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Specific targeting of insulin-like growth factor 1 receptor signaling in human estrogen dependent breast cancer cell by a novel tyrosine-based benzoxazepine derivative.
Mol Cell Endocrinol. 2011 May 16; 338(1-2):68-78.MC

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+Show Affiliations

Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Lucknow, India.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21457754

Citation

Chakravarti, Bandana, et al. "Specific Targeting of Insulin-like Growth Factor 1 Receptor Signaling in Human Estrogen Dependent Breast Cancer Cell By a Novel Tyrosine-based Benzoxazepine Derivative." Molecular and Cellular Endocrinology, vol. 338, no. 1-2, 2011, pp. 68-78.
Chakravarti B, Siddiqui JA, Dwivedi SK, et al. Specific targeting of insulin-like growth factor 1 receptor signaling in human estrogen dependent breast cancer cell by a novel tyrosine-based benzoxazepine derivative. Mol Cell Endocrinol. 2011;338(1-2):68-78.
Chakravarti, B., Siddiqui, J. A., Dwivedi, S. K., Deshpande, S., Samanta, K., Bhatta, R. S., Panda, G., Prabhakar, Y. S., Konwar, R., Sanyal, S., & Chattopadhyay, N. (2011). Specific targeting of insulin-like growth factor 1 receptor signaling in human estrogen dependent breast cancer cell by a novel tyrosine-based benzoxazepine derivative. Molecular and Cellular Endocrinology, 338(1-2), 68-78. https://doi.org/10.1016/j.mce.2011.03.012
Chakravarti B, et al. Specific Targeting of Insulin-like Growth Factor 1 Receptor Signaling in Human Estrogen Dependent Breast Cancer Cell By a Novel Tyrosine-based Benzoxazepine Derivative. Mol Cell Endocrinol. 2011 May 16;338(1-2):68-78. PubMed PMID: 21457754.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Specific targeting of insulin-like growth factor 1 receptor signaling in human estrogen dependent breast cancer cell by a novel tyrosine-based benzoxazepine derivative. AU - Chakravarti,Bandana, AU - Siddiqui,Jawed A, AU - Dwivedi,Shailendra K Dhar, AU - Deshpande,Shreekant, AU - Samanta,Krishnanda, AU - Bhatta,Rabi S, AU - Panda,Gautam, AU - Prabhakar,Yenamandra S, AU - Konwar,Rituraj, AU - Sanyal,Sabaysachi, AU - Chattopadhyay,Naibedya, Y1 - 2011/03/30/ PY - 2010/11/03/received PY - 2011/02/01/revised PY - 2011/03/01/accepted PY - 2011/4/5/entrez PY - 2011/4/5/pubmed PY - 2011/11/1/medline SP - 68 EP - 78 JF - Molecular and cellular endocrinology JO - Mol Cell Endocrinol VL - 338 IS - 1-2 N2 - 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. SN - 1872-8057 UR - https://www.unboundmedicine.com/medline/citation/21457754/Specific_targeting_of_insulin_like_growth_factor_1_receptor_signaling_in_human_estrogen_dependent_breast_cancer_cell_by_a_novel_tyrosine_based_benzoxazepine_derivative_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0303-7207(11)00172-9 DB - PRIME DP - Unbound Medicine ER -