Effective Killing of Cancer Cells Through ROS-Mediated Mechanisms by AMRI-59 Targeting Peroxiredoxin I.

Abstract

AIMS:

The intrinsic increase of reactive oxygen species (ROS) production in cancer cells after malignant transformation frequently induces redox adaptation, leading to enhanced antioxidant capacity. Peroxiredoxin I (PrxI), an enzyme responsible for eliminating hydrogen peroxide, has been found to be elevated in many types of cancer cells. Since overexpression of PrxI promoted cancer cells' survival and resistance to chemotherapy and radiotherapy, PrxI has been proposed as a therapeutic target for anticancer drugs. In this study, we aimed to investigate the anticancer efficacy of a small molecule inhibitor of PrxI.

RESULTS:

By a high-throughput screening approach, we identified AMRI-59 as a potent inhibitor of PrxI. AMRI-59 increased cellular ROS, leading to the activation of both mitochondria- and apoptosis signal-regulated kinase-1-mediated signaling pathways, resulting in apoptosis of A549 human lung adenocarcinoma. AMRI-59 caused no significant changes in ROS level, proliferation, and apoptosis of PrxI-knockdown A549 cells by RNA interference. PrxI overexpression or N-acetylcysteine pretreatment abrogated AMRI-59-induced cytotoxicity in A549 cells. AMRI-59 rendered tumorigenic ovarian cells more susceptible to ROS-mediated death compared with nontumorigenic cells. Moreover, significant antitumor activity of AMRI-59 was observed in mouse tumor xenograft model implanted with A549 cells with no apparent acute toxicity.

INNOVATION:

This study offers preclinical proof-of-concept for AMRI-59, a lead small molecule inhibitor of PrxI, as an anticancer agent.

CONCLUSIONS:

Our results highlight a promising strategy for cancer therapy that preferentially eradicates cancer cells by targeting the PrxI-mediated redox-dependent survival pathways.

• Authors: Yeon Ju Yang, Jin Young Baek, Jail Goo, Yoonho Shin, Jong Kuk Park, Ji Yong Jang, Su Bin Wang, Woojin Jeong, Hwa Jeong Lee, Hong-Duck Um, Sang Kook Lee, Yongseok Choi, Sue Goo Rhee, Tong-Shin Chang
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 24 Issue 8 Pg. 453-69 (Mar 10 2016) ISSN: 1557-7716 [Electronic] United States
• PMID: 26528922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AMRI-59
• Acetophenones
• Antineoplastic Agents
• Enzyme Inhibitors
• Piperidines
• Reactive Oxygen Species
• Small Molecule Libraries
• Peroxiredoxins

Topics

• Acetophenones (administration & dosage, pharmacology)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Enzyme Inhibitors (administration & dosage, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, metabolism)
• Mice
• Peroxiredoxins (antagonists & inhibitors)
• Piperidines (administration & dosage, pharmacology)
• Reactive Oxygen Species (metabolism)
• Small Molecule Libraries (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays