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Mitochondria-targeted platinum(II) complexes induce apoptosis-dependent autophagic cell death mediated by ER-stress in A549 cancer cells.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2018 Jul 15; Vol. 155, pp. 639-650. Date of Electronic Publication: 2018 Jun 09. - Publication Year :
- 2018
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Abstract
- Agents with multiple modes of tumor cell death can be effective chemotherapeutic drugs. One example of a bimodal chemotherapeutic approach is an agent that can induce both apoptosis and autophagic death. Thus far, no clinical anticancer drug has been shown to simultaneously induce both these pathways. Mono-functional platinum complexes are potent anticancer drug candidates which act through mechanisms distinct from cisplatin. Here, we describe the synthesis and characterize of two mono-functional platinum complexes containing 8-substituted quinoline derivatives as ligands, [PtL <subscript>1</subscript> Cl]Cl [L <subscript>1</subscript>  = (Z)-1-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) methanamine] (Mon-Pt-1) and [PtL <subscript>2</subscript> Cl]Cl [L <subscript>2</subscript>  = (Z)-2-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) ethanamine] (Mon-Pt-2). In comparison to cisplatin, Mon-Pt-2 exhibited a greater in vitro cytotoxicity, was more effective in resistant cells and elicited a better anticancer effect. Mechanistic experiments indicate that Mon-Pt-2 mainly accumulates in mitochondria, and stimulates significant TrxR inhibition ROS release and an ER stress response, mediated by mitochondrial dysfunction, ultimately resulting in a simultaneous induction of apoptosis and autophagy. Importantly, compared to cisplatin, Mon-Pt-2 exhibits lower acute toxicity and better anticancer activity in a murine tumor model. To the best of our knowledge, Mon-Pt-2 is the first mono-functional platinum complex inducing pro-death autophagy and apoptosis of cancer cells.<br /> (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Subjects :
- A549 Cells
Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Death drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Endoplasmic Reticulum Stress drug effects
Humans
Mice
Mice, Inbred Strains
Mice, Nude
Molecular Structure
Neoplasms, Experimental drug therapy
Neoplasms, Experimental pathology
Organoplatinum Compounds chemical synthesis
Organoplatinum Compounds chemistry
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Apoptosis drug effects
Endoplasmic Reticulum drug effects
Mitochondria drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 155
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29935437
- Full Text :
- https://doi.org/10.1016/j.ejmech.2018.06.018