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Induction of ROS-independent JNK-activation-mediated apoptosis by a novel coumarin-derivative, DMAC, in human colon cancer cells.
- Source :
-
Chemico-biological interactions [Chem Biol Interact] 2014 Jul 25; Vol. 218, pp. 42-9. Date of Electronic Publication: 2014 May 06. - Publication Year :
- 2014
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Abstract
- In this study, we investigated the antitumor activity of a novel coumarin derivative, 5,7-dihydroxy-4-methyl-6-(3-methylbutanoyl)-coumarin (DMAC), on colorectal carcinoma. DMAC treatment resulted in substantial proapoptotic activity against colon cancer HCT116 and LoVo cells. Induction of apoptotic characteristics, including cellular shrinkage, chromatin condensation, and Annexin V detection, was observed following DMAC treatment. Mechanistically, we observed that DMAC elicited induction of proteolytic cascade activation including cleavage of caspase-3 and poly ADP-ribose polymerase (PARP) expression and loss of the antiapoptotic proteins, Mcl-1 and Bcl-XL, accompanied by an increase in expression of the proapoptotic protein, Bak. In addition, suppressing c-Jun N-terminal protein kinase (JNK), but not extracellular-regulated protein kinase (ERK) or p38, substantially diminished DMAC-induced cell death and caspase-3 and PARP cleavage. However, pretreatment with antioxidants, including N-acetyl-l-cysteine (NAC) and diphenylene iodonium (DPI), failed to protect against DMAC-elicited apoptosis. Pretreatment with the JNK inhibitor, SP600125, suppressed DMAC-induced JNK phosphorylation, which was accompanied by a reversal of Bcl-XL expression. Moreover, combining DMAC treatment with the conventional anticancer drugs, 5-FU and CPT-11, considerably enhanced their therapeutic efficacies. Structural-activity relationship analyses further revealed that an alkylation substitution at position 6 of the coumarin ring was critical for inducing apoptosis, and the phenyl group at position 4 might have enhanced its bioactivity. Our data showed that DMAC can be used as part of a promising strategy to enhance therapeutic efficacies, and could be used to develop an approach for structure-based drug design for cancer treatment.<br /> (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Antineoplastic Agents chemistry
Arsenicals chemistry
Blotting, Western
Cell Line, Tumor
Colonic Neoplasms
Coumarins chemistry
Cysteine chemistry
Cysteine pharmacology
Enzyme Activation drug effects
Humans
Molecular Structure
Antineoplastic Agents pharmacology
Apoptosis drug effects
Arsenicals pharmacology
Cysteine analogs & derivatives
JNK Mitogen-Activated Protein Kinases metabolism
Reactive Oxygen Species
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7786
- Volume :
- 218
- Database :
- MEDLINE
- Journal :
- Chemico-biological interactions
- Publication Type :
- Academic Journal
- Accession number :
- 24812029
- Full Text :
- https://doi.org/10.1016/j.cbi.2014.04.015