Abstract
We studied a role of the inducible heat shock protein 70 (Hsp70) in cellular response to radiosensitizing treatments with inhibitors of the heat shock protein 90 (Hsp90) chaperone activity. Cell lines derived from solid tumors of different origin were treated with the Hsp90 inhibitors (17AAG, geldanamycin, radicicol, NVP-AUY922) or/and γ-photon radiation. For comparison, human cells of the non-cancerous origin were subjected to the same treatments. We found that the Hsp90 inhibitors yielded considerable radiosensitization only when they cause early and pronounced Hsp70 induction; moreover, a magnitude of radiosensitization was positively correlated with the level of Hsp70 induction. The quantification of Hsp70 levels in Hsp90 inhibitor-treated normal and cancer cells enabled to predict which of them will be susceptible to any Hsp90-inhibiting radiosensitizer as well as what concentrations of the inhibitors ensure the preferential cytotoxicity in the irradiated tumors without aggravating radiation damage to adjacent normal tissues. Importantly, the Hsp70 induction in the Hsp90 inhibitor-treated cancer cells appears to be their protective response that alleviates the tumor-sensitizing effects of the Hsp90 inactivation. Combination of the Hsp70-inducing inhibitors of Hsp90 with known inhibitors of the Hsp induction such as quercetin, triptolide, KNK437, NZ28 prevented up-regulation of Hsp70 in the cancer cells thereby increasing their post-radiation apoptotic/necrotic death and decreasing their post-radiation viability/clonogenicity. Similarly, co-treatment with the two inhibitors conferred the enhanced radiosensitization of proliferating rather than quiescent human vascular endothelial cells which may be used for suppressing the tumor-stimulated angiogenesis. Thus, the easily immunodetectable Hsp70 induction can be a useful marker for predicting effects of Hsp90-inhibiting radiosensitizers on tumors and normal tissues exposed to ionizing radiation. Moreover, targeting the Hsp70 induction in Hsp90 inhibitor-treated cancer cells and tumor vasculature cells may beneficially enhance the radiosensitizing effect.
Highlights
In fight against cancer, radiotherapy is a powerful modality and often used for treating solid malignancies
In MCF-7/ MDR1 cells, in which the intracellular accumulation of all heat shock protein 90 (Hsp90) inhibitors was suppressed owing to the overexpression of transmembrane P-glycoprotein working as a drug-excluding pump [32], the level of inducible heat shock protein 70 (Hsp70) was significantly lower than in wild type MCF-7 cells subjected to the same inhibitory treatment (Table 1)
During studying effects of the Hsp90 inhibitors (17AAG, NVP-AUY922, geldanamycin and radicicol) on the cellular radiation response, we found that 35–500 nM of the drugs significantly increased the radiosensitivity of MCF-7, human uterine cervical carcinoma (HeLa), KTC-1, PC-3, Myc-CaP, HT 1080 and A549 cancer cell lines as well as actively proliferating endothelial cells, i.e. only those cell cultures in which the prominent Hsp70 induction was found after the inhibitory treatment
Summary
Radiotherapy is a powerful modality and often used for treating solid malignancies. In order to develop an appropriate radiosensitizer, it is necessary to perform preliminary research on identification of molecular targets responsible for radioresistance of cancer cells and the focused screening of various agents interacting with those targets In this respect, heat shock proteins, in particular, the 90 kDa and 70 kDa heat shock proteins (Hsp and Hsp, respectively) seem to be the promising molecular targets for radiosensitization of tumors. Hsp and Hsp are the major ATP-dependent cytosolic chaperones functioning as regulators of protein molecule conformations and protectors from cellular stresses [1,2] Both chaperones are known to be involved in carcinogenesis, while their increased expression/activity in malignant cells is often correlated to the tumor progression, aggressiveness and resistance to therapeutics. That is why Hsp and Hsp are considered as very promising molecular targets for anticancer therapy and an active search of clinically applicable inhibitors of Hsps currently goes on
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