title: Combining paclitaxel with ABT-263 has a synergistic effect on paclitaxel resistant prostate cancer cells.
abstract: We assessed the capability of paclitaxel, one of the taxanes, to induce death in two prostate cancer lines, LNCaP and PC3. Paclitaxel drove an apoptotic pathway in LNCaP, but not in PC3 cells, in response to G2/M arrest. An examination of the levels of anti-apoptotic proteins revealed that Bcl-xl was much higher in PC3 cells than in LNCaP cells and Bcl2 could be detected only in PC3 cells, not in LNCaP cells. Knocking down Bcl-xl enhanced paclitaxel-induced apoptosis in LNCaP cells, while we were unable to knock down Bcl-xl efficiently in PC3 cells. Significantly, a comparison of ABT-263, a specific inhibitor of Bcl2 and Bcl-xl, with ABT-199, a Bcl2 selective inhibitor, disclosed that only ABT-263, not ABT-199, could induce apoptosis in LNCaP and PC3 cells. The results indicate that Bcl-xl has a protective role against paclitaxel-induced apoptosis in LNCaP and PC3 cells, and its overexpression causes the paclitaxel resistance seen in PC3 cells. Interestingly, combined paclitaxel with ABT-263 to treat LNCaP and PC3 cells demonstrated synergistic apoptosis activation, indicating that ABT-263 could enhance paclitaxel-induced apoptosis in LNCaP cells and overcome Bcl-xl overexpression to trigger paclitaxel-induced apoptosis in PC3 cells. We also observed that the activation of apoptosis in LNCaP cells was more efficient than in PC3 cells in response to paclitaxel plus ABT-263 or to ABT-263 alone, suggesting that the apoptosis pathway in PC3 cells might have further differences from that in LNCaP cells even after Bcl-xl overexpression is accounted for.
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Chihuei
authors: C
authors: Wang
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Shih-Bo
authors: SB
authors: Huang
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Min-Chi
authors: MC
authors: Yang
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Yi-Tsen
authors: YT
authors: Lin
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: I-Hung
authors: IH
authors: Chu
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Ya-Ni
authors: YN
authors: Shen
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Yueh-Ho
authors: YH
authors: Chiu
authors: Department of Orthopedic Surgery, Fooyin University Hospital, Pinutung, Taiwan.
authors: Shao-Hung
authors: SH
authors: Hung
authors: Graduate Institute of Clinical Medicine, National Cheng Kung University, Tainan City, Taiwan; Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, Tainan City, Taiwan.
authors: Lin
authors: L
authors: Kang
authors: Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Yi-Ren
authors: YR
authors: Hong
authors: Department of Orthopedics, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors: Chung-Hwan
authors: CH
authors: Chen
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D013449:Sulfonamides; D020169:Caspases; D017239:Paclitaxel; C528561:navitoclax