Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University , Chongqing , China.
Leuk Lymphoma. 2013 Oct;54(10):2263-8. doi: 10.3109/10428194.2013.775437. Epub 2013 Mar 13.
(-)- Gossypol, a natural inhibitor of anti-apoptotic Bcl-2 proteins, has presented an effective anti-tumor activity in numerous preclinical trials. More and more evidence in vivo and in vitro validates that (-)- gossypol can dramatically suppress cell proliferation and induce cell death in hematological malignancies. However, the detailed mechanisms are not well known. In the present study, we showed that treatment with (-)- gossypol stimulated reactive oxygen species (ROS) generation and induced autophagy in Burkitt lymphoma cells. Antioxidant N-acetyl-cysteine (NAC) pretreatment attenuated (-)- gossypol-induced autophagy. Furthermore, (-)- gossypol treatment increased the translocation of high mobility group box 1 (HMGB1) from nuclei to cytoplasm, which can be suppressed by NAC pretreatment. NAC pretreatment also dramatically enhanced (-)- gossypol-induced apoptosis and total cell death. These results indicate that (-)- gossypol induces a protective autophagy in Burkitt lymphoma cells, partly due to ROS induction and cytosolic translocation of HMGB1. Antioxidants may serve as potent chemosensitizers to enhance cell death through blocking (-)- gossypol-induced autophagy.
（-）棉酚是一种天然的抗凋亡 Bcl-2 蛋白抑制剂，在大量的临床前试验中表现出了有效的抗肿瘤活性。越来越多的体内和体外证据表明，（-）棉酚可以显著抑制血液系统恶性肿瘤细胞的增殖并诱导其死亡。然而，其详细的作用机制尚不清楚。在本研究中，我们发现（-）棉酚处理可刺激活性氧（ROS）的产生，并诱导 Burkitt 淋巴瘤细胞发生自噬。抗氧化剂 N-乙酰半胱氨酸（NAC）预处理可减弱（-）棉酚诱导的自噬。此外，（-）棉酚处理增加了高迁移率族蛋白 1（HMGB1）从细胞核向细胞质的易位，该易位可被 NAC 预处理所抑制。NAC 预处理还显著增强了（-）棉酚诱导的细胞凋亡和总细胞死亡。这些结果表明，（-）棉酚诱导 Burkitt 淋巴瘤细胞发生保护性自噬，部分原因是 ROS 的诱导和 HMGB1 的细胞质易位。抗氧化剂可能作为有效的化学增敏剂，通过阻断（-）棉酚诱导的自噬来增强细胞死亡。
