New piperidine derivative DTPEP acts as dual‐acting anti‐breast cancer agent by targeting ERα and downregulating PI3K/Akt‐PKCα leading to caspase‐dependent apoptosis. (9th August 2018)

• Record Type: Journal Article
• Authors: Arun, A.; Ansari, M.I.; Popli, P.; Jaiswal, S.; Mishra, A.K.; Dwivedi, A.; Hajela, K.; Konwar, R.
• Is Part Of: Cell proliferation. Volume 51:Number 6(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-08-09
• Subjects: Cell proliferation -- Periodicals; 571.84
• DOI: 10.1111/cpr.12501
• Languages: English
• ISSNs: 0960-7722

Abstract

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.