Concurrent use of DNA damaging agents with PARP inhibitors contribute to the effectiveness of the anticancer therapy. But there is a dearth of reports on the antiangiogenic effects of PARP inhibitors and the suppression of angiogenesis by this drug combination is not yet reported. For the successful development of cancer therapeutics, anti-cancer drugs ought to have anti-angiogenic potentiality along with their DNA damaging abilities. In this current piece of work, we investigated the in vitro and in ovo anti-angiogenic effect of Curcumin and Veliparib (a PARP inhibitor) in oral cancer. Recent evidences suggest an involvement of the NECTIN-4 in cancer angiogenesis and the exact molecular pathway of this involvement remains to be delineated. We observed that the soluble NECTIN-4 secreted from H357 oral cancer cells enhanced the angiogenesis of endothelial cells (HUVECs) and this was inhibited by Curcumin-Veliparib combination. NECTIN-4 enhanced vascularization, induced vasodilation and triggered the angiogenic sprouting via endothelial tip cell filopodia. Data indicated that NECTIN-4 mediated angiogenesis is associated with PI3K-AKT-mediated nitric oxide (NO) formation. A noticeable increase in the NO enhanced epithelial NO level through HIF-1α mediated iNOS activation. We observed that increased NO enhanced the NECTIN-4 mediated eNOS expression and thereby elicited further angiogenesis. Curcumin antagonised the NECTIN-4-induced angiogenesis through inhibition of PI3K-AKT mediated eNOS pathway and Veliparib synergized the effect of Curcumin. Our observations indicate that NO is cardinal in inducing NECTIN-4 mediated angiogenesis in H357 cells. Thus, Curcumin-Veliparib combination suppresses angiogenesis through deregulation of the PI3K-AKT-eNOS pathway downstream to the NECTIN-4.

DNA损伤剂与PARP抑制剂的同时使用有助于抗癌治疗的有效性。但是关于PARP抑制剂的抗血管生成作用的报道很少，而且这种药物组合对血管生成的抑制作用也没有报道。为了成功开发癌症疗法，抗癌药物应该具有抗血管生成的潜力以及它们的DNA损伤能力。在目前的这项工作中，我们研究了体外和卵内姜黄素和维利帕尼（一种 PARP 抑制剂）在口腔癌中的抗血管生成作用。最近的证据表明 NECTIN-4 参与了癌症血管生成，这种参与的确切分子途径仍有待描述。我们观察到 H357 口腔癌细胞分泌的可溶性 NECTIN-4 增强了内皮细胞 (HUVEC) 的血管生成，而姜黄素-Veliparib 组合抑制了这一点。NECTIN-4 增强血管形成，诱导血管舒张并通过内皮尖端细胞丝状伪足触发血管生成萌芽。数据表明 NECTIN-4 介导的血管生成与 PI3K-AKT 介导的一氧化氮 (NO) 形成有关。通过 HIF-1α 介导的 iNOS 激活，NO 的显着增加增强了上皮 NO 水平。我们观察到增加的 NO 增强了 NECTIN-4 介导的 eNOS 表达，从而引发了进一步的血管生成。姜黄素通过抑制 PI3K-AKT 介导的 eNOS 通路拮抗 NECTIN-4 诱导的血管生成，维利帕尼协同姜黄素的作用。我们的观察表明，NO 是诱导 H357 细胞中 NECTIN-4 介导的血管生成的主要因素。因此，姜黄素-Veliparib 组合通过放松 NECTIN-4 下游的 PI3K-AKT-eNOS 通路来抑制血管生成。