Specific targeting of insulin-like growth factor 1 receptor signaling in human estrogen dependent breast cancer cell by a novel tyrosine-based benzoxazepine derivative

Bandana Chakravarti, Jawed A. Siddiqui, Shailendra K.Dhar Dwivedi, Shreekant Deshpande, Krishnanda Samanta, Rabi S. Bhatta, Gautam Panda, Yenamandra S. Prabhakar, Rituraj Konwar, Sabaysachi Sanyal, Naibedya Chattopadhyay

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 IC50 value (~20μM), 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.

Original languageEnglish (US)
Pages (from-to)68-78
Number of pages11
JournalMolecular and Cellular Endocrinology
Volume338
Issue number1-2
DOIs
StatePublished - May 16 2011
Externally publishedYes

Keywords

  • Chemotherapeutic agent
  • Insulin-like growth factor receptor
  • Preclinical
  • Receptor tyrosine kinase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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