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Danazol has potential to cause PKC translocation, cell cycle dysregulation, and apoptosis in breast cancer cells
Author(s) -
Deka Suman Jyoti,
Roy Ashalata,
Ramakrishnan Vibin,
Manna Debasis,
Trivedi Vishal
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12921
Subject(s) - danazol , apoptosis , cancer cell , protein kinase c , microbiology and biotechnology , cell cycle , cancer research , viability assay , programmed cell death , biology , chemistry , cancer , signal transduction , biochemistry , medicine , endometriosis , genetics
Danazol, the established clinical drug, has given promising therapeutic results in a series of clinical trials with breast cancer patients. Danazol shares structural similarities with several known PKC agonists and fits well into the C1 domain. Danazol binds to the C1b domain of PKC with K d of 5.64 ± 1.27 μ m . MD simulation studies further support that the PKC –danazol molecular model is stable and showing minimum distortion to the structure during the simulation period. Immunofluorescence and Western blotting studies indicate that MDAMB ‐231 cells stimulated with danazol exhibit translocation of PKC α to the plasma membrane. Cells stimulated with danazol causes appearance of several phosphorylated proteins in lysate and plasma membrane. In addition, danazol affects carcinogenic molecule ( PMA )‐induced intracellular signaling in cancer cells. It halted the cancer cells in the G1 phase of the cell cycle and reduced the viability of ER +ve and triple‐negative breast cancer cells with an IC 50 of 31 ± 2.63 and 65 ± 4.27 μg/ml, respectively. DNA fragmentation and flow cytometry experiments revealed that the cell death follows the apoptotic pathway. It affects mitochondrial membrane potentials and releases cytochrome‐ C from mitochondria to induce downstream apoptosis in breast cancer cells. Hence, the current study may help clinicians to re‐design their treatment strategy to optimize therapeutic potentials of the molecule.