Flavonoids inhibit chronically exposed arsenic-induced proliferation and malignant transformation of HaCaT cells

Apart from exposure to UV-radiation, studies show relationship between skin cancer and chronic ingestion of arsenic through drinking water. Chemopreventive strategies could help in reducing the toxic effects of arsenic and arsenic-induced skin cancer.

Cytotoxicity of arsenic on human skin keratinocytes HaCaT cells was evaluated using MTT and trypan blue assays. Arsenic-induced malignant transformant HaCaT cells were selected through soft agar colony assay. Cell cycle progression was analyzed through FACS. The expressions of genes modulated by arsenic were studied through RT-PCR.

The lower concentrations (0.1-0.5 μmol/L) of arsenic were non-toxic and transformed HaCaT cells on chronic exposure, and also enhanced the cell proliferation. Silibinin and fisetin reduced the arsenic-induced cell proliferation and malignant transformation. A slight increase in G2-M phase cell population was also observed. The anti-proliferation effects of flavonoids on HaCaT transformants were further enhanced when combined with gamma radiation. Chronic and acute exposure to arsenic modulated the expression of transformation-associated genes including Bcl-2A1, IGFL-1, Rab31, and TNC in HaCaT cells.

Chronic exposure to lower arsenic concentrations caused malignant transformation of skin keratinocytes and that effect was attenuated by flavonoids silibinin and fisetin. Thus, chemoprevention could reduce arsenic-caused detrimental effects on skin cells.