title: Combination therapy with gossypol reveals synergism against gemcitabine resistance in cancer cells with high BCL-2 expression.
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.
authors.affiliation: Department of Haematology-Oncology, National University Health System, Singapore, Singapore. wf_ying@hotmail.com
authors.forename: Foong Ying
authors.initials: FY
authors.lastname: Wong
authors.forename: Natalia
authors.initials: N
authors.lastname: Liem
authors.forename: Chen
authors.initials: C
authors.lastname: Xie
authors.forename: Fui Leng
authors.initials: FL
authors.lastname: Yan
authors.forename: Wing Cheong
authors.initials: WC
authors.lastname: Wong
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Wang
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Yong
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006072:Gossypol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D020128:Inhibitory Concentration 50; D005810:Multigene Family / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D003841:Deoxycytidine; D006072:Gossypol; C028178:gossypol acetic acid; D000093542:Gemcitabine