TY - JOUR
T1 - The first-in-class pro-apoptotic peptide PEP-010 is effective in monotherapy and in combination with paclitaxel on resistant ovarian adenocarcinoma cell models
AU - Lacroix, Aline
AU - Farhat, Rayan
AU - Robert, Aude
AU - Brenner, Catherine
AU - Wiels, Joëlle
AU - Germini, Diego
N1 - Publisher Copyright:
Copyright © 2024 Lacroix, Farhat, Robert, Brenner, Wiels and Germini.
PY - 2024/1/1
Y1 - 2024/1/1
N2 - 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 IC50 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.
AB - 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 IC50 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.
KW - apoptosis
KW - combination therapy
KW - monotherapy
KW - ovarian adenocarcinoma
KW - peptide
UR - http://www.scopus.com/inward/record.url?scp=85201635958&partnerID=8YFLogxK
U2 - 10.3389/fphar.2024.1444973
DO - 10.3389/fphar.2024.1444973
M3 - Article
AN - SCOPUS:85201635958
SN - 1663-9812
VL - 15
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 1444973
ER -