PARP1 inhibitor niraparib exerts synergistic antimyeloma effect with bortezomib through inducing DNA damage and inhibiting DNA repair

Despite the improvements in outcomes for patients with multiple myeloma (MM) over the past decade, the disease remains incurable, and even those patients who initially respond favorably to induction therapy eventually suffer from relapse. Consequently, there is an urgent need for the development of novel therapeutic agents and strategies to enhance the treatment outcomes for patients with MM. The proteasome inhibitor bortezomib (BTZ) elicits endoplasmic reticulum (ER) stress and oxidative stress in MM cells, subsequent DNA damage, ultimately inducing cell apoptosis. Poly (ADP-ribose) polymerase 1 (PARP1) acts as a pivotal enzyme for DNA repair and thus deficient PARP1 renders cells more susceptible to DNA-damaging agents. Conceivably, targeting PARP1 may enhance BTZ-induced DNA damage and cell death in MM cells. In this study, Colony formation, CCK-8, and EdU-labeling assays were conducted to evaluate the effects on MM cell proliferation. The ZIP score was used to assess synergy. Apoptosis and intercellular ROS levels were analyzed using flow cytometry and fluorescence microscopy, respectively. Immunofluorescence and Western blot analyses were used to assess protein expression. The correlation between PARP1 expression levels and the clinical prognosis was examined by tumor-related databases and bioinformatics. The results show that PARP1 is overexpressed in patient MM cells and is associated with a poor prognosis. PARP1 inhibitor niraparib decreases MM cell growth and arrests cell cycle progression at the G2/M phase. When combined with BTZ, it synergistically increases DNA damage, inhibits proliferation, and induces apoptosis. Mechanistically, Niraparib facilitates BTZ-induced ROS elevation, causing DNA double-strand breaks (DSBs), and simultaneously inhibits lesion repair by impeding the expression of repair proteins XRCC1 (X-ray repair cross-complementing protein 1) and POLβ (DNA polymerase beta). Overall, Niraparib plus bortezomib represent a promising approach for treatment of MM.