Department of Medical Education and Research, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan.
Int J Oncol. 2018 Mar;52(3):1011-1022. doi: 10.3892/ijo.2018.4259. Epub 2018 Jan 31.
Pancreatic cancer is one of the most lethal types of cancer with a mortality rate of almost 95%. Treatment with current chemotherapeutic drugs has limited success due to poor responses. Therefore, the development of novel drugs or effective combination therapies is urgently required. Piperlongumine (PL) is a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular reactive oxygen species (ROS) levels. In the present study, we demonstrated that PL induced cancer cell death through, at least in part, the induction of ferroptosis, as the cancer cell-killing activity was inhibited by the antioxidant, N‑acetylcysteine, ferroptosis inhibitors (ferrostatin‑1 and liproxstatin‑1) and the iron chelator, deferoxamine (DFO), but not by the apoptosis inhibitor, Z-VAD-FMK, or the necrosis inhibitor, necrostatin‑1. Cotylenin A (CN‑A; a plant growth regulator) exhibits potent antitumor activities in several cancer cell lines, including pancreatic cancer cell lines. We found that CN‑A and PL synergistically induced the death of pancreatic cancer MIAPaCa‑2 and PANC‑1 cells for 16 h. CN‑A enhanced the induction of ROS by PL for 4 h. The synergistic induction of cell death was also abrogated by the ferroptosis inhibitors and DFO. The present results revealed that clinically approved sulfasalazine (SSZ), a ferroptosis inducer, enhanced the death of pancreatic cancer cells induced by PL and the combined effects were abrogated by the ferroptosis inhibitors and DFO. SSZ further enhanced the cancer cell-killing activities induced by combined treatment with PL plus CN‑A. On the other hand, the synergistic induction of cell death by PL and CN‑A was not observed in mouse embryonic fibroblasts (MEFs), and SSZ did not enhance the death of MEFs induced by PL plus CN‑A. These results suggest that the triple combined treatment with PL, CN‑A and SSZ is highly effective against pancreatic cancer.
胰腺癌是致死率几乎达到 95%的最致命癌症之一。由于反应不佳，目前使用的化疗药物治疗收效甚微。因此，迫切需要开发新型药物或有效的联合疗法。胡椒碱是一种天然产物，具有细胞毒性，通过显著增加细胞内活性氧（ROS）水平，将其限制在癌细胞内。在本研究中，我们证明 PL 通过诱导铁死亡导致癌细胞死亡，因为抗氧化剂 N-乙酰半胱氨酸、铁死亡抑制剂（ferrostatin-1 和 liproxstatin-1）和铁螯合剂去铁胺（DFO）抑制了癌细胞杀伤活性，但凋亡抑制剂 Z-VAD-FMK 或坏死抑制剂 necrostatin-1 则没有抑制作用。原花色素 A（CN-A；一种植物生长调节剂）在包括胰腺癌细胞系在内的几种癌细胞系中表现出强大的抗肿瘤活性。我们发现 CN-A 和 PL 协同诱导胰腺癌 MIAPaCa-2 和 PANC-1 细胞在 16 小时内死亡。CN-A 增强了 PL 诱导的 ROS 产生 4 小时。铁死亡抑制剂和 DFO 也阻断了协同诱导的细胞死亡。本研究结果揭示了临床上已批准的铁死亡诱导剂柳氮磺胺吡啶（SSZ）增强了 PL 诱导的胰腺癌细胞死亡，而铁死亡抑制剂和 DFO 则阻断了这种联合作用。SSZ 进一步增强了 PL 与 CN-A 联合治疗诱导的癌细胞杀伤活性。另一方面，PL 和 CN-A 协同诱导的细胞死亡在小鼠胚胎成纤维细胞（MEFs）中未观察到，SSZ 也未增强 PL 与 CN-A 联合诱导的 MEFs 死亡。这些结果表明，PL、CN-A 和 SSZ 的三联联合治疗对胰腺癌非常有效。
