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.
Radio- and chemoresistance of cancer stem cells (CSCs) is considered as one of the possible causes of adverse results of chemoradiotherapy for various malignancies, including cervical cancer. However, little is known about quantitative changes in the CSC subpopulation in the course of treatment and mechanisms for individual response of CSCs to therapy. The purpose of the study was to evaluate the association of radiation response of cervical CSCs with clinical and morphological parameters of disease and features of human papillomavirus (HPV) infection. The proportion of CD44+CD24low CSCs was determined by flow cytometry in cervical scrapings from 55 patients with squamous cell carcinoma of uterine cervix before treatment and after fractionated irradiation at a total dose of 10 Gy. Real-time PCR assay was used to evaluate molecular parameters of HPV DNA. Post-radiation increase in the CSC proportion was found in 47.3% of patients. Clinical and morphological parameters (stage, status of lymph node involvement, and histological type) were not significantly correlated with radiation changes in the CSC proportion. Single- and multifactor analyses revealed two independent indicators affecting the radiation response of CSCs: initial proportion of CSCs and physical status of HPV DNA (R = 0.86, p = 0.001 for the multiple regression model in the whole).
We studied the effect of dipeptide gamma-d-Glu-d-Trp (thymodepressin) on migration of CD34+ hemopoietic precursors and their direct adhesion to fibronectin in tumor-bearing mice on days 8, 11, 15, and 17 of tumor growth and on expression of CXCR-4 (CD184+) to SDF-1 and integrin beta1 (CD29+) by bone marrow cells. In tumor-bearing mice treated with gamma-d-Glu-d-Trp, the percent of CD34+ hemopoietic precursors in the peripheral blood considerably decreased throughout the observation period; the content of CD34+ hemopoietic precursors in the tumor tissue was 2-3-fold below the control against the background of increased content of CD34+ cells in the bone marrow. In animals treated with the peptide, the content of cells expressing CXCR-4 in the peripheral blood, bone marrow, and tumor tissue significantly decreased, while the percent of cells expressing integrin beta1 receptor (CD29+) in the bone marrow increased 2-fold, which was paralleled by an almost 2-fold increase in the percent of cells binding to fibronectin. We hypothesized that dipeptide gamma-d-Glu-d-Trp suppressed mobilization/migration of CD34+ hemopoietic precursor cells from the bone marrow to the peripheral blood of tumor-bearing mice.
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