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Midazolam induces cellular apoptosis in human cancer cells and inhibits tumor growth in xenograft mice

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Molecules and Cells

Abstract

Midazolam is a widely used anesthetic of the benzodiazepine class that has shown cytotoxicity and apoptosisinducing activity in neuronal cells and lymphocytes. This study aims to evaluate the effect of midazolam on growth of K562 human leukemia cells and HT29 colon cancer cells. The in vivo effect of midazolam was investigated in BALB/c-nu mice bearing K562 and HT29 cells human tumor xenografts. The results show that midazolam decreased the viability of K562 and HT29 cells by inducing apoptosis and S phase cell-cycle arrest in a concentration-dependent manner. Midazolam activated caspase-9, capspase-3 and PARP indicating induction of the mitochondrial intrinsic pathway of apoptosis. Midazolam lowered mitochondrial membrane potential and increased apoptotic DNA fragmentation. Midazolam showed reactive oxygen species (ROS) scavenging activity through inhibition of NADPH oxidase 2 (Nox2) enzyme activity in K562 cells. Midazolam caused inhibition of pERK1/2 signaling which led to inhibition of the anti-apoptotic proteins Bcl-XL and XIAP and phosphorylation activation of the pro-apoptotic protein Bid. Midazolam inhibited growth of HT29 tumors in xenograft mice. Collectively our results demonstrate that midazolam caused growth inhibition of cancer cells via activation of the mitochondrial intrinsic pathway of apoptosis and inhibited HT29 tumor growth in xenograft mice. The mechanism underlying these effects of midazolam might be suppression of ROS production leading to modulation of apoptosis and growth regulatory proteins. These findings present possible clinical implications of midazolam as an anesthetic to relieve pain during in vivo anticancer drug delivery and to enhance anticancer efficacy through its ROS-scavenging and pro-apoptotic properties.

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Author notes

  1. Siddhartha Kumar Mishra

    Present address: Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Central University, Sagar, 470003, M.P., India

Authors and Affiliations

  1. Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, 406-840, Korea

    Siddhartha Kumar Mishra, Seung Hyun Oh & Hwan Mook Kim

  2. Division of Cancer Biology, National Cancer Center, Goyang, 410-769, Korea

    Ju-Hee Kang

  3. Department of Food and Nutrition, Division of Natural Sciences, Chung-Ang University, Ansung, 456-756, Korea

    Ju-Hee Kang

  4. Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon, 363-883, Korea

    Chang Woo Lee

  5. Head and Neck Oncology Clinic, Center for Specific Organs Cancer, Center for Thyroid Cancer, National Cancer Center, Goyang, 410-769, Korea

    Jun Sun Ryu

  6. Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul, 120-750, Korea

    Yun Soo Bae

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  1. Siddhartha Kumar Mishra
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Mishra, S.K., Kang, JH., Lee, C.W. et al. Midazolam induces cellular apoptosis in human cancer cells and inhibits tumor growth in xenograft mice. Mol Cells 36, 219–226 (2013). https://doi.org/10.1007/s10059-013-0050-9

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  • DOI: https://doi.org/10.1007/s10059-013-0050-9

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