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Antiapoptotic mechanism of cannabinoid receptor 2 agonist on cisplatin-induced apoptosis in the HEI-OC1 auditory cell line

Authors

  • Hyun-Ja Jeong,

    1. Department of Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
    2. College of Pharmacy, VestibuloCochlear Research Center of Wonkwang University, Jeonbuk, Republic of Korea
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  • Su-Jin Kim,

    1. Department of Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
    2. College of Pharmacy, VestibuloCochlear Research Center of Wonkwang University, Jeonbuk, Republic of Korea
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  • Phil-Dong Moon,

    1. Department of Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
    2. College of Pharmacy, VestibuloCochlear Research Center of Wonkwang University, Jeonbuk, Republic of Korea
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  • Na-Hyun Kim,

    1. College of Pharmacy, VestibuloCochlear Research Center of Wonkwang University, Jeonbuk, Republic of Korea
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  • Jung-Sun Kim,

    1. College of Pharmacy, VestibuloCochlear Research Center of Wonkwang University, Jeonbuk, Republic of Korea
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  • Rae-Kil Park,

    1. Vestibulocochlear Research Center and Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk, Republic of Korea
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  • Min-Sun Kim,

    1. Vestibulocochlear Research Center and Department of Physiology, Wonkwang University School of Medicine, Jeonbuk, Republic of Korea
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  • Byung-Rim Park,

    1. Vestibulocochlear Research Center and Department of Physiology, Wonkwang University School of Medicine, Jeonbuk, Republic of Korea
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  • Sejin Jeong,

    1. Basic Institute of Natural Science, Wonkwang University, Jeonbuk, Republic of Korea
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  • Jae-Young Um,

    1. Department of Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
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  • Hyung-Min Kim,

    1. Department of Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
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  • Seung-Heon Hong

    Corresponding author
    1. College of Pharmacy, VestibuloCochlear Research Center of Wonkwang University, Jeonbuk, Republic of Korea
    • College of Pharmacy, VestibuloCochlear Research Center of Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea
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Abstract

Cisplatin is a highly effective chemotherapeutic agent but with significant ototoxic side effects. Apoptosis is an important mechanism of cochlear hair cell loss following exposure to an ototoxic level of cisplatin. The present study investigated the effects of the cannabinoid receptor 2 (CB2) ligand JWH-015 on cisplatin-induced apoptosis. CB2 mRNA was constitutively expressed in the auditory cell line HEI-OC1. By using MTT assay, DNA fragmentation, and FACS analysis, we demonstrated that apoptosis induced by cisplatin was inhibited by treatment with JWH-015 in a dose-dependent manner. Activation of caspase-3, caspase-8, and caspase-9 was detected after treatment with cisplatin, and the cleavage of poly-(ADP)-ribose polymerase (PARP) was observed within cisplatin-treated HEI-OC1 cells. JWH-015 inhibited the activation of caspase-3, caspase-8, and caspase-9; cleavage of PARP; and release of cytochrome c. JWH-015 also inhibited the apoptosis through activation of the extracellular signal-regulated kinase pathway. Finally, JWH-015 inhibited cisplatin-induced reactive oxygen species and tumor necrosis factor-α production. Collectively, these findings show that blocking a critical step in apoptosis by using JWH-015 may be a useful strategy to prevent harmful side effects of cisplatin ototoxicity in patients having to undergo chemotherapy. © 2006 Wiley-Liss, Inc.

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