title: Synergistic cytotoxicity of Bcl-xL inhibitor, gossypol and chemotherapeutic agents in non-Hodgkin's lymphoma cells.
abstract: Anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in 80% of non Hodgkin's lymphoma cells and are thought to play an important role in the resistance of lymphoma cells to current chemotherapeutic agents. Gossypol, an orally-active polyphenolic aldehyde derived from the cotton plant, has been known to have potential anti-neoplastic activity. Recently, gossypol was found to bind to the BH3 binding groove of Bcl-xL and with lesser affinity to Bcl-2. The present study was conducted to determine whether gossypol increases the sensitivity of non-Hodgkin's lymphoma cells to the actions of chemotherapeutic agents by potentiating treatment-induced apoptosis. The interactions observed between gossypol and chemotherapeutic drugs were analyzed using the median effect principle (CalcuSyn analysis). Our data showed that treatment of Ramos cells with gossypol not only induced cell arrest on the G(0)/G(1) phase, but also augmented apoptosis and growth inhibition induced by etoposide (VP-16), doxorubicin hydrochloride (ADM), vincristine (VCR), and paclitaxel (taxol). However, when gossypol was combined with cisplatin (DDP) an antagonistic effect was observed. Gossypol-induced cell cycle arrest was accompanied by decreased expression of cyclin D1 in Ramos cells. In addition, the peroxisome proliferator-activated receptor (PARP) pathway is, at least in part, involved in the gossypol-induced apoptosis when combined with VP-16. These data indicate that single-agent gossypol is effective in inhibiting growth of non-Hodgkin's lymphoma cells in vitro and combination studies with certain secondary chemotherapeutic agents further demonstrate it's synergistic cytotoxicity. These findings support future preclinical and clinical studies of gossypol in the treatment of non-Hodgkin's lymphoma.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Li
authors.forename: Wen-Qi
authors.initials: WQ
authors.lastname: Jiang
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Zhu
authors.forename: Xiao-feng
authors.initials: XF
authors.lastname: Zhu
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Zhou
authors.forename: Zong-Chao
authors.initials: ZC
authors.lastname: Liu
authors.forename: Da-Jun
authors.initials: DJ
authors.lastname: Yang
authors.forename: Zhong-Zhen
authors.initials: ZZ
authors.lastname: Guang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056741:Cyclin D; D016213:Cyclins / Q000032:analysis; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006072:Gossypol / Q000494:pharmacology*; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D011239:Prednisolone / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D014750:Vincristine / Q000627:therapeutic use; D051028:bcl-2-Associated X Protein / Q000032:analysis; D051020:bcl-X Protein / Q000032:analysis / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D056741:Cyclin D; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; D053148:Caspase 3; D006072:Gossypol; D017239:Paclitaxel