Shi Yonghua, Yu Yang, Wang Zhenyu, Wang Hao, Bieerkehazhi Shayahati, Zhao Yanling, Suzuk Lale, Zhang Hong
Department of Pathology, Basic Medicine College, Xinjiang Medical University, Urumqi, Xinjiang 830011, China.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Oncotarget. 2016 Nov 8;7(45):73697-73710. doi: 10.18632/oncotarget.12048.
Proteasome inhibition is an attractive approach for anticancer therapy. Doxorubicin (DOX) is widely used for treatment in a number of cancers including breast cancer; however, the development of DOX resistance largely limits its clinical application. One of the possible mechanisms of DOX-resistance is that DOX might induce the activation of NF-κB. In this case, proteasome inhibitors could inhibit the activation of NF-κB by blocking inhibitory factor κB (IκB) degradation. Carfilzomib, a second-generation proteasome inhibitor, overcomes bortezomib resistance and lessens its side-effects. Currently, the effect of carfilzomib on breast cancer cell proliferation remains unclear. In this study, we exploited the role of carfilzomib in seven breast cancer cell lines, MCF7, T-47D, MDA-MB-361, HCC1954, MDA-MB-468, MDA-MB-231, and BT-549, representing all major molecular subtypes of breast cancer. We found that carfilzomib alone had cytotoxic effects on the breast cancer cells and it increased DOX-induced cytotoxic effects and apoptosis in combination by enhancing DOX-induced JNK phosphorylation and inhibiting DOX-induced IκBα degradation. The results suggest that carfilzomib has potent antitumor effects on breast cancer in vitro and can sensitize breast cancer cells to DOX treatment. DOX in combination with carfilzomib may be an effective and feasible therapeutic option in the clinical trials for treating breast cancer.
蛋白酶体抑制是一种颇具吸引力的抗癌治疗方法。阿霉素（DOX）广泛用于包括乳腺癌在内的多种癌症的治疗；然而，DOX耐药性的出现很大程度上限制了其临床应用。DOX耐药的一种可能机制是DOX可能诱导核因子κB（NF-κB）的激活。在这种情况下，蛋白酶体抑制剂可通过阻断抑制因子κB（IκB）的降解来抑制NF-κB的激活。第二代蛋白酶体抑制剂卡非佐米克服了硼替佐米的耐药性并减轻了其副作用。目前，卡非佐米对乳腺癌细胞增殖的影响仍不清楚。在本研究中，我们探究了卡非佐米在七种乳腺癌细胞系MCF7、T-47D、MDA-MB-361、HCC1954、MDA-MB-468、MDA-MB-231和BT-549中的作用，这些细胞系代表了乳腺癌的所有主要分子亚型。我们发现，卡非佐米单独使用对乳腺癌细胞具有细胞毒性作用，并且通过增强DOX诱导的JNK磷酸化和抑制DOX诱导的IκBα降解，它与DOX联合使用时可增强DOX诱导的细胞毒性作用和细胞凋亡。结果表明，卡非佐米在体外对乳腺癌具有强大的抗肿瘤作用，并且可使乳腺癌细胞对DOX治疗敏感。DOX与卡非佐米联合使用可能是乳腺癌临床试验中一种有效且可行的治疗选择。
