Ganetespib radiosensitization for liver cancer therapy.
Ganetespib radiosensitization for liver cancer therapy.
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DOI：
10.1080/15384047.2016.1156258
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发表时间：
2016-04-02
影响因子：
3.6
通讯作者：
Tran PT
中科院分区：
文献类型：
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作者：
Chettiar ST;Malek R;Annadanam A;Nugent KM;Kato Y;Wang H;Cades JA;Taparra K;Belcaid Z;Ballew M;Manmiller S;Proia D;Lim M;Anders RA;Herman JM;Tran PT
肝癌的治疗方法，特别是包括放射治疗在内的治疗方法仍然不足。抑制应激反应机制是一种有吸引力的抗癌和放射增敏治疗策略。热休克蛋白 90 (HSP90) 是一种分子伴侣，是应激反应机制的重要效应子，在肝癌细胞中过度表达。 HSP90 客户蛋白包括与肝癌细胞存活和放射抗性相关的途径的关键成分。使用体外克隆存活、细胞凋亡、细胞周期分布、γH2AX 病灶动力学和对肝癌存活和放射抗性重要的途径中的客户蛋白表达，检查了新型非格尔德霉素 HSP90 抑制剂 ganetespib 与放射组合对 3 种肝癌细胞系 Hep3b、HepG2 和 HUH7 的影响。然后，我们在 HepG2 后胁腹肿瘤移植模型中评估了肿瘤生长延迟以及联合 ganetespib 放射治疗对肿瘤细胞增殖的影响。纳摩尔水平的 ganetespib 单独在体外表现出肝癌细胞抗癌活性，表现为克隆形成存活率降低，这与细胞凋亡增加、显着的 G2-M 停滞以及 PI3K/AKT/mTOR 和 RAS/MAPK 客户蛋白活性的显着变化有关。 Ganetespib 在低纳摩尔剂量下对所有肝癌细胞系产生超加性放射增敏作用，增强比率在 1.33-1.78 之间。这些结果在体内得到了证实，在 HepG2 肿瘤移植物中，与单独使用任何一种疗法相比，ganetespib-放射联合疗法产生了超累加的肿瘤生长延迟。我们的数据表明，ganetespib 联合放射治疗对肝癌细胞表现出有希望的活性，应该在临床研究中进行研究。
Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33–1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies.