The first-in-class pro-apoptotic peptide PEP-010 is effective in monotherapy and in combination with paclitaxel on resistant ovarian adenocarcinoma cell models.

Autor: Lacroix A; PEP-Therapy, Paris, France., Farhat R; PEP-Therapy, Paris, France., Robert A; UMR1279 INSERM, Université Paris-Saclay, Villejuif, France., Brenner C; CNRS UMR9018, Metabolic and Systemic Aspects of Oncogenesis for New Therapeutic Approaches, Université Paris-Saclay, Villejuif, France., Wiels J; CNRS UMR9018, Metabolic and Systemic Aspects of Oncogenesis for New Therapeutic Approaches, Université Paris-Saclay, Villejuif, France., Germini D; PEP-Therapy, Paris, France.
Jazyk: angličtina
Zdroj: Frontiers in pharmacology [Front Pharmacol] 2024 Aug 07; Vol. 15, pp. 1444973. Date of Electronic Publication: 2024 Aug 07 (Print Publication: 2024).
DOI: 10.3389/fphar.2024.1444973
Abstrakt: Ovarian adenocarcinoma is the gynecological malignancy with the worst prognosis and the highest mortality rate. In the first stages of treatment, chemotherapy results effective, but its prolonged use and high doses lead to the appearance of resistance to treatments and relapse in most patients, representing a major challenge for clinicians. We developed PEP-010, a cell penetrating proapoptotic peptide disrupting the protein-protein interaction between caspase-9 and protein phosphatase 2A, thereby leading to the recovery of their activity in the apoptotic pathway. MTT assay or Annexin-V/Propidium Iodide staining and flow cytometry analysis were used to assess sensitivity to chemotherapies and apoptosis after treatment with PEP-010 in monotherapy or in combination with paclitaxel in ovarian carcinoma cell lines. DNA damage was assessed by immunofluorescence using γH2AX marker. We show here that PEP-010 effectively induces cell death in monotherapy on in up to 55% of cells from ovarian adenocarcinoma cell models resistant to different chemotherapies. Moreover, when used in combination with paclitaxel, one of the therapeutic options for recurrent ovarian carcinoma, PEP-010 showed a beneficial effect leading to the reduction of the IC 50 of paclitaxel of 2.2 times and to apoptosis in 87% of cells. The described results suggest the potential therapeutic interest for PEP-010 and lead to the choice of ovarian adenocarcinoma as one of the major indications of the ongoing clinical trial.
Competing Interests: Authors AL, RF, and DG were employed by PEP-Therapy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Lacroix, Farhat, Robert, Brenner, Wiels and Germini.)
Databáze: MEDLINE
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