AI Article Synopsis
- - Poly(ADP-ribose) polymerase inhibitors (PARPi), like olaparib, are effective in cancer treatment but not all tumors, including those with BRCA1/2 mutations, respond well to them.
- - NADP+ has been identified as a natural inhibitor that could enhance the effectiveness of PARPi, but its clinical use is limited due to its inability to effectively enter cells.
- - This study introduces nanoparticles that release NADP+ in tumor cells, increasing its concentration and working together with olaparib to significantly inhibit tumor growth, suggesting a new approach for cancer therapy.
Article Abstract
Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown success in cancer chemotherapy; however, not all tumors respond effectively to PARPi treatment, even in the presence of BRCA1/2 mutations or homologous recombination (HR) repair defects. NADP+ was recently identified as an endogenous inhibitor of ADP-ribosylation with the potential to sensitize cancer cells to PARPi, yet its lack of membrane permeability poses a significant challenge to its clinical application. In this study, we developed reduction-responsive nanoparticles (NPs) containing disulfide bonds, which can be cleaved in the reductive environment of tumor cells. These NPs encapsulate NADP+ and the commercially available PARP inhibitor olaparib. The uptake of these NPs significantly increases the intracellular concentration of NADP+, which negatively regulates DNA damage-induced PARylation and impairs DNA damage repair. The combined effects of elevated NADP+ levels and olaparib synergistically suppress tumor cell growth. Overall, our study offers a promising strategy for the clinical application of NADP+.
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| http://dx.doi.org/10.1039/d4tb01797h | DOI Listing |
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