Hsp90 Inhibitor; NVP-AUY922 in Combination with Doxorubicin Induces Apoptosis and Downregulates VEGF in MCF-7 Breast Cancer Cell Line

Abstract

Objective: Breast cancer is one of the most prevalent malignancies and leading causes of females’ mortality worldwide. Because of resistance to various treatment options, new treatments based on molecular targeting has introduced as noticeable strategies in cancer treatment. In this regard, heat shock protein 90 (Hsp90) inhibitors are proposed as effective anticancer drugs. The goal of the study was to utilize a combination of the doxorubicin (DOX) and NVP-AUY 922 on the MCF-7 breast cancer model to investigate the possible cytotoxic mechanisms. Methods: MCF-7 breast cancer cell line was prepared and treated with various concentrations of DOX and NVP-AUY922 in single-drug treatments. We investigated the growth-inhibitory pattern by MTT assay after continuous exposure to NVP-AUY922 and DOX in order to determine dose-response. Then the combinatorial effects were evaluated in concentrations of 0.5 × IC 50 , 0.2 × IC 50 , 1 × IC 50 and, 2 × IC 50 of each drugs. Based on MTT results of double combinations, low effective doses were selected for Real-time PCR [caspase3 and vascular endothelial growth factor (VEGF)] and caspase 3 enzyme activity. Results: A dose-dependent inhibitory effects were presented with increasing the doses of both drugs in single treatments. The upregulation of caspase 3 and downregulation of VEGF mRNA were observed in double combinations of NVP-AUY922 and DOX versus single treatments. Also, in these combinations in low doses of examined drugs (0.5 × IC 50 , 0.2 × IC 50 ), higher caspase 3 activity were presented in comparison to single treatments (p<0.05). Conclusions: Our findings indicate an effective action of NVP-AUY922 in combined with DOX in this cell line. These results can predict the treatment outcome in this model.

Effects of Radiotherapy in Combination With Irinotecan and 17-AAG on Bcl-2 and Caspase 3 Gene Expression in Colorectal Cancer Cells

“…Thus, evaluating effective treatments and related molecular mechanisms are important. 22,48,[61][62][63] In this study, increased efficacy of radiotherapy with 17-AAG and irinotecan may be related to apoptosis induction and accelerate radiation sensitivity. In fact, the induction of apoptosis and Bcl-2 downregulation are engaged in possible mechanisms of 17-AAG in combination cases with anti-cancer agent and radiation.…”

Cytotoxic and Radiosensitizing Effects of Folic Acid-Conjugated Gold Nanoparticles and Doxorubicin on Colorectal Cancer Cells

“…The resistance to cancer therapies is not frequently exclusive and the cancer cells can be resistant to several treatments. 38 Consequently, evaluating the cancer cell response to new treatments for enhancing the treatment outcome is necessary. 39,40 Thus, in this study we aimed to evaluate the effects of DOX and GNP-F in combination with radiotherapy in CRC cells.…”

The Chaperone System in Breast Cancer: Roles and Therapeutic Prospects of the Molecular Chaperones Hsp27, Hsp60, Hsp70, and Hsp90

“…The combination of Ganetespib with paclitaxel and TZMB is well tolerated and safe in a heavily pretreated population of HER2-positive metastatic breast cancer [ 139 ] ( Table 1 ). In addition to Ganetespib, there are other second-generation Hsp90 inhibitors that are in preclinical or clinical testing in patients with BC, such as NVP-AUY922 (resorcinol derivative) [ 146 ], PU-H71 (purine derivative) [ 147 ], and other inhibitors of the benzamide class, including XL888.…”