Liu Dao-Lu, Li Ying-Jie, Yang Dong-Hua, Wang Chen-Ran, Xu Jun, Yao Nan, Zhang Xiao-Qi, Chen Zhe-Sheng, Ye Wen-Cai, Zhang Dong-Mei
College of Pharmacy, Jinan University, Guangzhou 510632, P.R. China.
Biosample Repository, Core Facility, Fox Chase Cancer Center, Philadelphia, PA, USA.
Int J Oncol. 2015 May;46(5):2029-38. doi: 10.3892/ijo.2015.2925. Epub 2015 Mar 12.
Chemotherapy is one of the most common therapeutic option for metastatic tumors and hematological malignancies. ABCB1-mediated multidrug resistance is the major obstacle for chemotherapy. Natural products with diversified structures are ideal source of ABCB1 modulators. Ganoderenic acid B, a lanostane-type triterpene isolated from Ganoderma lucidum, exhibited potent reversal effect on ABCB1-mediated multidrug resistance of HepG2/ADM cells to doxorubicin, vincristine and paclitaxel. Similarly, ganoderenic acid B could also significantly reverse the resistance of ABCB1-overexpressing MCF-7/ADR cells to doxorubicin. Furthermore, ganoderenic acid B notably enhanced intracellular accumulation of rhodamine-123 in HepG2/ADM cells through inhibition of its efflux. ABCB1 siRNA interference assay indicated that the reversal activity of ganoderenic acid B was dependent on ABCB1. Further mechanistic investigations found that ganoderenic acid B did not alter the expression level of ABCB1 and the activity of ABCB1 ATPase. Molecular docking model displayed that the positions of ganoderenic acid B binding to ABCB1 were different from the region of verapamil interacted with ABCB1. Collectively, ganoderenic acid B can enhance the cytotoxicity of chemotherapeutics towards ABCB1-mediated MDR cancer cells via inhibition of the transport function of ABCB1. These findings provide evidence that ganoderenic acid B has the potential to be developed into an ABCB1-mediated multidrug resistance reversal agent.
化疗是转移性肿瘤和血液系统恶性肿瘤最常见的治疗选择之一。ABCB1介导的多药耐药是化疗的主要障碍。结构多样的天然产物是ABCB1调节剂的理想来源。灵芝烯酸B是从灵芝中分离得到的一种羊毛甾烷型三萜，对ABCB1介导的HepG2/ADM细胞对阿霉素、长春新碱和紫杉醇的多药耐药具有显著的逆转作用。同样，灵芝烯酸B也能显著逆转过表达ABCB1的MCF-7/ADR细胞对阿霉素的耐药性。此外，灵芝烯酸B通过抑制罗丹明-123的外排，显著增强了其在HepG2/ADM细胞内的积累。ABCB1 siRNA干扰试验表明，灵芝烯酸B的逆转活性依赖于ABCB1。进一步的机制研究发现，灵芝烯酸B并未改变ABCB1的表达水平和ABCB1 ATP酶的活性。分子对接模型显示，灵芝烯酸B与ABCB1结合的位置不同于维拉帕米与ABCB1相互作用的区域。总之，灵芝烯酸B可通过抑制ABCB1的转运功能增强化疗药物对ABCB1介导的多药耐药癌细胞的细胞毒性。这些发现为灵芝烯酸B有潜力开发成为一种ABCB1介导的多药耐药逆转剂提供了证据。
