Triazole analog 1-(1-benzyl-5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(4-bromophenylamino)-1-(4-chlorophenyl)ethanol induces reactive oxygen species and autophagy-dependent apoptosis in both in vitro and in vivo breast cancer models.

Abstract

Autophagy is considered as an important cell death mechanism that closely interacts with other common cell death programs like apoptosis. Critical role of autophagy in cell death makes it a promising, yet challenging therapeutic target for cancer. We identified a series of 1,2,3-triazole analogs having significant breast cancer inhibition property. Therefore, we attempted to study whether autophagy and apoptosis were involved in the process of cancer cell inhibition. The lead molecule, 1-(1-benzyl-5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(4-bromophenylamino)-1-(4-chlorophenyl)ethanol (T-12) induced significant cell cycle arrest, mitochondrial membrane depolarization, apoptosis and autophagy in MCF-7 and MDA-MB-231 cells. T-12 increased reactive oxygen species and its inhibition by N-acetyl-L-cysteine protected breast cancer cells from autophagy and apoptosis. Autophagy inhibitor, 3-methyladenine abolished T-12 induced apoptosis, mitochondrial membrane depolarization and reactive oxygen species generation. This suggested that T-12 induced autophagy facilitated cell death rather than cell survival. Pan-caspase inhibition did not abrogate T-12 induced autophagy, suggesting that autophagy precedes apoptosis. In addition, T-12 inhibited cell survival pathway signaling proteins, Akt, mTOR and Erk1/2. T-12 also induced significant regression of tumor with oral dose of as low as 10mg/kg bodyweight in rat mammary tumor model without any apparent toxicity. In presence of reactive oxygen species inhibitor (N-acetyl-L-cysteine) and autophagy inhibitor (chloroquine), T-12 induced tumor regression was significantly decreased. In conclusion, T-12 is a potent inducer of autophagy-dependent apoptosis in breast cancer cells both in vitro and in vivo and can serve as an important lead in development of new anti-tumor therapy.

• Authors: Hamidullah, Karan Singh Saini, Arya Ajay, N Devender, Arindam Bhattacharjee, Sharmistha Das, Sonam Dwivedi, Munna Prasad Gupt, Himangsu Kousik Bora, Kalyan Mitra, Rama Pati Tripathi, Rituraj Konwar
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 65 Pg. 275-87 (Aug 2015) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 26115963 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Reactive Oxygen Species
• Triazoles
• Ethanol

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Ethanol (analogs & derivatives, pharmacology)
• Female
• HEK293 Cells
• Humans
• MCF-7 Cells
• Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Triazoles (pharmacology)