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Sodium arsenite alters cell cycle progression and induces apoptosis in melanoma cell lines
Author(s) -
McNeely Samuel Clark,
States J. Christopher
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a806-b
Subject(s) - arsenic trioxide , sodium arsenite , poly adp ribose polymerase , mitosis , apoptosis , arsenite , programmed cell death , buthionine sulfoximine , cyclin b1 , cell cycle checkpoint , cancer research , cyclin b , biology , cyclin dependent kinase 1 , microbiology and biotechnology , cell cycle , chemistry , biochemistry , cyclin d1 , glutathione , arsenic , polymerase , organic chemistry , gene , enzyme
Arsenic trioxide is used to treat acute promyelocytic leukemia and is in clinical trials for use with other cancers. This study examines arsenic as a drug for melanoma. A375 and SK‐Mel‐2 melanoma cell lines were sensitive to clinically achievable concentrations of arsenite. SK‐Mel‐3 and SK‐Mel‐28 cell lines were resistant to arsenite but were sensitized by pretreatment with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor. Arsenic resistance was also overcome by co‐treatment with MK571, an inhibitor of MRP‐family transport proteins. Arsenite alone or with BSO or MK571 induced caspase 3 and poly(ADP‐ribose) polymerase (PARP) cleavage suggesting apoptotic cell death. Apoptosis in arsenite‐sensitive cell lines was associated with mitotic arrest and cyclin B stabilization. In A375 cells, active caspase 3 co‐localized with mitotic marker phospho‐histone H3. Degradation or inhibition of cyclin B is needed for mitotic exit. Roscovitine, a cyclin B/CDK1 inhibitor, lowered the mitotic index of mitotic arsenite‐treated cells and abrogated caspase 3 and PARP cleavage. Arsenite with or without BSO or MK571 did not arrest SK‐Mel‐3 and SK‐Mel‐28 cells in mitosis, but induced GADD45α, suggesting G2 arrest. Arsenite’s ability to induce apoptosis in these cells warrants further study of its use with melanoma. (Support by PHS grants R01ES011314 and T32ES011564.)