Piperlonguminine and Piperine Analogues as TrxR Inhibitors that Promote ROS and Autophagy and Regulate p38 and Akt/mTOR Signaling,Journal of Natural Products

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Piperlonguminine and Piperine Analogues as TrxR Inhibitors that Promote ROS and Autophagy and Regulate p38 and Akt/mTOR Signaling
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-10-07 , DOI: 10.1021/acs.jnatprod.0c00599
Peng Zhu _{1,

2} , Jianqiang Qian ₁ , Zhongyuan Xu ₁ , Chi Meng ₁ , Ji Liu ₁ , Wenpei Shan ₁ , Weizhong Zhu ₁ , Yongjun Wang ₃ , Yumin Yang _{1,

3} , Wei Zhang ₂ , Yanan Zhang ₁ , Yong Ling _{1,

2}

Affiliation

The natural products piperlongumine and piperine have been shown to inhibit cancer cell proliferation through elevation of reactive oxidative species (ROS) and eventually cell death, but only have modest cytotoxic potencies. A series of 14 novel phenylallylidenecyclohexenone analogues based on piperlongumine and piperine therefore were designed and synthesized, and their pharmacological properties were evaluated. Most of the compounds produced antiproliferative activities against five human cancer cells with IC₅₀ values lower than those of piperlongumine and piperine. Among these, compound 9m exerted the most potent antiproliferative activity against drug-resistant Bel-7402/5-FU human liver cancer 5-FU resistant cells (IC₅₀ = 0.8 μM), which was approximately 10-fold lower than piperlongumine (IC₅₀ = 8.4 μM). Further, 9m showed considerably lower cytotoxicity against LO2 human normal liver epithelial cells compared to Bel-7402/5-FU. Mechanistically, compound 9m inhibited thioredoxin reductase (TrxR) activity, increased ROS levels, reduced mitochondrial transmembrane potential (MTP), and induced autophagy in Bel-7402/5-FU cells via regulation of autophagy-related proteins LC3, p62, and beclin-1. Finally, 9m activated significantly the p38 signaling pathways and suppressed the Akt/mTOR signaling pathways. In conclusion, 9m could be a promising candidate for the treatment of drug-resistant cancer cells and, as such, warrants further investigation.

中文翻译：

Piperlonguminine 和 Piperine 类似物作为 TrxR 抑制剂，促进 ROS 和自噬并调节 p38 和 Akt/mTOR 信号转导

天然产物胡椒长明和胡椒碱已被证明可以通过提高活性氧化物质（ROS）并最终抑制细胞死亡来抑制癌细胞增殖，但仅具有适度的细胞毒性效力。因此，设计并合成了一系列基于胡椒长明和胡椒碱的14种新型苯基烯丙环己烯酮类似物，并评估了它们的药理学特性。大多数化合物对五种人类癌细胞产生抗增殖活性，IC ₅₀值低于胡椒长明和胡椒碱。其中，化合物9m对耐药Bel-7402/5-FU人肝癌5-FU耐药细胞发挥最有效的抗增殖活性（IC ₅₀ = 0.8 μM），比胡椒长明（IC _50）低约10倍。 = 8.4 μM）。此外，与 Bel-7402/5-FU 相比， 9m对 LO2 人正常肝上皮细胞的细胞毒性显着降低。从机制上讲，化合物9m抑制硫氧还蛋白还原酶 (TrxR) 活性，增加 ROS 水平，降低线粒体跨膜电位 (MTP)，并通过调节自噬相关蛋白 LC3、p62 和 beclin- 诱导 Bel-7402/5-FU 细胞中的自噬。 1.最后， 9m显着激活 p38 信号通路并抑制 Akt/mTOR 信号通路。总之， 9m可能是治疗耐药癌细胞的有希望的候选者，因此值得进一步研究。

更新日期：2020-10-26

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