The PARP inhibitor olaparib enhances the cytotoxicity of combined gemcitabine, busulfan and melphalan in lymphoma cells

Abstract

The combination of gemcitabine (Gem), busulfan (Bu) and melphalan (Mel) is a promising regimen for autologous stem-cell transplantation (SCT) for lymphomas. To further improve the efficacy of [Gem+Bu+Mel], we added PARP inhibitor olaparib (Ola). We hypothesized that Ola would inhibit the repair of damaged DNA caused by [Gem+Bu+Mel]. Exposure of J45.01 and Toledo cell lines to IC10–20 of individual drug inhibited proliferation by 6%–16%; [Gem+Bu+Mel] by 20%–27%; and [Gem+Bu+Mel+Ola] by 61%–67%. The synergistic cytotoxicity of the 4-drug combination may be attributed to activation of the DNA-damage response, inhibition of PARP activity and DNA repair, decreased mitochondrial membrane potential, increased production of reactive oxygen species, and activation of the SAPK/JNK stress signaling pathway, all of which may enhance apoptosis. Similar observations were obtained using mononuclear cells isolated from patients with T-cell lymphocytic leukemia. Our results provide a rationale for undertaking clinical trials of this drug combination for lymphoma patients undergoing SCT.

High PARP-1 expression Predicts Poor Survival in Acute Myeloid Leukemia and PARP-1 Inhibitor and SAHA-Bendamustine Hybrid Inhibitor Combination Treatment Synergistically Enhances Anti-Tumor Effects

“…However, long-term survival of AML patients remains poor for refractory/relapse cases [44][45][46]. We hope to explore new treatments that induce DNA PARP-1 plays a pivotal role in DNA repair, particularly in response to DNA-damaging agents [47,48]. We found that PARP-1 was highly expressed in CN-AML patients and AML cell lines compared to normal BM donors.…”

High PARP-1 expression predicts poor survival in acute myeloid leukemia and PARP-1 inhibitor and SAHA-bendamustine hybrid inhibitor combination treatment synergistically enhances anti-tumor effects

“…PARP-1 plays a pivotal role in DNA repair, particularly in response to DNA-damaging agents [47,48]. We found that PARP-1 was highly expressed in CN-AML patients and AML cell lines compared to normal BM donors.…”

Metformin Affects Olaparib Sensitivity through Induction of Apoptosis in Epithelial Ovarian Cancer Cell Lines

“…The simultaneous occurrence of both types of cellular stress may transmit signals to the mitochondria, as suggested by the decreased mitochondrial membrane potential due to increased ROS production ( Figure 3 B). Such mitochondrial stress is triggered by DNA damage, which also induces apoptosis by phosphorylating mitochondrial proteins involved in the release of cytochrome c [ 71 ]. Metformin combined with 2.5 mM glucose upregulates cytosolic cytochrome c in SKOV3 cells and decreases mitochondrial membrane potential, suggesting that low glucose and metformin trigger cell apoptosis through the mitochondria-associated pathway [ 38 ].…”