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A Rhenium Isonitrile Complex Induces Unfolded Protein Response‐Mediated Apoptosis in Cancer Cells
Author(s) -
King A. Paden,
Marker Sierra C.,
Swanda Robert V.,
Woods Joshua J.,
Qian ShuBing,
Wilson Justin J.
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201902223
Subject(s) - apoptosis , unfolded protein response , endoplasmic reticulum , chemistry , programmed cell death , hyperphosphorylation , microbiology and biotechnology , cancer cell , cisplatin , flow cytometry , mitochondrion , cancer research , biology , biochemistry , cancer , phosphorylation , genetics , chemotherapy
Complexes of the element Re have recently been shown to possess promising anticancer activity through mechanisms of action that are distinct from the conventional metal‐based drug cisplatin. In this study, we report our investigations on the anticancer activity of the complex [Re(CO) 3 (dmphen)( p ‐tol‐ICN)] + (TRIP) in which dmphen=2,9‐dimethyl‐1,10‐phenanthroline and p ‐tol‐ICN= para ‐tolyl isonitrile. TRIP was synthesized by literature methods and exhaustively characterized. This compound exhibited potent in vitro anticancer activity in a wide variety of cell lines. Flow cytometry and immunostaining experiments indicated that TRIP induces intrinsic apoptosis. Comprehensive biological mechanistic studies demonstrated that this compound triggers the accumulation of misfolded proteins, which causes endoplasmic reticulum (ER) stress, the unfolded protein response, and apoptotic cell death. Furthermore, TRIP induced hyperphosphorylation of eIF2α, translation inhibition, mitochondrial fission, and expression of proapoptotic ATF4 and CHOP. These results establish TRIP as a promising anticancer agent based on its potent cytotoxic activity and ability to induce ER stress.