper (aqueous solutions of dichromate and sulfite were mixed) and apparently in some cases precipitates were produced.
Speciation in the nutrient broth is a problem. If the pH (not stated) is near neutral part, at least, of the supplied heptamolybdate would be in equilibrium with molybdate. In the presence of phosphate we might expect some phosphomolybdate. So the nature of the species interacting with the bacteria is uncertain. This is even more so for MoCl5 which would hydrolyse (vigorously) and its solution would oxidise in air (probably giving Mo blue under the conditions of the experiment).
There are too many uncertainties and inconsistencies in this paper for the results to be accepted as definitive proof that heptamolybdate is mutagenic.
Nishioka, H., Mutagenic activities of metal compounds in bacteria, Mutation research, 1975, 31, 185-189.
The cytotoxicity of commercially pure Nb and Mo metals and Nb-Mo alloys was tested in a 72 h direct contact test [Pypen et al., 1998]. Compared to a negative control Nb was non-toxic, but Mo was moderately toxic. None of the powder metallurgically produced materials were toxic. Neither differences in molybdenum concentration, nor in porosity of the samples, due to different production routes, had any influence on the toxicity of the materials. Mo powder is moderately toxic, however, as an alloying element it is non- toxic.
Pypen, C.M.J.M., Dessein, K., Helsen, J.A., Gomes, M., Leenders, H., DeBruijn, J.D., Comparison of the cytotoxicity of molybdenum as powder and as alloying element in a niobium-molybdenum alloy, Journal Of Materials Science-Materials In Medicine, 1998, 9, 761-765.
The cytotoxicity of molybdenum has been investigated in relation to the release of Mo (and other metals) from alloy dental, knee and hip inserts [Okazaki et al., 1998].. Mo metal particles were stired with simulated biological fluids and then separated by centrifuging. The growth rates of cells (V79 cells taken from the lungs of Chinese hamsters, murine fibroblast L929 and murine osteoblast-like MC3T3-E1 cells). Growth inhibition due to Mo was much less than inhibition due to other metals (Fe, Ni, Co) at comparable concentrations. For Mo the relative growth ratio of MC3T3-E1 cells started to decrease at Mo > 10 ppm compared with 1 - 2 ppm for the other metals. Mo is not cytotoxic.
Possible Effects of Metallosis on Spermatozoal Apoptotic Genes Expression in Individuals with Intramedullary Nailing Prosthesis
Seminal quality could be affected by metallosis caused by intramedullary nailing (IMN).
Our objectives were to estimate metal ion levels in the seminal plasma of subjects with IMN, to determine their effects on semen parameters and on spermatozoal apoptotic gene expression, and to determine whether these expressed genes could be used as candidate biomarkers of seminal deterioration in individuals with IMN or not.
Semen samples were collected from 60 subjects with IMN and 30 age-matched healthy controls. Seminal plasma contents of cobalt (Co), chromium (Cr), and molybdenum (Mo) were assayed. Spermatozoal Bcl-2 and Bax gene expressions were determined.
Studied semen parameters were significantly lower in subjects with IMN for a parts per thousand ≥5 years in relation to controls while the concentrations of Co, Cr, and Mo in the seminal plasma samples were significantly higher.
There were significantly lower spermatozoal Bcl-2 expression, higher Bax expression, and lower Bcl-2/Bax ratio in subjects with IMN for a parts per thousand ≥5 years than in controls.
In subjects with IMN for a parts per thousand ≥5 years, receiver operating characteristic (ROC) curve analysis of studied gene expressions and Bcl-2/Bax ratio were done showing priority of the ratio with 86.7 % sensitivity, 100 % specificity, 100 % positive predictive value, and 93.8 % negative predictive value at cutoff values a parts per thousand ≤0.777.
Co, Cr, and Mo metals are found at high concentrations in the seminal plasma of individuals with IMN leading to increased spermatozoal apoptotic activity. Spermatozoal Bcl-2/Bax ratio could be used as a candidate biomarker of reproductive disorders in individuals with intramedullary nailing
Elsamanoudy, A. Z., Shaalan, D., Gaballah, M. A., El Atta, H. M. A., and Helaly, A. M. N., Possible Effects of Metallosis on Spermatozoal Apoptotic Genes Expression in Individuals with Intramedullary Nailing Prosthesis, Biological Trace Element Research, 2014, 158, 334-341.
[Metallosis, or metal poisoning, is caused by toxic metal levels in the blood and is a complication of some metal-on-metal hip implants.
Intramedullary nail (IM nail) or inter-locking nail is a metal rod forced into the medullary cavity of a bone used to treat fractures of long bones of the body.]