2. Academic Validation
  3. PARP1 inhibition by Olaparib reduces the lethality of pancreatic cancer cells and increases their sensitivity to Gemcitabine

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

  • Biomed Pharmacother. 2022 Sep 13;155:113669. doi: 10.1016/j.biopha.2022.113669.
Francisco Quiñonero 1,  Cristina Mesas 1,  Jose A Muñoz-Gámez 2,  Cristina Jiménez-Luna 1,  Gloria Perazzoli 1,  Jose Prados 3,  Consolación Melguizo 1,  Raul Ortiz 1
Affiliations

Affiliations

  • 1 Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain; Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada 18071, Spain; Instituto Biosanitario de Granada (ibs. GRANADA), Granada 18014, Spain.
  • 2 Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain.
  • 3 Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain; Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada 18071, Spain; Instituto Biosanitario de Granada (ibs. GRANADA), Granada 18014, Spain. Electronic address: [email protected].
PMID: 36113257 DOI: 10.1016/j.biopha.2022.113669
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.

Keywords

Drug resistance; Gemcitabine; Olaparib; PARP1; Pancreatic cancer.

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