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An indolylquinoline derivative promotes apoptosis in human lung cancer cells by impairing mitochondrial functions

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Abstract

A number of effective anti-cancer drugs contain either indole or quinoline group. Compounds fused indole and quinoline moieties altogether as indolylquinoline were rarely reported as anti-cancer agents. We reported here that a synthetic indolylquinoline derivative, 3-((7-ethyl-1H-indol-3-yl)-methyl)-2-methylquinoline (EMMQ), inhibited the growth of human non-small cell lung cancer (NSCLC) cells in dose- and time-dependent manners. The cytotoxicity was mediated through apoptotic cell death that began with mitochondrial membrane potential interruption and DNA damage. EMMQ caused transient elevation of p53 that assists in cytochrome c release, cleavage of downstream PARP and procaspase-3 and mitochondria-related apoptosis. The degree of apoptotic cell death depends on the status of tumor suppressor p53 of the target cells. H1299 cells with stable ectopic expression of p53 induced cytotoxicity by disrupting mitochondria functions that differed with those transfected with mutant p53. Knocking-down of p53 attenuated drug effects. EMMQ suppressed the growth of A549 tumor cells in xenograft tumors by exhibiting apoptosis characteristics. Given its small molecular weight acting as an effective p53 regulator in NSCLC cells, EMMQ could be an addition to the current list of lung cancer treatment.

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Acknowledgments

This work is supported by Grants from National Taiwan Normal University (99D, 103T3040B2 and 104T3040C2). Technical assistance of College of Life Science and Instrumentation Center, National Taiwan University with the confocal laser microscopy is appreciated.

Author Contribution

Chun-Yen Liu and Pei-Tsen Wu designed and performed experiments, discussed and interpreted the data. Jing-Ping Wang, Po-Wei Fan, Chang-Hung Hsieh and JG performed experiments. Ching-Fa Yao provided and purified the tested material. Chun-Li Su and Chien-Chih Chiu gave suggestion on study design, discussed and interpreted the data. Kang Fang designed, supervised study, discussed, interpreted the data and wrote the manuscript. All authors read and approved the final manuscript.

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    Authors and Affiliations

    1. Department of Life Science, National Taiwan Normal University, 88 Ting-Chow Rd, Sec 4, Taipei, 116, Taiwan

      Chun-Yen Liu, Pei-Tsen Wu, Jing-Ping Wang, Po-Wei Fan, Chang-Hung Hsieh & Kang Fang

    2. Department of Human Development and Family Studies, National Taiwan Normal University, Taipei, Taiwan

      Chun-Li Su

    3. Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan

      Chien-Chih Chiu

    4. Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan

      Ching-Fa Yao

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    1. Chun-Yen Liu
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    All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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    Chun-Yen Liu and Pei-Tsen Wu have contributed equally.

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    Liu, CY., Wu, PT., Wang, JP. et al. An indolylquinoline derivative promotes apoptosis in human lung cancer cells by impairing mitochondrial functions. Apoptosis 20, 1471–1482 (2015). https://doi.org/10.1007/s10495-015-1165-6

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