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

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.

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

“…More recently, we also observed a similar functional mechanism in the AdipoR-induced osteosarcoma stunting ( Sapio et al, 2020 ). In agreement with the exhibiting findings, our results confirmed the ability of this compound in affecting G0/G1, as well as of Gem in blocking the S-phase ( Miao et al, 2016 ; Montano et al, 2017 ; Waissi et al, 2021 ). Surprisingly, each compound retains its respective peculiarity even when combined.…”

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

“…Rather, the inhibitor forces PARP to become stuck on DNA, thus preventing replication restart and causing RS-induced DNA damage (79). It was also linked to decreased replication fork length with greater ssDNA gaps, which in turn cause more genomic instability at G2/M (80). With all the evidence of PARP inhibitors in RS-induced DNA damage, researchers have reported on various preclinical models of combination therapy with PARP inhibitors and ionizing radiation (IR) (81).…”

PD-1 Inhibitor Maintenance Therapy Combined Iodine-125 Seed Implantation Successfully Salvage Recurrent Cervical Cancer after CCRT: A Case Report

“…As previously mentioned, PARP is an intracellular protein involved in the repair of single and double-stranded DNA breaks [ 7 , 8 ], and radiotherapy exerts its cytotoxic mitotic effects on tumor cells through DNA damage [ 58 , 59 ], so the combination with a PARP inhibitor would sensitize the effect to DNA-damaging induced by radiation. This sensitizing effect has been demonstrated in in vitro studies for both fraction radiotherapy and continuous LDR radiotherapy [ 60 , 61 , 62 , 63 ]; meanwhile, some clinical studies have investigated it [ 64 , 65 ].…”