title: 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.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India.
authors.lastname: Hamidullah
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India.
authors.forename: Karan Singh
authors.initials: KS
authors.lastname: Saini
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India.
authors.forename: Arya
authors.initials: A
authors.lastname: Ajay
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India.
authors.forename: N
authors.initials: N
authors.lastname: Devender
authors.affiliation: Electron Microscopy Unit, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India.
authors.forename: Arindam
authors.initials: A
authors.lastname: Bhattacharjee
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India.
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Das
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Dwivedi
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India.
authors.forename: Munna Prasad
authors.initials: MP
authors.lastname: Gupt
authors.affiliation: Laboratory Animal Division, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Himangsu Kousik
authors.initials: HK
authors.lastname: Bora
authors.affiliation: Electron Microscopy Unit, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Mitra
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India. Electronic address: rp_tripathi@cdri.res.in.
authors.forename: Rama Pati
authors.initials: RP
authors.lastname: Tripathi
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, 10/1, Jankipuram Extension, Lucknow, UP 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India. Electronic address: r_konwar@cdri.res.in.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Konwar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000431:Ethanol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D014230:Triazoles; D000431:Ethanol
keywords: Apoptosis; Autophagy; Breast cancer; ROS; Triazole