Combination treatment with doxorubicin and gamitrinib synergistically augments anticancer activity through enhanced activation of Bim.
Combination treatment with doxorubicin and gamitrinib synergistically augments anticancer activity through enhanced activation of Bim.
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DOI：
10.1186/1471-2407-14-431
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发表时间：
2014-06-13
期刊：
影响因子：
3.8
通讯作者：
Kang BH
中科院分区：
文献类型：
--
作者：
Park HK;Lee JE;Lim J;Jo DE;Park SA;Suh PG;Kang BH
在临床实践中，癌症治疗的一种常见方法是组合几种药物以增强可用药物的抗癌活性，同时抑制其不希望的副作用。在这方面，我们研究了广泛使用的遗传毒性药物阿霉素和神经毒性Hsp 90抑制剂gamitrinib联合治疗的疗效，以利用不同的应激信号通路进行癌症治疗。通过MTT法分析药物作为单一药剂或组合对几种癌细胞类型的细胞毒性，并通过计算组合指数来评价药物组合的协同作用。为了了解药物协同作用的分子机制，分析了药物联合后的应激信号通路。使用具有乳腺癌和前列腺癌细胞的两种异种移植物模型来评估药物组合的体内抗癌活性。通过组织组织学和血清肌酸磷酸激酶浓度评估药物毒性。Gamitrinib使多种人类癌细胞对阿霉素治疗敏感，并且与两种药物的联合治疗协同增加细胞凋亡。药物组合的细胞毒性涉及促凋亡Bcl-2家族成员Bim的活化和线粒体积累。Bim的激活与促凋亡转录因子C/EBP同源蛋白的表达增加和应激激酶c-Jun N-末端激酶的激活增强相关。在前列腺和乳腺异种移植模型中，多柔比星和加米替尼的联合药物治疗显著降低了体内肿瘤生长，而不增加心脏毒性。该药物组合显示出对各种癌细胞的协同抗癌活性，而不会加重多柔比星的心脏毒性副作用，这表明多柔比星的全部治疗潜力可以通过与gamitrinib组合来释放。
A common approach to cancer therapy in clinical practice is the combination of several drugs to boost the anticancer activity of available drugs while suppressing their unwanted side effects. In this regard, we examined the efficacy of combination treatment with the widely-used genotoxic drug doxorubicin and the mitochondriotoxic Hsp90 inhibitor gamitrinib to exploit disparate stress signaling pathways for cancer therapy. The cytotoxicity of the drugs as single agents or in combination against several cancer cell types was analyzed by MTT assay and the synergism of the drug combination was evaluated by calculating the combination index. To understand the molecular mechanism of the drug synergism, stress signaling pathways were analyzed after drug combination. Two xenograft models with breast and prostate cancer cells were used to evaluate anticancer activity of the drug combination in vivo. Cardiotoxicity was assessed by tissue histology and serum creatine phosphokinase concentration. Gamitrinib sensitized various human cancer cells to doxorubicin treatment, and combination treatment with the two drugs synergistically increased apoptosis. The cytotoxicity of the drug combination involved activation and mitochondrial accumulation of the proapoptotic Bcl-2 family member Bim. Activation of Bim was associated with increased expression of the proapoptotic transcription factor C/EBP-homologous protein and enhanced activation of the stress kinase c-Jun N-terminal kinase. Combined drug treatment with doxorubicin and gamitrinib dramatically reduced in vivo tumor growth in prostate and breast xenograft models without increasing cardiotoxicity. The drug combination showed synergistic anticancer activities toward various cancer cells without aggravating the cardiotoxic side effects of doxorubicin, suggesting that the full therapeutic potential of doxorubicin can be unleashed through combination with gamitrinib.
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影响因子：
16.2
作者：
Putcha, GV;Le, SY;Johnson, EM
通讯作者：
Johnson, EM
DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
50.3
作者：
Chae YC;Caino MC;Lisanti S;Ghosh JC;Dohi T;Danial NN;Villanueva J;Ferrero S;Vaira V;Santambrogio L;Bosari S;Languino LR;Herlyn M;Altieri DC
通讯作者：
Altieri DC
影响因子：
5.8
作者：
Lopez-Royuela, Nuria;Perez-Galan, Patricia;Marzo, Isabel
通讯作者：
Marzo, Isabel
影响因子：
45.3
作者：
Liedtke, Cornelia;Mazouni, Chafika;Pusztai, Lajos
通讯作者：
Pusztai, Lajos