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High-dose chemotherapeutics of intravesical chemotherapy rapidly induce mitochondrial dysfunction in bladder cancer-derived spheroids.

Yoshida T, Okuyama H, Nakayama M, Endo H, Nonomura N, Nishimura K, Inoue M - Cancer Sci. (2014)

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.

View Article: PubMed Central - PubMed

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.

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Rapid decrease of ATP levels in cancer-tissue originated spheroids (CTOS) after exposure to high-dose epirubicin (EPI) and mitomycin C (MMC). (a) Time course of ATP levels in CTOS after exposure to EPI or MMC (1 mg/mL). (b) ATP levels in CTOS after 2-h exposure to indicated concentrations of EPI or MMC. (c) ATP levels were measured after 2-h exposure to MMC (1 mg/mL) with the indicated concentration of DPQ or cyclosporine A (CsA). DMSO was used as a vehicle control. All values are presented relative to control.
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fig04: Rapid decrease of ATP levels in cancer-tissue originated spheroids (CTOS) after exposure to high-dose epirubicin (EPI) and mitomycin C (MMC). (a) Time course of ATP levels in CTOS after exposure to EPI or MMC (1 mg/mL). (b) ATP levels in CTOS after 2-h exposure to indicated concentrations of EPI or MMC. (c) ATP levels were measured after 2-h exposure to MMC (1 mg/mL) with the indicated concentration of DPQ or cyclosporine A (CsA). DMSO was used as a vehicle control. All values are presented relative to control.

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).


High-dose chemotherapeutics of intravesical chemotherapy rapidly induce mitochondrial dysfunction in bladder cancer-derived spheroids.

Yoshida T, Okuyama H, Nakayama M, Endo H, Nonomura N, Nishimura K, Inoue M - Cancer Sci. (2014)

Rapid decrease of ATP levels in cancer-tissue originated spheroids (CTOS) after exposure to high-dose epirubicin (EPI) and mitomycin C (MMC). (a) Time course of ATP levels in CTOS after exposure to EPI or MMC (1 mg/mL). (b) ATP levels in CTOS after 2-h exposure to indicated concentrations of EPI or MMC. (c) ATP levels were measured after 2-h exposure to MMC (1 mg/mL) with the indicated concentration of DPQ or cyclosporine A (CsA). DMSO was used as a vehicle control. All values are presented relative to control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317779&req=5

fig04: Rapid decrease of ATP levels in cancer-tissue originated spheroids (CTOS) after exposure to high-dose epirubicin (EPI) and mitomycin C (MMC). (a) Time course of ATP levels in CTOS after exposure to EPI or MMC (1 mg/mL). (b) ATP levels in CTOS after 2-h exposure to indicated concentrations of EPI or MMC. (c) ATP levels were measured after 2-h exposure to MMC (1 mg/mL) with the indicated concentration of DPQ or cyclosporine A (CsA). DMSO was used as a vehicle control. All values are presented relative to control.
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).

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.

View Article: PubMed Central - PubMed

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
Related in: MedlinePlus