HSP-90 inhibitor ganetespib is synergistic with doxorubicin in small cell lung cancer.
HSP-90 inhibitor ganetespib is synergistic with doxorubicin in small cell lung cancer.
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晚期SCLC被认为是一种无法治愈的疾病。尽管对初始化疗反应良好，但转移性SCLC患者的反应持续时间短，不可避免地会出现耐药性。尽管一些靶向特异性药物已经改变了许多其他癌症的治疗模式，但我们还没有在SCLC治疗中看到同样规模的革命。蒽环类药物，如阿霉素，在这种疾病中有明确的活性，而ganetespib在临床前模型中显示出有希望的活性，但作为单一药物在SCLC患者中的活性不足。在SCLC细胞系中，我们证明了ganetespib （IC50: 31nM）比格尔达霉素衍生物17-AAG （IC50: 16 μM）更有效。Ganetespib通过诱导持续的G2/M阻滞和Caspase 3依赖性细胞死亡来抑制SCLC细胞的生长。MTS试验显示，ganetespib与多柔比星和依托泊苷协同作用，这两种拓扑异构酶II抑制剂通常用于SCLC化疗。RIP1是一种可能在tnfr1激活的细胞中作为促生存支架蛋白或促死亡激酶的蛋白，它的表达被阿霉素诱导，并被ganetespib下调。RIP1 siRNA或ganetespib对RIP1的消耗都使阿霉素诱导的细胞死亡增敏，这表明RIP1可能促进阿霉素处理细胞的存活，并且ganetespib可能部分通过下调RIP1与阿霉素协同作用。与单独使用ganetespib或阿霉素相比，ganetespib +阿霉素联合使用在免疫受损小鼠中引起的人类SCLC异种移植物生长衰退和死亡显著增加。我们得出结论，在体外和小鼠异种移植模型中，genetespib和阿霉素联合使用显示出显著的协同作用，有效抑制SCLC的生长。我们的临床前研究表明，ganetespib和阿霉素联合治疗可能是一种有效的治疗SCLC的策略，值得临床试验。
SCLC at advanced stage is considered an incurable disease. Despite good response to initial chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for many other cancers, we have yet to witness a revolution of the same magnitude in SCLC treatment. Anthracyclines, such as doxorubicin, have definite activity in this disease, and ganetespib has shown promising activity in preclinical models, but underwhelming activity as a single agent in SCLC patients. Using SCLC cell lines, we demonstrated that ganetespib (IC50: 31nM) was much more potent than 17-AAG, a geldanamycin derivative (IC50: 16 μM). Ganetespib inhibited SCLC cell growth via induction of persistent G2/M arrest and Caspase 3-dependent cell death. MTS assay revealed that ganetespib synergized with both doxorubicin and etoposide, two topoisomerase II inhibitors commonly used in SCLC chemotherapy. Expression of RIP1, a protein that may function as a pro-survival scaffold protein or a pro-death kinase in TNFR1-activated cells, was induced by doxorubicin and downregulated by ganetespib. Depletion of RIP1 by either RIP1 siRNA or ganetespib sensitized doxorubicin-induced cell death, suggesting that RIP1 may promote survival in doxorubicin-treated cells and that ganetespib may synergize with doxorubicin in part through downregulation of RIP1. In comparison to ganetespib or doxorubicin alone, the ganetespib + doxorubicin combination caused significantly more growth regression and death of human SCLC xenografts in immuocompromised mice. We conclude that genetespib and doxorubicin combination exhibits significant synergy and is efficacious in inhibiting SCLC growth in vitro and in mouse xenograft models. Our preclinical study suggests that ganetespib and doxorubicin combination therapy may be an effective strategy for SCLC treatment, which warrants clinical testing.
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DOI：
10.2741/e249
发表时间：
2011-01-01
期刊：
Frontiers in bioscience (Elite edition)
影响因子：
--
作者：
Park, Kang-Seo;Kim, Dae-Seok;Kim, Soo-Youl
通讯作者：
Kim, Soo-Youl
DOI：
10.1186/1478-811x-8-31
发表时间：
2010-12-22
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Chaitanya GV;Steven AJ;Babu PP
通讯作者：
Babu PP
影响因子：
11.4
作者：
Blagosklonny, MV;Fojo, T;Neckers, LM
通讯作者：
Neckers, LM
影响因子：
4.8
作者：
Lewis, J;Devin, A;Liu, ZG
通讯作者：
Liu, ZG
影响因子：
4
作者：
Gangadharan, Charitha;Thoh, Maikho;Manna, Sunil K.
通讯作者：
Manna, Sunil K.