title: An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway.
abstract: Persistent activation of signal transducer and activator of transcription 3 (STAT3) is associated with the progression of a range of tumors. In this report, we present the anticancer activity of 2-(1-(4-(2-cyanophenyl)1-benzyl‑1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5)undecane (CIMO) against breast cancer cells. We observed that CIMO suppresses the proliferation of both estrogen receptor-negative (ER-) (BT-549, MDA-MB‑231) and estrogen receptor-positive (ER+) (MCF-7, and BT-474) breast cancer (BC) cells with IC50 of 3.05, 3.41, 4.12 and 4.19 µM, respectively, and without significantly affecting the viability of normal cells. CIMO was observed to mediate its anti-proliferative effect in ER- BC cells by inhibiting the phosphorylation of JAK2 and STAT3 proteins. Quantitative PCR analysis demonstrated that CIMO decreases the relative mRNA expression of genes that are involved in cell cycle progression (CCND1) and cell survival (BCL2, BCL-xL, BAD, CASP 3/7/9, and TP53). In addition, CIMO was observed to arrest BC cells at G0/G1 phase and of the cell cycle. Furthermore, CIMO suppressed BC cell migration and invasion with concordant regulation of genes involved in epithelial to mesechymal transition (CDH1, CDH2, OCLN and VIM). Thus, we report the utility of a synthetic azaspirane which targets the JAK-STAT pathway in ER- BC.
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
authors: Nurfarhanah Bte Syed
authors: NB
authors: Sulaiman
authors: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
authors: Chakrabhavi Dhananjaya
authors: CD
authors: Mohan
authors: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Bangalore 560001, India.
authors: Salundi
authors: S
authors: Basappa
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
authors: Vijay
authors: V
authors: Pandey
authors: Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 060-0808, Japan.
authors: Shobith
authors: S
authors: Rangappa
authors: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Bangalore 560001, India.
authors: Hanumantharayappa
authors: H
authors: Bharathkumar
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
authors: Alan Prem
authors: AP
authors: Kumar
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
authors: Peter E
authors: PE
authors: Lobie
authors: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
authors: Kanchugarakoppal S
authors: KS
authors: Rangappa
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: C000595668:2-(1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5)undecane; C530104:CCND1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013141:Spiro Compounds; D019938:Cyclin D1; C507924:JAK2 protein, human; D053614:Janus Kinase 2