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Protection of zinc against etoposide-induced hematopoietic toxicity Purtzki, Markus J.

Abstract

Metallothionein (MT) is a low-molecular weight protein with many physiological functions, including contributing to zinc homeostasis and serving as an antioxidant. MT can reduce the efficacy of chemotherapy drugs by inducing drug resistance in cancerous cells. On the other hand, it can also offer protection to normal cells against side effects of cancer treatment (i.e. radiation therapy). Clearly, optimum levels of MT in a tissue-specific manner are important for to the ultimate positive outcomes of cancer treatment. Zinc is a potent inducer of MT in a various tissues (i.e. peripheral blood cells) and has been linked to resistance to chemotherapy drugs. However, it presently is not known whether zinc supplementation influences the resistance of breast cancer cells to chemotherapy drugs and offers protection to normal cells from chemotherapy drug-induced cytotoxicity. Human blood mononuclear THP-1 cells and breast cancer MBA-MB-231 cells were cultured in DMEM for 3 days followed by zinc supplementation using zinc sulfite at 0, 25, 50 or 100 μM for 24 hrs. Zinc supplementation resulted in a dose-dependent increase in total cellular zinc concentration and the abundance of the labile intracellular pool of zinc in THP-1 cells, but not in MDA-MB-231 cells. Similarly, zinc supplementation at 50 and 100 μM also significantly increased the abundance of MT1x and MT2a mRNA in THP-1 cells, while zinc supplementation at 100 μM increased the abundance of MT3a mRNA. In contrast, the abundance of MT1x, MT2a and MT3a mRNAs was not affected by zinc supplementations in MDA-MB-231. When THP-1 cells were exposed to 2μM etoposide, a chemotherapy drug, for 24 hrs, zinc supplementation at 50 and 100 μM reduced etoposide-induced apoptosis by 15 and 33%, respectively with an inverse correlation between zinc supplementation and etoposide-induced apoptosis (r² = 0.99). Furthermore, zinc supplementation also significantly reduced caspase-3 and -9 activities and etoposide-induced DNA oxidative damage. The antioxidant properties of MT likely reduced the oxidative stress of etoposide resulting in the inhibition of apoptosis. Overall, these results suggested that zinc plays a potentially pivotal role in against chemotherapy (i.e. etoposide)-induced cytotoxicity in normal cells.

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