Gemcitabine-Based Chemoradiotherapy Enhanced by a PARP Inhibitor in Pancreatic Cancer Cell Lines.

Waisse Waissi,Carole Mura,Georges Noël,Hélène Burckel,Jean-Christophe Amé

doi:10.3390/ijms22136825

Abstract

Pancreatic ductal adenocarcinoma is a devastating disease with a 5-year overall survival of 9% for all stages. Gemcitabine-based chemoradiotherapy for locally advanced pancreatic cancer is highly toxic. We conducted an in vitro study to determine whether poly(ADP-ribose) polymerase-1 inhibition radiosensitized gemcitabine-based chemotherapy. Human pancreatic cancer cell lines, MIA PaCa-2, AsPC-1, BxPC-3 and PANC-1 were treated with gemcitabine (10 nM) and/or olaparib (1 µM). Low-LET gamma single dose of 2, 5 and 10 Gy radiations were carried out. Clonogenic assay, PAR immunoblotting, cell cycle distribution, γH2Ax, necrotic and autophagic cell death quantifications were performed. Treatment with olaparib alone was not cytotoxic, but highly radiosensitized cell lines, particularly at high dose per fraction A non-cytotoxic concentration of gemcitabine radiosensitized cells, but less than olaparib. Interestingly, olaparib significantly enhanced gemcitabine-based radiosensitization in PDAC cell lines with synergistic effect in BxPC-3 cell line. All cell lines were radiosensitized by the combination of gemcitabine and olaparib, through an increase of unrepaired double-strand, a G2 phase block and cell death. Radiosensitization was increased with high dose of radiation. The combination of olaparib with gemcitabine-based chemoradiotherapy could lead to an enhancement of local control in vivo and an improvement in disease-free survival.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis with a 5-year overall survival of approximately 9% [1]
These data displayed that olaparib at a concentration of 1 μM and gemcitabine at 10 nM were not toxic for PDAC cell lines
Cells co-treated with gemcitabine and olaparib with or without irradiation, did not significantly modify cell cycle distribution, compared to olaparib alone. These results showed that olaparib and irradiation had a combined effect on cell cycle arrest in G2-phase, whereas gemcitabine blocked cells in early S-phase, independently of olaparib and/or irradiation treatment

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis with a 5-year overall survival of approximately 9% [1]. At the time of diagnosis, up to 30% of patients present with unresectable locally advanced pancreatic cancer. In a subset of these patients, failing to control the primary tumor may result in complications that can lead to death. Making unresectable tumors resectable may improve outcomes. As gemcitabine has been shown to both be effective and to enhance radiosensitivity on PDAC cells, chemoradiotherapy (CRT) with gemcitabine is one of the current effective option for treating non-metastatic unresectable pancreatic cancer [2]. Gemcitabine-based CRT has a high of rate toxicity, leading to a reduction of gemcitabine dose or chemotherapy discontinuation. Using modern techniques of radiotherapy such as intensity-modulated radiotherapy (IMRT) or stereotactic body radiotherapy (SBRT) may simultaneously enhance dose to tumor and decrease dose to organ-at-risk, leading to a reduction of gemcitabine-radiation related toxicity. Besides targeted therapies that could be radiosensitizers and/or chemopotentiating agents may enhance this synergy

Objectives

Methods

Results

Discussion

Conclusion