Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells
Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells
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DOI：
10.3892/or.2016.4867
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发表时间：
2016-08-01
期刊：
影响因子：
4.2
通讯作者：
Kumakura, Shunichi
中科院分区：
文献类型：
--
作者：
Kasukabe, Takashi;Honma, Yoshio;Kumakura, Shunichi
胰腺癌是最具侵袭性的胃肠道恶性肿瘤之一，由于其化疗耐药性和预后不良，目前的化疗药物治疗效果有限。因此，迫切需要开发新药或有效的联合疗法。 Cotylenin A (CN-A)（一种植物生长调节剂）是骨髓性白血病细胞分化的有效诱导剂，并在多种癌细胞系中表现出有效的抗肿瘤活性。在本研究中，我们证明 CN-A 和异硫氰酸苯乙酯 (PEITC)（一种活性氧 (ROS) 诱导剂和膳食抗癌化合物）可协同抑制 MIAPaCa-2、PANC-1 和吉西他滨耐药 PANC-1 细胞的增殖。 CN-A 和 PEITC 的联合治疗也有效抑制了这些癌细胞的非贴壁依赖性生长。 CN-A 和 PEITC 联合处理在 1 天内强烈诱导细胞死亡，其浓度单独使用 CN-A 或 PEITC 不会影响细胞活力。合成 CN-A 衍生物（ISIR-005 和 ISIR-042）或 Fusicoccin J（CN-A 相关天然产物）和 PEITC 联合治疗对细胞死亡没有协同作用。 CN-A和PEITC联合处理协同诱导ROS的产生。抗氧化剂（N-乙酰半胱氨酸和曲乐）、铁死亡抑制剂（ferrostatin-1 和 liproxstatin）和溶酶体铁螯合剂去铁胺取消了协同细胞死亡。凋亡抑制剂（Z-VAD-FMK 和 Q-VD-OPH）和坏死抑制剂 necrostatin-1s 不能抑制协同细胞死亡。自噬抑制剂（3-甲基腺嘌呤和氯喹）可部分阻止细胞死亡。这些结果表明CN-A和PEITC联合处理诱导的协同细胞死亡主要是由于铁死亡的诱导。因此，CN-A 和 PEITC 的组合具有作为胰腺癌新治疗策略的潜力。
The treatment of pancreatic cancer, one of the most aggressive gastrointestinal tract malignancies, with current chemotherapeutic drugs has had limited success due to its chemoresistance and poor prognosis. Therefore, the development of new drugs or effective combination therapies is urgently needed. Cotylenin A (CN-A) (a plant growth regulator) is a potent inducer of differentiation in myeloid leukemia cells and exhibits potent antitumor activities in several cancer cell lines. In the present study, we demonstrated that CN-A and phenethyl isothiocyanate (PEITC), an inducer of reactive oxygen species (ROS) and a dietary anticarcinogenic compound, synergistically inhibited the proliferation of MIAPaCa-2, PANC-1 and gemcitabine-resistant PANC-1 cells. A combined treatment with CN-A and PEITC also effectively inhibited the anchorage-independent growth of these cancer cells. The combined treatment with CN-A and PEITC strongly induced cell death within 1 day at concentrations at which CN-A or PEITC alone did not affect cell viability. A combined treatment with synthetic CN-A derivatives (ISIR-005 and ISIR-042) or fusicoccin J (CN-A-related natural product) and PEITC did not have synergistic effects on cell death. The combined treatment with CN-A and PEITC synergistically induced the generation of ROS. Antioxidants (N-acetylcysteine and trolox), ferroptosis inhibitors (ferrostatin-1 and liproxstatin), and the lysosomal iron chelator deferoxamine canceled the synergistic cell death. Apoptosis inhibitors (Z-VAD-FMK and Q-VD-OPH) and necrosis inhibitor necrostatin-1s did not inhibit synergistic cell death. Autophagy inhibitors (3-metyladenine and chloroquine) partially prevented cell death. These results show that synergistic cell death induced by the combined treatment with CN-A and PEITC is mainly due to the induction of ferroptosis. Therefore, the combination of CN-A and PEITC has potential as a novel therapeutic strategy against pancreatic cancer.