Inhibition of heat shock protein 90 sensitizes melanoma cells to thermosensitive ferromagnetic particle-mediated hyperthermia with low Curie temperature
Inhibition of heat shock protein 90 sensitizes melanoma cells to thermosensitive ferromagnetic particle-mediated hyperthermia with low Curie temperature
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DOI：
10.1111/j.1349-7006.2008.01072.x
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发表时间：
2009-03-01
期刊：
影响因子：
5.7
通讯作者：
Ogawa, Jun-ichi
中科院分区：
文献类型：
--
作者：
Ito, Aki;Saito, Hajime;Ogawa, Jun-ichi
热休克蛋白（Hsp）90是多种癌基因产物和细胞信号分子的关键调节因子，并且已经研究了其抑制与放射或化学疗法组合的治疗益处。此外，热疗已被用于治疗各种恶性肿瘤多年。我们先前描述了一种系统，其中使用居里温度（Tc = 43摄氏度）低到足以介导自动温度控制的热敏铁磁颗粒（FMP）诱导高热，并在小鼠黑色素瘤模型中证明了其抗肿瘤作用。在本研究中，我们研究了结合热休克蛋白90抑制剂（格尔德霉素; GA）与FMP介导的热疗的抗肿瘤作用。在培养的B16黑色素瘤细胞中，GA通过增加细胞对高温的敏感性和降低Akt的表达来发挥抗肿瘤作用。在体内研究中，将黑素瘤细胞皮下注射到C57 BL/6小鼠的背部。然后将FMP注射到所得肿瘤中，并将小鼠分为四组：组I，无治疗（对照）;组II，一次热疗治疗;组III，单独GA;和组IV，GA与热疗。当暴露于磁场时，含有FMP的组织的温度升高并稳定在Tc。在组IV中，在9只小鼠中的5只（56%）中观察到肿瘤完全消退，而在组I-III中未观察到肿瘤消退。我们的研究结果表明，抑制热休克蛋白90与高温增加其抗肿瘤作用。因此，FMP介导的自我调节热疗与Hsp 90抑制的组合对于癌症的治疗具有重要意义。（Cancer Sci 2009; 100：558-564）。
Heat shock protein (Hsp) 90 is a key regulator of a variety of oncogene products and cell-signaling molecules, and the therapeutic benefit of its inhibition in combination with radiation or chemotherapy has been investigated. In addition, hyperthermia has been used for many years to treat various malignant tumors. We previously described a system in which hyperthermia was induced using thermosensitive ferromagnetic particles (FMP) with a Curie temperature (Tc = 43 degrees C) low enough to mediate automatic temperature control, and demonstrated its antitumor effect in a mouse melanoma model. In the present study, we examined the antitumor effects of combining a Hsp90 inhibitor (geldanamycin; GA) with FMP-mediated hyperthermia. In cultured B16 melanoma cells, GA exerted an antitumor effect by increasing the cells' susceptibility to hyperthermia and reducing expression of Akt. In an in vivo study, melanoma cells were subcutaneously injected into the backs of C57BL/6 mice. FMP were then injected into the resultant tumors, and the mice were divided into four groups: group I, no treatment (control); group II, one hyperthermia treatment; group III, GA alone; and group IV, GA with hyperthermia. When exposed to a magnetic field, the temperature of tissues containing FMP increased and stabilized at the Tc. In group IV, complete regression of tumors was observed in five of nine mice (56%), whereas no tumor regression was seen in groups I-III. Our findings suggest that inhibition of Hsp90 with hyperthermia increases its antitumor effect. Thus, the combination of FMP-mediated, self-regulating hyperthermia with Hsp90 inhibition has important implications for the treatment of cancer. (Cancer Sci 2009; 100: 558-564).