title: Platinums sensitize human epithelial tumor cells to lymphotoxin alpha by inhibiting NFkappaB-dependent transcription.
abstract: Lymphotoxin alpha (LTalpha) was first identified as a direct anti-tumor factor, whereas increasing evidence has recently shown that in most cases the growth inhibition mediated by LTalpha requires the synergistic action of other factors, such as RNA transcription or protein synthesis inhibitor. In this study, we evaluated the combined effects of LTalpha and ten chemotherapeutic drugs on cell growth in a panel of human epithelial tumor cells, and explored the molecular mechanism of their mutual action. The results showed that platinums (cisplatin, carboplatin, oxaliplatin) are more universally effective than other chemotherapeutic drugs (doxorubicin, epi-doxorubicin, 5-flourouracil, mitomycin, cyclophosphamide, vincristine and vinorelbine) to enhance the response of six human epithelial tumor cell lines (A375, Bcap37, NCI-H157, SW480, BGC-823 and HeLa) to LTalpha. A systemic treatment with a combination of LTalpha and cisplatin in a human Bcap37 breast cancer xenograft nude mice model dramatically improved the therapeutic efficacy of LTalpha. Further analysis revealed that the sensitization of platinums was associated with platinums-induced suppression of nuclear factor-kappaB (NFkappaB) and subsequent downregulation of X-linked inhibitor of apoptosis protein (XIAP), which rescued caspase-3 from inhibition. Our results suggested that a proper combination of bio-agents such as LTalpha and conventional chemotherapeutic drugs such as platinums may be an efficient treatment strategy for human epithelial cancers.
authors: Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.
authors: Yijun
authors: Y
authors: Shen
authors: Jing
authors: J
authors: Wang
authors: Tong
authors: T
authors: Yang
authors: Yuhong
authors: Y
authors: Li
authors: Wenqi
authors: W
authors: Jiang
authors: Zhongzhen
authors: Z
authors: Guan
authors: Zheng
authors: Z
authors: Wang
authors: Jingwei
authors: J
authors: Tan
authors: Jinsong
authors: J
authors: Wu
authors: Gang
authors: G
authors: Li
authors: Qing
authors: Q
authors: Xu
authors: Fang
authors: F
authors: Wu
authors: Luochun
authors: L
authors: Wang
authors: Yanjun
authors: Y
authors: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008233:Lymphotoxin-alpha / Q000378:metabolism / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D010984:Platinum / Q000378:metabolism / Q000494:pharmacology*; D000091402:Prohibitins; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D008233:Lymphotoxin-alpha; D016328:NF-kappa B; C000717331:PHB2 protein, human; C000717333:Phb2 protein, mouse; D000091402:Prohibitins; D010984:Platinum; D053148:Caspase 3