A Arun1, M I Ansari2, P Popli1, S Jaiswal2, A K Mishra3, A Dwivedi1,4, K Hajela2, R Konwar1,4. 1. Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, UP, India. 2. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, UP, India. 3. Department of Endocrine Surgery, King George's Medical University, Lucknow, UP, India. 4. Academy of Scientific and Innovative Research (AcSIR), CSIR-Central Drug Research Institute Campus, Lucknow, UP, India.
Abstract
OBJECTIVES: In our ongoing studies to develop ER targeting agents, we screened for dual-acting molecules with a hypothesis that a single molecule can also target both ER positive and negative groups of breast cancer. MATERIALS AND METHODS: 1-(2-(4-(Dibenzo[b,f]thiepin-10-yl)phenoxy)ethyl)piperidine (DTPEP) was synthesized and screened in both MCF-7 (ER+ve) and MDA-MB-231 (ER-ve) cells. Assays for analysis of cell cycle, ROS, apoptosis and MMP loss were carried out using flow cytometry. Its target was investigated using western blot, transactivation assay and RT-PCR. In vivo efficacy of DTPEP was validated in LA-7 syngeneic rat mammary tumour model. RESULTS: Here, we report identification of dual-acting molecule DTPEP that downregualtes PI3K/Akt and PKCα expression, induces ROS and ROS-dependent apoptosis, loss of mitochondrial membrane potential, induces expression of caspase indicative of both intrinsic and extrinsic apoptosis in MCF-7 and MDA-MB-231 cells. In MCF-7 cells, DTPEP downregulates ERα expression and activation. In MDA-MB-231 cells, primary cellular target of DTPEP is not clearly known, but it downregualtes PI3K/Akt and PKCα expression. In vivo study showed regression of LA-7 syngeneic mammary tumour in SD rat. CONCLUSIONS: We identified a new dual-acting anti-breast cancer molecules as a proof of concept which is capable of targeting both ER-positive and ER-negative breast cancer.
OBJECTIVES: In our ongoing studies to develop ER targeting agents, we screened for dual-acting molecules with a hypothesis that a single molecule can also target both ER positive and negative groups of breast cancer. MATERIALS AND METHODS:1-(2-(4-(Dibenzo[b,f]thiepin-10-yl)phenoxy)ethyl)piperidine (DTPEP) was synthesized and screened in both MCF-7 (ER+ve) and MDA-MB-231 (ER-ve) cells. Assays for analysis of cell cycle, ROS, apoptosis and MMP loss were carried out using flow cytometry. Its target was investigated using western blot, transactivation assay and RT-PCR. In vivo efficacy of DTPEP was validated in LA-7 syngeneic rat mammary tumour model. RESULTS: Here, we report identification of dual-acting molecule DTPEP that downregualtes PI3K/Akt and PKCα expression, induces ROS and ROS-dependent apoptosis, loss of mitochondrial membrane potential, induces expression of caspase indicative of both intrinsic and extrinsic apoptosis in MCF-7 and MDA-MB-231 cells. In MCF-7 cells, DTPEP downregulates ERα expression and activation. In MDA-MB-231 cells, primary cellular target of DTPEP is not clearly known, but it downregualtes PI3K/Akt and PKCα expression. In vivo study showed regression of LA-7 syngeneic mammary tumour in SD rat. CONCLUSIONS: We identified a new dual-acting anti-breast cancer molecules as a proof of concept which is capable of targeting both ER-positive and ER-negative breast cancer.
Authors: Pooja R Kamath; Dhanya Sunil; Manu M Joseph; Abdul Ajees Abdul Salam; Sreelekha T T Journal: Eur J Med Chem Date: 2017-05-11 Impact factor: 6.514
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