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: We studied the responses of CTOS to high-dose chemotherapeutics, which are used in IVC for patients with NMIBC after TUR. To provide a reproducible setting, we first analyzed CTOS from a patient-derived xenograft of bladder cancer, BC23.24 We investigated delivery of EPI into CTOS after exposure to high-dose EPI (1 mg/mL), which is used in clinical settings. It is clinically recommended that high-dose chemotherapeutics be retained for 1–2 h after they are instilled into the patient's bladder. Thus, we conducted a 2-h time-course experiment. We took advantage of the intrinsic fluorescence of EPI to monitor drug delivery. Fluorescence microscopy analysis (Fig.2a) and flow cytometric analysis (Fig.2b) revealed that EPI was promptly and homogeneously distributed into the cancer cells comprising CTOS. According to flow cytometric analysis, EPI levels in cancer cells reached a plateau within 1 h. Notably, spheroidal shape was maintained intact even after 2 h exposure to high-dose EPI.
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.