Bortezomib sensitizes human osteosarcoma cells to adriamycin-induced apoptosis through ROS-dependent activation of p-eIF2 alpha/ATF4/CHOP axis
Bortezomib sensitizes human osteosarcoma cells to adriamycin-induced apoptosis through ROS-dependent activation of p-eIF2 alpha/ATF4/CHOP axis
复制标题
硼替佐米通过 ROS 依赖性激活 p-eIF2 α/ATF4/CHOP 轴使人骨肉瘤细胞对阿霉素诱导的细胞凋亡敏感
DOI：
10.1002/ijc.30792
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发表时间：
2017
影响因子：
6.4
通讯作者：
He Qiaojun
中科院分区：
文献类型：
--
作者：
Xian Miao;Cao H;i;Cao Ji;Shao Xuejing;Zhu Difeng;Zhang Ning;Huang Ping;Li Weixu;Yang Bo;Ying Meidan;He Qiaojun
骨肉瘤是最常见的骨癌，目前化疗是治疗骨肉瘤不可或缺的手段。阿霉素被认为是治疗骨肉瘤最有效的药物，然而，阿霉素化疗的结果仍然不令人满意。在这里，我们报道了一种有效的联合治疗，硼替佐米，一种蛋白酶体抑制剂，增强阿霉素诱导的细胞凋亡，以消除骨肉瘤细胞，我们揭示了p - eIF2α/ATF4/CHOP轴的激活是潜在的相关机制。首先，我们观察到硼替佐米增强阿霉素介导的骨肉瘤细胞系细胞增殖抑制和细胞凋亡。此外，该药物组合在人类骨肉瘤细胞系KHOS/NP异种移植物中产生更有效的肿瘤生长抑制作用。我们的研究表明，活性氧（ROS）在阿霉素联合硼替佐米诱导的细胞凋亡中起重要作用，而活性氧清除剂NAC几乎可以完全阻断联合治疗诱导的细胞凋亡。同时，联合用药组p - eIF2α显著升高。因此，ATF4表现出强烈的激活，从而诱导CHOP的激活，导致细胞死亡。最后，13个原发性骨肉瘤细胞对联合治疗表现出强有力的反应。在人骨肉瘤患者来源的异种移植（PDX）模型中，我们的发现表明，当与硼替佐米联合使用时，相对低剂量的阿霉素产生更有效的肿瘤生长抑制作用，而不会增加毒性。因此，我们的研究结果不仅提供了一种治疗骨肉瘤的有希望的联合策略，而且为ROS增加和蛋白酶体抑制的联合策略提供了新的思路，为化疗方案的临床开发开辟了新的机会。
Osteosarcoma is the most common bone cancer, and chemotherapy is currently indispensable for its treatment. Adriamycin has been claimed to be the most effective agent for osteosarcoma, however, the outcome of adriamycin chemotherapy remains unsatisfactory. Here, we reported a potent combination therapy that bortezomib, a proteasome inhibitor, enhances adriamycin‐induced apoptosis to eliminate osteosarcoma cells and we revealed that the activation of p‐eIF2α/ATF4/CHOP axis is the underlying associated mechanisms. First, we observed that bortezomib enhances adriamycin‐mediated inhibition of cell proliferation and enhances the apoptosis in osteosarcoma cell lines. Moreover, this drug combination produced more potent tumor‐growth inhibitory effects in human osteosarcoma cell line KHOS/NP xenografts. Our study showed that reactive oxygen species (ROS) plays an important role in apoptosis induced by adriamycin plus bortezomib, whereas ROS scavenger NAC could almost completely block the apoptosis induced by the combination treatment. Meanwhile, p‐eIF2α is remarkably elevated in the combination group. As a result, ATF4 exhibits strong activation which consequently induces the activation of CHOP and leads to the cell death. Finally, 13 primary osteosarcoma cells demonstrated potent response to the combination treatment. In a human osteosarcoma patient‐derived xenograft (PDX) model, our finding suggests that when combined with bortezomib, a relatively low dose of adriamycin produced more potent tumor‐growth inhibitory effects without increased toxicity. Thus, our findings not only provide a promising combination strategy to overcome osteosarcoma but also shed new light on the strategy of combining increased ROS and inhibited proteasome to open up new opportunities for the clinical development of chemotherapy regimens.