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Translational Oncology

Translational Oncology

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Niraparib perturbs autophagosome-lysosome fusion in pancreatic ductal adenocarcinoma and exhibits anticancer potential against gemcitabine-resistant PDAC

Published:27 November 2024 DOI: 10.1016/j.tranon.2024.102206
Zehui Yao , Huihui Zhang , Kewei Huang , Guizhong Huang , Pu Xi , Lingmin Jiang , Dailei Qin , Fan Chen , Shengping Li , Ran Wei

Abstract

While poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have achieved specific clinical benefits in a subset of pancreatic ductal adenocarcinoma (PDAC) patients, the potential role of the PARPi niraparib in PDAC necessitates further exploration. In this study, we demonstrated that Niraparib exhibited a pronounced inhibitory effect on autophagy in PDAC both in vitro and in vivo. Mechanistically, this inhibition was primarily attributed to niraparib's ability to disrupt the fusion process between autophagosomes and lysosomes, while potentially exerting a relatively minor impact on the initial stage of autophagy. The blockade effect observed may be mediated via modulation of the ERK signaling pathway, and this effect can be mitigated by the application of an ERK inhibitor (FR180204). Notably, the combined treatment regimen of niraparib and gemcitabine failed to elicit the anticipated synergistic effects in wild-type PANC-1 cells, instead exhibiting pronounced antagonistic interactions. However, in gemcitabine-resistant PANC-1 cells, the combination of niraparib and gemcitabine exhibited modest additive effects. Furthermore, niraparib demonstrated a heightened cytotoxic potency against gemcitabine-resistant PANC-1 cells compared to wild-type PANC-1 cells, both in vitro and in vivo. Our research established that niraparib inhibits late-stage autophagy in PDAC, potentially representing a valuable salvage therapy for gemcitabine-resistant PDAC. Further clinical studies are justified.

Substances (18)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Rapamycin 53123-88-9 C51H79NO13 1040 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1040 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1040 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1040 suppliers $9.00-$6160.00
Gemcitabine 95058-81-4 C9H11F2N3O4 669 suppliers $5.00-$6080.00
Gemcitabine 95058-81-4 C9H11F2N3O4 669 suppliers $5.00-$6080.00
Gemcitabine 95058-81-4 C9H11F2N3O4 669 suppliers $5.00-$6080.00
Gemcitabine 95058-81-4 C9H11F2N3O4 669 suppliers $5.00-$6080.00
CHLOROQUINE 54-05-7 C18H26ClN3 219 suppliers $5.00-$1550.00
CHLOROQUINE 54-05-7 C18H26ClN3 219 suppliers $5.00-$1550.00

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