Piperlonguminine and Piperine Analogues as TrxR Inhibitors that Promote ROS and Autophagy and Regulate p38 and Akt/mTOR Signaling

J Nat Prod. 2020 Oct 23;83(10):3041-3049. doi: 10.1021/acs.jnatprod.0c00599. Epub 2020 Oct 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemical synthesis
  • Alkaloids / chemistry
  • Alkaloids / pharmacology*
  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Agents, Phytogenic / chemical synthesis
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Autophagy / drug effects*
  • Benzodioxoles / chemical synthesis
  • Benzodioxoles / chemistry
  • Benzodioxoles / pharmacology*
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dioxolanes / chemical synthesis
  • Dioxolanes / chemistry
  • Dioxolanes / pharmacology*
  • Drug Resistance, Neoplasm / drug effects
  • Fluorouracil / pharmacology
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Molecular Structure
  • Oncogene Protein v-akt / drug effects*
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Polyunsaturated Alkamides / chemical synthesis
  • Polyunsaturated Alkamides / chemistry
  • Polyunsaturated Alkamides / pharmacology*
  • Reactive Oxygen Species
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / drug effects*
  • Thioredoxin Reductase 1 / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / drug effects*

Substances

  • Alkaloids
  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents, Phytogenic
  • Benzodioxoles
  • Dioxolanes
  • Piperidines
  • Polyunsaturated Alkamides
  • Reactive Oxygen Species
  • TXNRD1 protein, human
  • Thioredoxin Reductase 1
  • MTOR protein, human
  • Oncogene Protein v-akt
  • TOR Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • piperlongumine
  • Fluorouracil
  • piperine