Antiapoptotic mechanism of cannabinoid receptor 2 agonist on cisplatin-induced apoptosis in the HEI-OC1 auditory cell line.
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-alpha 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.
Jeong
Hyun-Ja
HJ
Department of Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea.
Kim
Su-Jin
SJ
Moon
Phil-Dong
PD
Kim
Na-Hyun
NH
Kim
Jung-Sun
JS
Park
Rae-Kil
RK
Kim
Min-Sun
MS
Park
Byung-Rim
BR
Jeong
Sejin
S
Um
Jae-Young
JY
Kim
Hyung-Min
HM
Hong
Seung-Heon
SH
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018072:Hair Cells, Auditory, Outer / Q000166:cytology / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D009925:Organ of Corti / Q000166:cytology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007211:Indoles; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D020169:Caspases; D002945:Cisplatin; C402944:JHW 015