4.6 Article

Prodigiosin Sensitizes Sensitive and Resistant Urothelial Carcinoma Cells to Cisplatin Treatment

Journal

MOLECULES
Volume 26, Issue 5, Pages -

Publisher

MDPI
DOI: 10.3390/molecules26051294

Keywords

prodigiosin; urothelial carcinoma; cisplatin; chemoresistance; autophagy; apoptosis

Funding

  1. Deutsche Forschungsgemeinschaft [STO 864/5-1, STO 864/6-1, GRK 2158]
  2. BMBF [031B0918A]
  3. Dusseldorf School of Oncology - (Comprehensive Cancer Center Dusseldorf/Deutsche Krebshilfe)
  4. Dusseldorf School of Oncology - (Medical Faculty of the Heinrich-Heine-University Dusseldorf)

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Prodigiosin has been shown to block autophagy and sensitize cisplatin-resistant cells to apoptotic cell death in urothelial carcinoma cells. It exhibits potent anticancer activity with nanomolar IC50 values and synergistic effects when combined with cisplatin. The effects of prodigiosin are partially mediated by altering lysosomal function, making it a promising candidate for therapy of cisplatin-resistant urothelial carcinomas.
Cisplatin-based treatment is the standard of care therapy for urothelial carcinomas. However, complex cisplatin resistance mechanisms limit the success of this approach. Both apoptosis and autophagy have been shown to contribute to this resistance. Prodigiosin, a secondary metabolite from various bacteria, exerts different biological activities including the modulation of these two cellular stress response pathways. We analyzed the effect of prodigiosin on protein levels of different autophagy- and apoptosis-related proteins in cisplatin-sensitive and -resistant urothelial carcinoma cells (UCCs). Furthermore, we investigated the effect on cell viability of prodigiosin alone or in combination with cisplatin. We made use of four different pairs of cisplatin-sensitive and -resistant UCCs. We found that prodigiosin blocked autophagy in UCCs and re-sensitized cisplatin-resistant cells to apoptotic cell death. Furthermore, we found that prodigiosin is a potent anticancer agent with nanomolar IC50 values in all tested UCCs. In combination studies, we observed that prodigiosin sensitized both cisplatin-sensitive and -resistant urothelial carcinoma cell lines to cisplatin treatment with synergistic effects in most tested cell lines. These effects of prodigiosin are at least partially mediated by altering lysosomal function, since we detected reduced activities of cathepsin B and L. We propose that prodigiosin is a promising candidate for the therapy of cisplatin-resistant urothelial carcinomas, either as a single agent or in combinatory therapeutic approaches.

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