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Enhancement of arsenic trioxide‐mediated apoptosis using docosahexaenoic acid in arsenic trioxide‐resistant solid tumor cells
Author(s) -
Baumgartner Melanie,
Sturlan Sanda,
Roth Erich,
Wessner Barbara,
BachleitnerHofmann Thomas
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20462
Subject(s) - arsenic trioxide , docosahexaenoic acid , apoptosis , chemistry , cancer research , cytotoxic t cell , reactive oxygen species , cancer cell , pharmacology , polyunsaturated fatty acid , cancer , medicine , biochemistry , fatty acid , in vitro
It has been shown that the polyunsaturated fatty acid docosahexaenoic acid (DHA) can sensitize various tumor cells to reactive oxygen species (ROS)‐inducing anticancer agents. Recently, we demonstrated that DHA also enhances the apoptotic effect of clinically achievable concentrations (1–2 μM) of arsenic trioxide (As 2 O 3 ) in several As 2 O 3 ‐resistant human leukemic cell lines via a ROS‐dependent mechanism. The aim of the present study was to evaluate whether this combined effect of As 2 O 3 and DHA is also applicable to As 2 O 3 ‐resistant solid tumor cells. We have tested 12 different tumor cell lines, including MDA‐MB‐468, SK‐BR‐3, MCF‐7 (breast cancer), ES‐2, SKOV‐3 (ovarian cancer), HT‐29, SW‐620, LS‐174T (colon cancer), PC‐3 (prostate cancer), HeLa (cervical cancer), PANC‐1 (pancreatic cancer) and one primary melanoma cell line. With the exception of MDA‐MB‐468 and ES‐2, all cells were resistant to treatment with either As 2 O 3 or DHA alone. However, combined treatment with As 2 O 3 and DHA significantly reduced viability in 7 of the 10 As 2 O 3 ‐resistant solid tumors tested. The cytotoxic effect of As 2 O 3 and DHA was associated with the induction of apoptosis and a concomitant increase of intracellular lipid peroxidation products. Importantly, the combined effect of As 2 O 3 and DHA was selectively toxic for malignant cells since no cytotoxic effect was observed in normal skin fibroblasts, human microvascular endothelial cells and peripheral blood mononuclear cells derived from healthy donors. Our data indicate that DHA may help to extend the therapeutic spectrum of As 2 O 3 in the treatment of solid tumors since it may overcome de novo or acquired resistance to As 2 O 3 . © 2004 Wiley‐Liss, Inc.