RT Journal Article
T1 PARP1 inhibition by Olaparib reduces the lethality of pancreatic cancer cells and increases their sensitivity to Gemcitabine.
A1 Quiñonero, Francisco
A1 Mesas, Cristina
A1 Muñoz-Gamez, Jose A
A1 Jimenez-Luna, Cristina
A1 Perazzoli, Gloria
A1 Prados, Jose
A1 Melguizo, Consolacion
A1 Ortiz, Raul
K1 Drug resistance
K1 Gemcitabine
K1 Olaparib
K1 PARP1
K1 Pancreatic cancer
AB 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.
PB Elsevier Masson
YR 2022
FD 2022-09-05
LK http://hdl.handle.net/10668/22049
UL http://hdl.handle.net/10668/22049
LA en
NO 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.
NO This work was supported by the Project Innbio INB-009 (Granada University and ibs. GRANADA), Project DTS17/00081 (Instituto de Salud Carlos III) and by the CTS-107 Group and Projects A-CTS-666-UGR20  and  B-CTS-122-UGR20  of the Junta de Andalucía (FEDER) (Spain). FQ acknowledges the  FPU2018  grant from the Ministerio de Educación, Ciencia y Deporte y Competitividad (Spain). We thank Instrumentation Scientific Center (CIC) from University of Granada for technical assistance.
DS RISalud
RD Apr 17, 2025