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      Debio-0932, a second generation oral Hsp90 inhibitor, induces apoptosis in MCF-7 and MDA-MB-231 cell lines.

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          Abstract

          Heat shock protein 90 (Hsp90) is a key chaperone that is abnormally expressed in cancer cells, and therefore, designing novel compounds to inhibit chaperone activities of the Hsp90 is a promising therapeutic approach for cancer drug discovery. Debio-0932 is a second-generation Hsp90 inhibitor that exhibited promising anticancer activity against a wide variety of cancer types with a strong binding affinity for Hsp90 and high oral bioavailability. Anticancer activities of the Debio-0932 were tested in MCF-7 and MDA-MB-231 cell lines. Molecular docking results indicated that Debio-0932 was selectively bound to the ATP binding pocket of the Hsp90 with an estimated free energy of binding - 7.24 kcal/mol. Antiproliferative activity of Debio-0932 was determined by XTT assay and Debio-0932 exhibited a cytotoxic effect on MCF-7 and MDA-MB-231 cells in a time and dose-depended manner. Apoptosis inducer role of Debio-0932 was evaluated in MCF-7 and MDA-MB-231 cells with fluorometric apoptosis/necrosis detection kit. Treatment with Debio-0932 stimulated apoptosis in both breast cancer cell lines. mRNA and protein expression levels of Bax, Bcl-2 and Casp-9 were determined in MCF-7 and MDA-MB-231 cells by RT-PCR and Western blotting respectively. Debio-0932 stimulated the down-regulation of anti-apoptotic protein Bcl-2 and the up-regulation of apoptotic protein Bax and cleavage of Casp-9 in cancer cells. Moreover, the anti-invasive potential of Debio-0932 was evaluated in endothelial cells (HUVEC) by wound-healing assay. Debio-0932 decreased the migration of HUVEC cells as compared to the control group. These results indicate that Debio-0932 is a promising compound to treat triple-negative breast cancer and hormone receptor-positive breast cancer, and their metastases.

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          Author and article information

          Journal
          Mol Biol Rep
          Molecular biology reports
          Springer Science and Business Media LLC
          1573-4978
          0301-4851
          Apr 2021
          : 48
          : 4
          Affiliations
          [1 ] Department of Veterinary Medicine, Laboratory and Veterinary Health Program, Artova Vocational School, Tokat Gaziosmanpaşa University, Tokat, Turkey. aykut.ozgur@gop.edu.tr.
          [2 ] TUBITAK Marmara Research Center, Gene Engineering and Biotechnology Institute, Gebze, Turkey.
          [3 ] Department of Biomaterials and Tissue Engineering, Faculty of Engineering and Architecture, Tokat Gaziosmanpaşa University, Tokat, Turkey.
          [4 ] Division of Medical Biology, Department of Basic Medical Sciences, Hamidiye Faculty of Medicine, University of Health Sciences, Turkey, Istanbul, Turkey.
          [5 ] Experimental Medicine Application & Research Center, Validebag Research Park, University of Health Sciences, Istanbul, Turkey.
          [6 ] Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Tokat Gaziosmanpaşa University, Tokat, Turkey.
          Article
          10.1007/s11033-021-06392-z
          10.1007/s11033-021-06392-z
          33999319
          7562aeb3-dae6-424b-a19c-45234d492ed7
          History

          MDA-MB-231,Breast cancer,Chemotherapy,Debio-0932,Hsp90,MCF-7
          MDA-MB-231, Breast cancer, Chemotherapy, Debio-0932, Hsp90, MCF-7

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