Enhancement of arsenic trioxide‐mediated apoptosis using docosahexaenoic acid in arsenic trioxide‐resistant solid tumor cells

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 ar...

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Published in:International journal of cancer 2004-11, Vol.112 (4), p.707-712
Main Authors: Baumgartner, Melanie, Sturlan, Sanda, Roth, Erich, Wessner, Barbara, Bachleitner‐Hofmann, Thomas
Format: Article
Language:English
Subjects:
Antineoplastic agents
apoptosis
Apoptosis - drug effects
arsenic trioxide
Arsenicals - pharmacology
Biological and medical sciences
docosahexaenoic acid
Docosahexaenoic Acids - pharmacology
Drug Interactions
Drug Resistance, Neoplasm
General aspects
Humans
lipid peroxidation
Medical sciences
Neoplasms - pathology
Oxides - pharmacology
Pharmacology. Drug treatments
Reactive Oxygen Species
solid tumor cells
Tumor Cells, Cultured - pathology
Tumors
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Summary: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 (As2O3) in several As2O3‐resistant human leukemic cell lines via a ROS‐dependent mechanism. The aim of the present study was to evaluate whether this combined effect of As2O3 and DHA is also applicable to As2O3‐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 As2O3 or DHA alone. However, combined treatment with As2O3 and DHA significantly reduced viability in 7 of the 10 As2O3‐resistant solid tumors tested. The cytotoxic effect of As2O3 and DHA was associated with the induction of apoptosis and a concomitant increase of intracellular lipid peroxidation products. Importantly, the combined effect of As2O3 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 As2O3 in the treatment of solid tumors since it may overcome de novo or acquired resistance to As2O3. © 2004 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.20462