Hsp90 Inhibitors NVP-AUY922 and NVP-BEP800 May Exert a Significant Radiosensitization on Tumor Cells along with a Cell Type-Specific Cytotoxicity

Abstract

Targeting heat shock protein 90 (Hsp90) provides a promising therapeutic approach to enhance the sensitivity of tumor cells to ionizing radiation (IR). To explore the impact of scheduling drug-IR administration, in the present study, we analyzed the response of lung carcinoma A549 and glioblastoma SNB19 cells to simultaneous drug-IR treatment followed by a long-term drug administration. Cellular response was evaluated at different time intervals after IR-alone, drug-alone, or combined drug-IR treatments by colony counts and expression profiles of Hsp90 and its clients, along with several apoptotic markers and cell cycle-related proteins, as well as by IR-drug-induced cell cycle arrest, DNA damage, and repair. A short 30-minute exposure to either Hsp90 inhibitor did not affect the radiosensitivity of both tumor cell lines. Increasing the duration of post-IR-drug treatment progressively enhanced the sensitivity of SNB19 cells to IR. In contrast, the response of A549 cells to drug-IR combination was largely determined by the cytotoxic effects of both drugs without radiosensitization. Combined drug-IR treatment induced more severe DNA damage in both tumor cell lines than each treatment alone and also protracted the kinetics of DNA damage repair in SNB19 cells. In addition to large cell cycle disturbances, drug-IR treatment also caused depletion of the antiapoptotic proteins Akt and Raf-1 in both cell lines, along with a decrease of survivin in A549 cells in case of NVP-AUY922. The data show that simultaneous Hsp90 inhibition and irradiation may induce cell type-specific radiosensitization as well as cytotoxicity against tumor cells.

Dual PI3K- and mTOR-inhibitor PI-103 can either enhance or reduce the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in tumor cells: The role of drug-irradiation schedule

“…A number of anticancer agents including several inhibitors of Hsp90 are known to synergistically enhance the cytotoxicity of IR. Numerous studies, including our own, have already explored Hsp90 as a potential target for tumor cells' radiosensitization [9–11]. A major drawback of Hsp90 inhibition, however, is that it causes up-regulation of Hsp90 itself and his major co-chaperone Hsp70, thereby promoting cell survival by inhibition of caspase-dependent and –independent cell death [13].…”

“…It also exhibits strong antiproliferative activity against various tumor cell lines and primary tumors in vitro and in vivo at well-tolerated doses [31]. We have shown previously that NVP-AUY922 can radiosensitize diverse tumor cell lines [10, 11]. …”

“…Indeed, a number of studies have already explored Hsp90 as a potential molecular target for tumor cells' radiosensitization [9–11]. Thus, various geldanamycin (17-DMAG or 17-AAG) or ansamycin derivatives (NVP-AUY922 or NVP-BEP800) significantly enhance the radiosensitivity of tumor cell lines derived from a variety of histologies, including glioma, prostate, and lung carcinoma [9–11]. …”

Hsp90 Inhibitor Ganetespib Sensitizes Non–Small Cell Lung Cancer to Radiation but Has Variable Effects with Chemoradiation

“…As Hsp90 inhibitors are known to affect the cell cycle checkpoint (19, 21–24, 35, 36), as does irradiation, which causes a G1/S arrest in P53 WT cells (37), we next determined the interaction of radiation with ganetespib on the cell cycle effects in both H460 and A549 cells (Figure 3A–D). G2/M arrest was induced by ganestepib, radiation, and the combination, at 4 hours postirradiation.…”

“…These sensitizing effects are the result of the Hsp90 inhibitor-mediated abrogation of the G2 checkpoint, apoptosis and the inhibition of DNA repair. Studies have shown that one of the causes of sensitization could be inhibition of DNA double strand break (DSB) repair (17–21, 36). Checkpoint arrest mainly at G2/M phase has also been suggested as a cause of radiosensitization with Hsp90 inhibitors (19–24, 36).…”