High-dose chemotherapeutics of intravesical chemotherapy rapidly induce mitochondrial dysfunction in bladder cancer-derived spheroids.
Bottom Line: Two hours after exposure to MMC, the mitochondrial membrane potential decreased and the mitochondria were fragmented, while plasma membrane integrity was maintained.ATP levels rapidly decreased in CTOS after exposure to EPI or MMC.In the CTOS prepared directly from 19 surgical specimens exposed to EPI and MMC, the decrease of ATP levels varied among patients.
Affiliation: Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan; Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.Show MeSH
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Mentions: Because a collapse of Δψm can lead to ATP depletion,27,29 we measured ATP levels in CTOS after exposure to high-dose chemotherapeutics. The ATP levels in CTOS decreased rapidly after exposure to high-dose EPI and MMC, reaching a nadir within 1 h. At 2 h, ATP levels in EPI-treated and MMC-treated CTOS were approximately 20% and 30% of the levels of non-treated CTOS, respectively, and were reduced in a dose-dependent manner (Fig.4a,b). An inhibitor of cyclophilin D, CsA, and an inhibitor of PARP, DPQ, reportedly rescue necrosis by suppressing the ATP decrease caused by oxidative stress30 and alkylating DNA damage,31 respectively. Neither CsA nor DPQ rescued the reduction of ATP levels in CTOS caused by exposure to high-dose MMC (Fig.4c).
Affiliation: Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan; Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.