Combination therapy with protein kinase inhibitor H89 and Tetrandrine elicits enhanced synergistic antitumor efficacy.
Combination therapy with protein kinase inhibitor H89 and Tetrandrine elicits enhanced synergistic antitumor efficacy.
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蛋白激酶抑制剂 H89 和粉防己碱联合治疗可增强协同抗肿瘤功效
DOI：
10.1186/s13046-018-0779-2
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发表时间：
2018-06-04
期刊：
影响因子：
--
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Yu M;Liu T;Chen Y;Li Y;Li W
粉防己碱是从药用植物粉防己碱中分离得到的一种双苄基异喹啉生物碱，最近被鉴定为一种新的化疗药物。汉防己甲素对多种癌症具有潜在的抗肿瘤作用。值得注意的是，当粉防己碱与分子靶向剂结合时，发现了一种增强的治疗效果。H89是一种有效的蛋白激酶A抑制剂，是一种异喹啉磺胺。体外观察H89与汉防己甲素联合应用对细胞存活率、细胞凋亡率和自噬的影响，并通过计算联合指数评价其协同作用。采用免疫印迹、流式细胞仪和荧光显微镜等方法对其作用机制进行研究。这种组合也在小鼠异种移植模型中进行了评估；分析了肿瘤生长和肿瘤裂解物，并进行了TUNEL检测。H89与汉防己甲素联合应用，对体内外人类癌细胞有较强的协同抗肿瘤作用，而对正常细胞无明显影响。在机制上，联合治疗显著诱导癌细胞的凋亡和自噬，这是由ROS调节的PKA和ERK信号介导的。此外，Mcl-1和c-Myc在H89/粉防己碱联合治疗中起关键作用。MCL-1的异位表达显著降低H89/粉防己碱的敏感性，并增强c-Myc致敏的癌细胞。我们的研究结果表明，汉防己甲素和H89的联合应用显示了增强的治疗效果，并可能成为癌症患者的一种有前途的治疗策略。它们还表明粉防己碱在治疗人类癌症方面有重要的临床应用。此外，H89/粉防己碱的结合为c-Myc扩增患者提供了新的选择性靶向治疗策略。本文的在线版本(10.1186/s13046-0180779-2)包含补充材料，可供授权用户使用。
Tetrandrine, a bisbenzylisoquinoline alkaloid that was isolated from the medicinal plant Stephania tetrandrine S. Moore, was recently identified as a novel chemotherapy drug. Tetrandrine exhibited a potential antitumor effect on multiple types of cancer. Notably, an enhanced therapeutic efficacy was identified when tetrandrine was combined with a molecularly targeted agent. H89 is a potent inhibitor of protein kinase A and is an isoquinoline sulfonamide. The effects of H89 combined with tetrandrine were investigated in vitro with respect to cell viability, apoptosis and autophagy, and synergy was assessed by calculation of the combination index. The mechanism was examined by western blot, flow cytometry and fluorescence microscopy. This combination was also evaluated in a mouse xenograft model; tumor growth and tumor lysates were analyzed, and a TUNEL assay was performed. Combined treatment with H89 and tetrandrine exerts a mostly synergistic anti-tumor effect on human cancer cells in vitro and in vivo while sparing normal cells. Mechanistically, the combined therapy significantly induced cancer cell apoptosis and autophagy, which were mediated by ROS regulated PKA and ERK signaling. Moreover, Mcl-1 and c-Myc were shown to play a critical role in H89/tetrandrine combined treatment. Mcl-1 ectopic expression significantly diminished H89/tetrandrine sensitivity and amplified c-Myc sensitized cancer cells in the combined treatment. Our findings demonstrate that the combination of tetrandrine and H89 exhibits an enhanced therapeutic effect and may become a promising therapeutic strategy for cancer patients. They also indicate a significant clinical application of tetrandrine in the treatment of human cancer. Moreover, the combination of H89/tetrandrine provides new selectively targeted therapeutic strategies for patients with c-Myc amplification. The online version of this article (10.1186/s13046-018-0779-2) contains supplementary material, which is available to authorized users.
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影响因子：
16
作者：
Bhola PD;Letai A
通讯作者：
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影响因子：
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作者：
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影响因子：
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DOI：
10.1124/jpet.105.100032
发表时间：
2006-08-01
影响因子：
3.5
作者：
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通讯作者：
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影响因子：
78.5
作者：
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通讯作者：
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