Publication:
PARP1 inhibition by Olaparib reduces the lethality of pancreatic cancer cells and increases their sensitivity to Gemcitabine.

Loading...
Thumbnail Image

Date

2022-09-05

Authors

Quiñonero, Francisco
Mesas, Cristina
Muñoz-Gamez, Jose A
Jimenez-Luna, Cristina
Perazzoli, Gloria
Prados, Jose
Melguizo, Consolacion
Ortiz, Raul

Advisors

Journal Title

Journal ISSN

Volume Title

Publisher

Elsevier Masson
Metrics
Google Scholar
Export

Research Projects

Organizational Units

Journal Issue

Abstract

Pancreatic cancer (PC) is one of the tumors with the lowest survival rates due to the poor efficacy of the treatments currently used. Gemcitabine (GMZ), one of the chemotherapeutic agents employed when the tumor is unresectable, frequently fails due to the development of drug resistance. PARP1 is a relevant protein in this phenomenon and appears to be related to cancer progression in several types of tumors, including PC. To determine the relevance of PARP1 in the development and treatment of PC, we used the Panc02 cell line to generate modified PC cells with stably inhibited PARP1 expression (Panc02-L) and used GMZ, Olaparib (OLA) and GMZ+OLA as therapeutic strategies. Viability, radiosensitization, angiogenesis, migration, colony formation, TUNEL, cell cycle, multicellular tumorsphere induction and in vivo assays were performed to test the influence of PARP1 inhibition on resistance phenomena and tumor progression. We demonstrated that stable inhibition or pharmacological blockade of PARP1 using OLA-sensitized Panc02 cells against GMZ significantly decreased their IC50, reducing colony formation capacity, cell migration and vessel formation (angiogenesis) in vitro. Furthermore, in vivo analyses revealed that Panc02-L-derived (PARP1-inhibited) tumors showed less growth and lethality, and that GMZ+OLA treatment significantly reduced tumor growth. In conclusion, PARP1 inhibition, both alone and in combination with GMZ, enhances the effectiveness of this chemotherapeutic agent and represents a promising strategy for the treatment of PC.

Description

MeSH Terms

Humans
Xenograft Model Antitumor Assays
Cell Line, Tumor
Poly (ADP-Ribose) Polymerase-1
Pancreatic Neoplasms
Antineoplastic Agents
Gemcitabine

DeCS Terms

Antineoplásicos
Ensayos antitumor por modelo de xenoinjerto
Gemcitabina
Humanos
Línea celular tumoral
Neoplasias pancreáticas
Poli(ADP-Ribosa) polimerasa-1

CIE Terms

Keywords

Drug resistance, Gemcitabine, Olaparib, PARP1, Pancreatic cancer

Citation

Quiñonero F, Mesas C, Muñoz-Gámez JA, Jiménez-Luna C, Perazzoli G, Prados J, et al. PARP1 inhibition by Olaparib reduces the lethality of pancreatic cancer cells and increases their sensitivity to Gemcitabine. Biomed Pharmacother. 2022 Nov;155:113669.