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

作者：A., Arun; M.I., Ansari; P., Popli; S., Jaiswal; A.K., Mishra; A., Dwivedi; K., Hajela; R., Konwar

来源：Cell Proliferation, 2018, 51(6): e12501.

DOI：10.1111/cpr.12501

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>In our ongoing studies to develop <jats:styled-content style="fixed-case">ER</jats:styled-content> targeting agents, we screened for dual‐acting molecules with a hypothesis that a single molecule can also target both <jats:styled-content style="fixed-case">ER</jats:styled-content> positive and negative groups of breast cancer.</jats:p></jats:sec><jats:sec><jats:title>Materials and methods</jats:title><jats:p>1‐(2‐(4‐(Dibenzo[b,f]thiepin‐10‐yl)phenoxy)ethyl)piperidine (<jats:styled-content style="fixed-case">DTPEP</jats:styled-content>) was synthesized and screened in both <jats:styled-content style="fixed-case">MCF</jats:styled-content>‐7 (<jats:styled-content style="fixed-case">ER</jats:styled-content>+ve) and <jats:styled-content style="fixed-case">MDA</jats:styled-content>‐<jats:styled-content style="fixed-case">MB</jats:styled-content>‐231 (<jats:styled-content style="fixed-case">ER</jats:styled-content>‐ve) cells. Assays for analysis of cell cycle, ROS, apoptosis and <jats:styled-content style="fixed-case">MMP</jats:styled-content> loss were carried out using flow cytometry. Its target was investigated using western blot, transactivation assay and <jats:styled-content style="fixed-case">RT</jats:styled-content>‐<jats:styled-content style="fixed-case">PCR</jats:styled-content>. In vivo efficacy of <jats:styled-content style="fixed-case">DTPEP</jats:styled-content> was validated in <jats:styled-content style="fixed-case">LA</jats:styled-content>‐7 syngeneic rat mammary tumour model.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Here, we report identification of dual‐acting molecule <jats:styled-content style="fixed-case">DTPEP</jats:styled-content> that downregualtes <jats:styled-content style="fixed-case">PI</jats:styled-content>3K/Akt and <jats:styled-content style="fixed-case">PKC</jats:styled-content>α expression, induces <jats:styled-content style="fixed-case">ROS</jats:styled-content> and <jats:styled-content style="fixed-case">ROS</jats:styled-content>‐dependent apoptosis, loss of mitochondrial membrane potential, induces expression of caspase indicative of both intrinsic and extrinsic apoptosis in <jats:styled-content style="fixed-case">MCF</jats:styled-content>‐7 and <jats:styled-content style="fixed-case">MDA</jats:styled-content>‐<jats:styled-content style="fixed-case">MB</jats:styled-content>‐231 cells. In <jats:styled-content style="fixed-case">MCF</jats:styled-content>‐7 cells, <jats:styled-content style="fixed-case">DTPEP</jats:styled-content> downregulates <jats:styled-content style="fixed-case">ER</jats:styled-content>α expression and activation. In <jats:styled-content style="fixed-case">MDA</jats:styled-content>‐<jats:styled-content style="fixed-case">MB</jats:styled-content>‐231 cells, primary cellular target of <jats:styled-content style="fixed-case">DTPEP</jats:styled-content> is not clearly known, but it downregualtes <jats:styled-content style="fixed-case">PI</jats:styled-content>3K/Akt and <jats:styled-content style="fixed-case">PKC</jats:styled-content>α expression. In vivo study showed regression of <jats:styled-content style="fixed-case">LA</jats:styled-content>‐7 syngeneic mammary tumour in <jats:styled-content style="fixed-case">SD</jats:styled-content> rat.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>We identified a new dual‐acting anti‐breast cancer molecules as a proof of concept which is capable of targeting both <jats:styled-content style="fixed-case">ER</jats:styled-content>‐positive and <jats:styled-content style="fixed-case">ER</jats:styled-content>‐negative breast cancer.</jats:p></jats:sec>

• 出版日期2018-12
• 单位南方医科大学