Superfund Research Program
Low Levels of Arsenite May Serve as a Treatment for Melanoma
Melanoma is the most aggressive and most serious form of skin cancer. Despite dramatic increases in the incidence of malignant melanoma in recent decades, the molecular mechanisms of its progression and its extreme resistance to treatments remain largely unknown. Metastatic melanoma, which has spread to other parts of the body such as the liver, lungs, or brain, is often deadly because:
- It responds poorly to chemotherapy and gamma irradiation which often kill cells by induction of programmed cell death (apoptosis).
- Although melanoma-specific antigens and melanoma-specific immune cells exist in human body, they do not cause immune-mediated destruction of malignant melanomas.
- Melanomas actively suppress the immune system.
Recent studies conducted in the laboratory of Dr. Tom K. Hei, Professor of Environmental Health Sciences in the Mailman School of Public Health at Columbia University, have shown that short term treatment with low to moderate concentrations of sodium arsenite (2-10 uM), which has little or no effects on normal melanocytes, induces apoptosis of human melanoma, including highly metastatic ones, by more than 6 fold. These data suggest that arsenic may be effective as a therapeutic regimen of an otherwise refractory and highly malignant disease.
Human malignant melanomas are likely to have altered and suppressed apoptotic pathways. Fas is a member of the TNF receptor family that promotes apoptosis. Down-regulation of the Fas death receptor in lymphoid and solid tumors is often associated with resistance to drug- and radiation-induced cell death, and human malignant melanomas that lack surface expression of Fas have a poor prognosis. Therefore, it is important to develop alternative approaches in the treatment of this often fatal disease including effective induction/acceleration of programmed cell death despite suppression of Fas-mediating death signaling.
Melanoma cells express many different growth factors, cytokines and their receptors to support their autonomous growth and to suppress the immune system. One cytokine, TNF-alpha, mediates a variety of biological functions such as cell proliferation, differentiation and cell death. In normal non-stress conditions, TNF-alpha-induced death is actively suppressed by NF-kB-dependent gene expression.
Arsenic compounds have been successfully used as inducers of stress and apoptosis for treatment of several forms of leukemia and some solid tumors. In studies conducted in Dr. Hei's laboratory, Dr. Vladimir Ivanov has found that low to moderate concentrations of arsenite has little or no effect on normal melanocytes, but induces high levels of apoptosis in melanomas in spite of their low surface Fas levels. There are two important effects of arsenite treatments:
- Arsenite acts as a sulfhydryl reagent that binds to the free thiol (-SH) group of enzymes and inhibits their functions. The most prominent target of enzymatic inhibition by arsenite is IkB kinase-beta. This results in the suppression of NF-kB transcription factor, allowing for activation of TNF-alpha-induced death pathways.
- Arsenite induces production of reactive oxygen species at high levels with subsequent development of oxidative stress, which affects multiple targets in the cell.
Suppression of protective signaling pathways that play a protective role against arsenite-induced oxidative stress and apoptosis dramatically accelerates arsenite-induced apoptosis of resistant metastatic melanomas. Taken together, these findings suggest that arsenite may be a powerful therapeutic agent in the treatment of metastatic melanoma.
Arsenic is an important environmental carcinogen that affects millions of people worldwide through contaminated water supplies. Epidemiological data have shown that chronic exposure of humans to inorganic arsenical compounds is associated with liver injury, peripheral neuropathy, and an increased incidence of cancer of the lung, skin, bladder, and liver. The extent of human sufferings bestowed by arsenic exposure simply cannot be overstated. This study, however, indicates that arsenic can be a double-edged sword and could, potentially, benefit thousands of melanoma patients each year who fail conventional therapeutic regimen.
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To learn more about this research, please refer to the following sources:
- Ivanov VN, Hei TK. 2004. Arsenic sensitizes human melanomas to apoptosis via TNF-alpha mediated pathways. J Biol Chem 279(21):22747-22758. PMID:15028728
- Kessel M, Liu S, Xu A, Santella RM, Hei TK. 2002. Arsenic induces oxidative DNA damage in mammalian cells. Mol Cell Biochem 234-235:301-308. PMID:12162448
- Liu S, Athar M, Lippai I, Waldren CA, Hei TK. 2001. Induction of oxyradicals by arsenic: Implication for mechanisms of genotoxicity. Proc Natl Acad Sci U S A 98(4):1643-1648. PMID:11172004
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