A Rhenium Isonitrile Complex Induces Unfolded Protein Response-Mediated Apoptosis in Cancer Cells.
A Paden KingSierra C MarkerRobert V SwandaJoshua J WoodsShu-Bing QianJustin J WilsonPublished in: Chemistry (Weinheim an der Bergstrasse, Germany) (2019)
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.
Keyphrases
- endoplasmic reticulum
- cell death
- endoplasmic reticulum stress
- flow cytometry
- cell cycle arrest
- oxidative stress
- anti inflammatory
- binding protein
- protein protein
- systematic review
- diffuse large b cell lymphoma
- amino acid
- diabetic rats
- drug induced
- transcription factor
- emergency department
- long non coding rna
- small molecule
- cell proliferation
- case control
- electronic health record