title: Specific targeting of insulin-like growth factor 1 receptor signaling in human estrogen dependent breast cancer cell by a novel tyrosine-based benzoxazepine derivative.
abstract: The present study sought to investigate the in vitro and in vivo effects of a tyrosine-based benzoxazepine, 4-[4-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-3-ylmethyl]-phenol) [THBP] in human breast cancer cells, with a focus on determining its molecular target. THBP had growth inhibitory effect on MCF-7 and MDA-MD-231 cells. At IC(50) value (∼20 μM), THBP resulted in G1 arrest, decrease in cyclin D1 levels and induction of apoptosis of MCF-7 cells. Mechanistically, activation of caspase 8 contributes critically to the induction of apoptotic cell death as copresence of selective inhibition of caspase 8 effectively abrogates the cytotoxic effect of THBP in MCF-7 cells. Further, THBP increased pro-apoptotic protein, Bax; decreased anti-apoptotic protein, Bcl-2; and decreased mitochondrial membrane potential in MCF-7 cells, indicating involvement of an intrinsic pathway of apoptosis following caspase 8 activation. Out of the various growth factors/hormones, THBP selectively abrogated increased viability of MCF-7 cells by insulin-like growth factor 1 (IGF-1). Molecular docking studies revealed that THBP occupied the ATP binding pocket of IGF-1 receptor (IGF-1R). Accordingly THBP was found to inhibit IGF-1-induced phosphorylation of IGF-1R and insulin receptor substrate-1 (IRS-1) without inhibiting insulin signaling in MCF-7 cells. In athymic nude mice, compared with vehicle, THBP treatment significantly reduced the growth of MCF-7 xenograft tumors through inhibition of cancer cell proliferation as well as promotion of cell death that correlated with reduced phospho-IGF-1R levels. We suggest that interfering with the IGF-1R signaling by the benzoxazepine THBP offers a novel and selective therapeutic strategy for estrogen receptor-positive, postmenopausal breast cancer patients.
authors: Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Lucknow, India.
authors: Bandana
authors: B
authors: Chakravarti
authors: Jawed A
authors: JA
authors: Siddiqui
authors: Shailendra K Dhar
authors: SK
authors: Dwivedi
authors: Shreekant
authors: S
authors: Deshpande
authors: Krishnanda
authors: K
authors: Samanta
authors: Rabi S
authors: RS
authors: Bhatta
authors: Gautam
authors: G
authors: Panda
authors: Yenamandra S
authors: YS
authors: Prabhakar
authors: Rituraj
authors: R
authors: Konwar
authors: Sabaysachi
authors: S
authors: Sanyal
authors: Naibedya
authors: N
authors: Chattopadhyay
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010077:Oxazepines / Q000494:pharmacology*; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: C562035:4-(4-(toluene-4-sulfonyl)-2,3,4,5-tetrahydrobenzo(f)(1,4)oxazepin-3-ylmethyl)phenol; D000970:Antineoplastic Agents; D004967:Estrogens; D007328:Insulin; D010077:Oxazepines; D013449:Sulfonamides; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D053181:Caspase 8