Effects of gambogic acid on the activation of caspase-3 and downregulation of SIRT1 in RPMI-8226 multiple myeloma cells via the accumulation of ROS
Effects of gambogic acid on the activation of caspase-3 and downregulation of SIRT1 in RPMI-8226 multiple myeloma cells via the accumulation of ROS
复制标题
藤黄酸通过ROS积累对RPMI-8226多发性骨髓瘤细胞中caspase-3的激活和SIRT1的下调的影响。
DOI：
10.3892/ol.2012.634
复制
发表时间：
2012-05-01
期刊：
影响因子：
2.9
通讯作者：
Cui, Guo-Hui
中科院分区：
文献类型：
--
作者：
Yang, Li-Jing;Chen, Yan;Cui, Guo-Hui
多发性骨髓瘤 (MM) 是第二常见的血液恶性肿瘤。尽管硼替佐米和来那度胺等新药改善了多发性骨髓瘤患者的治疗前景，但多发性骨髓瘤仍然无法治愈。因此，筛选新型抗骨髓瘤药物十分必要。藤黄酸 (GA) 是藤黄树分泌的藤黄的主要活性成分，据报道在某些实体瘤和血液恶性肿瘤中表现出有效的抗癌活性，但关于其对 MM 细胞的影响的研究很少。在本研究中，我们研究了 GA 对 MM RPMI-8226 细胞的抗癌活性，并进一步研究了 GA 影响细胞的潜在机制。培养RPMI-8226细胞，采用MTT法分析GA对细胞增殖的影响。使用 Hoechst 33258 染色观察核碎片，并检测活性氧 (ROS) 水平。研究发现 GA 对 RPMI-8226 细胞的生长抑制和凋亡诱导具有显着的剂量依赖性作用。这种活性与 ROS 的积累有关，ROS 有助于 caspase-3 的激活和聚（ADP-核糖）聚合酶（PARP）的裂解，并伴随 GA 处理的 RPMI-8226 细胞的凋亡。哺乳动物SIRT1作为酵母Sir2最接近的同源物，广泛参与调节细胞过程，包括细胞衰老、衰老和神经元保护，并具有抗凋亡特性。此外，SIRT1 过度表达已被证明可以保护癌细胞免受化疗和电离辐射的影响。在本研究中，我们证明 GA 有可能通过 ROS 积累下调 SIRT1 的表达。总之，我们的研究发现 GA 能够通过 ROS 积累、随后 caspase-3 激活、PARP 裂解和 SIRT1 下调来诱导 RPMI-8226 细胞凋亡。这些结果表明，GA 可能不仅具有诱导 MM 细胞凋亡的潜力，而且还具有降低 MM 复发率的潜力。
Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy. Although new drugs, including bortezomib and lenalidomide, have improved the treatment landscape for MM patients, MM remains incurable. Therefore, screening for novel anti-myeloma drugs is necessary. Gambogic acid (GA), the main active ingredient of gamboges secreted from the Garcinia hanburryi tree, has been reported to exhibit potent anticancer activity in certain solid tumors and hematological malignancies, while there are few studies that are available concerning its effects on MM cells. In the present study, we investigated the anticancer activity of GA on the MM RPMI-8226 cells and further studied the underlying mechanisms by which GA affected the cells. RPMI-8226 cells were cultured and the effect of GA on cell proliferation was analyzed using MTT assay. Hoechst 33258 staining was used to visualize nuclear fragmentation, and reactive oxygen species (ROS) levels were detected. GA was found to have a significant, dose-dependent effect on growth inhibition and apoptosis induction in RPMI-8226 cells. This activity is associated with the accumulation of ROS, which contributes to the activation of caspase-3 and the cleavage of poly (ADP-ribose) polymerase (PARP), accompanied with apoptosis in RPMI-8226 cells treated with GA. Mammalian SIRT1, as the closest homolog of the yeast Sir2, was extensively involved in regulating cell processes, including cell senescence, aging and neuronal protection, as well as having anti-apoptotic properties. Moreover, SIRT1 overexpression has been shown to protect cancer cells from chemotherapy and ionizing radiation. In the present study, we demonstrated that GA has the potential to downregulate the expression of SIRT1 via ROS accumulation. In conclusion, our study found that GA is able to induce apoptosis in RPMI-8226 cells via ROS accumulation followed by caspase-3 activation, PARP cleavage and SIRT1 downregulation. These results suggest that GA may have the potential to not only induce apoptosis in MM cells, but also to decrease the relapse rate of MM.