Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 25, Issue 39, Pages 9206-9210Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201902223
Keywords
bioinorganic chemistry; cancer; endoplasmic reticulum stress; metallodrugs; translation inhibition
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Funding
- Howard Hughes Medical Institute [55108556] Funding Source: Medline
- National Institute of Health [R21CA227917, T32GM008500, R01GM1222814] Funding Source: Medline
- National Science Foundation [DGE-1650441, CHE-1531632] Funding Source: Medline
- NCI NIH HHS [R21 CA227917] Funding Source: Medline
- NIGMS NIH HHS [R01 GM122814, T32 GM008500] Funding Source: Medline
- US Department of Defense [W81XWH-17-1-0097] Funding Source: Medline
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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 eIF2 alpha, 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.
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