Induction of ROS-independent JNK-activation-mediated apoptosis by a novel coumarin-derivative, DMAC, in human colon cancer cells

Mei Hsiang Lin, Chia Hsiung Cheng, Ku Chung Chen, Wai Theng Lee, Yen Fang Wang, Cai Qin Xiao, Cheng Wei Lin

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)42-49
Number of pages8
JournalChemico-Biological Interactions
Volume218
DOIs
Publication statusPublished - Jul 25 2014

Keywords

  • Apoptosis
  • Coumarin
  • MAPK
  • Reactive oxygen species

ASJC Scopus subject areas

  • Toxicology

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