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Research Paper

Platinums sensitize human epithelial tumor cells to lymphotoxin α by inhibiting NF-κB-dependent transcription

Yijun Shen, Jing Wang, Tong Yang, Yuhong Li, Wen-Qi Jiang, Zhongzhen Guan, Zheng Wang, Jingwei Tan, Jinsong Wu, Gang Li, Qing Zu, Fang Wu, Luochun Wang and Yanjun Liu

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Lymphotoxin α (LTα) was first identified as a direct anti-tumor factor, whereas increasing evidence has recently shown that in most cases the growth inhibition mediated by LTα requires the synergistic action of other factors, such as RNA transcription or protein synthesis inhibitor. In this study, we evaluated the combined effects of LTα 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 LTα. A systemic treatment with a combination of LTα and cisplatin in a human Bcap37 breast cancer xenograft nude mice model dramatically improved the therapeutic efficacy of LTα. Further analysis revealed that the sensitization of platinums was associated with platinums-induced suppression of nuclear factor-kappaB (NF-κB) and subsequent down-regulation 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 LTα and conventional chemotherapeutic drugs such as platinums may be an efficient treatment strategy for human epithelial cancers.

Authors

Yijun Shen

Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China

Jing Wang

Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd.

Tong Yang

Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd.

Yuhong Li

Department of Medical Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, P. R. China

Wen-Qi Jiang

State Key Laboratory of Oncology in South China

Zhongzhen Guan

Department of Medical Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, P. R. China

Zheng Wang

Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China

Jingwei Tan

Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China

Jinsong Wu

Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China

Gang Li

Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China

Qing Zu

3Department of Oncology, Shanghai Tenth People's Hospital, No. 301 Yanchang Rd, Shanghai, 200072, China

Fang Wu

Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd.

Luochun Wang

Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd.

Yanjun Liu

Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd.

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