Abstract
Although gemcitabine is highly active in several cancer types, intrinsic and acquired drug resistance remains a major challenge. Overexpression of Bcl-2 has been associated with gemcitabine resistance. The aim of this study is to determine whether gossypol can overcome gemcitabine resistance in cell lines with high level of Bcl-2 expression in combination drug therapy. Our study demonstrated that in 10 cell lines derived from different cancers, high Bcl-2 baseline expression was observed in cell lines that were resistant to gemcitabine (GEM-R). Furthermore, synergistic effect of combination therapy was observed in gemcitabine-resistant (GEM-R) cell lines with high Bcl-2 expression, but not in a gemcitabine-sensitive (GEM-S) cell lines regardless of Bcl-2 expression. Gossypol treatment resulted in the decrease of anti-apoptotic genes such as Bcl-2 and Bcl-xl and an upregulation of the pro-apoptotic gene, Noxa. Furthermore, the addition of gossypol to gemcitabine resulted in lower expressions of anti-apoptotic genes compared to gemcitabine alone. Gene expression profiling in GEM-R and GEM-S cell lines suggest that anti-apoptotic genes such as pAkt and PI3KR2 may play important role in gemcitabine resistance, while pro-apoptotic Bcl-2 related genes (Bad, Caspase-6 and Calpain-1) may regulate synergistic interaction in combination therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Line, Tumor
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Deoxycytidine / analogs & derivatives*
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Deoxycytidine / pharmacology
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Deoxycytidine / therapeutic use
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Drug Interactions
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Drug Resistance, Neoplasm* / drug effects
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Drug Synergism
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Gemcitabine
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Gene Expression Regulation, Neoplastic / drug effects
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Gossypol / analogs & derivatives
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Gossypol / pharmacology
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Gossypol / therapeutic use*
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Humans
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Inhibitory Concentration 50
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Multigene Family / genetics
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Neoplasms / drug therapy*
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Neoplasms / genetics*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Reproducibility of Results
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Up-Regulation / drug effects
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Up-Regulation / genetics
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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PMAIP1 protein, human
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Proto-Oncogene Proteins c-bcl-2
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bcl-X Protein
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Deoxycytidine
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Gossypol
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gossypol acetic acid
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Gemcitabine
Grants and funding
This work is supported by grant NMRC/TCR/001-NUH/2007 from National Medical Research Council, Singapore. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.