Inhibition of the tumour necrosis factor-alpha autocrine loop enhances the sensitivity of multiple myeloma cells to anticancer drugs

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• 作者：Masanobu Tsubaki ; Makiko Komai ; Tatsuki Itoh ; Motohiro Imano ; Kotaro Sakamoto ; Hirotaka Shimaoka ; Naoki Ogawa ; Kenji Mashimo ; Daichiro Fujiwara ; Tomoya Takeda ; Junji Mukai ; Katsuhiko Sakaguchi ; Takao Satou ; Shozo Nishida
• 关键词：TNF-伪 ; NF-魏B ; mTOR ; Multiple myeloma
• 刊名：European Journal of Cancer
• 出版年：November, 2013
• 年：2013
• 卷：49
• 期：17
• 页码：3708-3717
• 全文大小：1970 K

文摘

Several autocrine soluble factors, including macrophage inflammatory protein-1伪 and tumour necrosis factor-alpha (TNF-伪), promote the survival and growth of multiple myeloma (MM) cells. We hypothesised that inhibition of the TNF-伪 autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines. In the present study, a TNF-伪-neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of anticancer drugs on MM cells. In addition, combination treatment with the TNF-伪-neutralizing antibody and the chemotherapy agent melphalan inhibited nuclear factor 魏B (NF-魏B) p65 nuclear translocation and mammalian target of rapamycin (mTOR) activation and upregulated the expression of Bax and Bim. Treatment of ARH-77 cells with the NF-魏B inhibitor dimethyl fumarate or the mTOR inhibitor rapamycin suppressed NF-魏B p65 nuclear translocation and enhanced the cytotoxic effect of melphalan. Furthermore, infliximab, a monoclonal antibody against TNF-伪, also enhanced the cytotoxic effect of anticancer drugs in ARH-77 cells. These results indicated that TNF-伪-neutralizing antibodies or infliximab enhanced the cytotoxic effect of anticancer drugs by suppressing the TNF receptor/mTOR/NF-魏B pathways. The inhibition of TNF-伪 may thus provide a new therapeutic approach to control tumour progression and bone destruction in MM patients.