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01.12.2018 | Research article | Ausgabe 1/2018 Open Access

BMC Cancer 1/2018

Epoxyazadiradione suppresses breast tumor growth through mitochondrial depolarization and caspase-dependent apoptosis by targeting PI3K/Akt pathway

BMC Cancer > Ausgabe 1/2018
Dhiraj Kumar, Saikat Haldar, Mahadeo Gorain, Santosh Kumar, Fayaj A. Mulani, Amit S. Yadav, Lucio Miele, Hirekodathakallu V. Thulasiram, Gopal C. Kundu
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Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12885-017-3876-2) contains supplementary material, which is available to authorized users.



Breast cancer is one of the most commonly diagnosed invasive cancers among women around the world. Among several subtypes, triple negative breast cancer (TNBC) is highly aggressive and chemoresistant. Treatment of TNBC patients has been challenging due to heterogeneity and devoid of well-defined molecular targets. Thus, identification of novel effective and selective agents against TNBC is essential.


We used epoxyazadiradione to assess the cell viability, mitochondrial potential, ROS level, cell migration, apoptosis and protein expression in cell culture models of TNBC MDA-MB-231 and ER+ MCF-7 breast cancer cells. The molecular mechanism was examined in two different type of breast cancer cells in response to epoxyazadiradione. We have also analyzed the effect of epoxyazadiradione on breast tumor growth using in vivo mice model.


In this study, we for the first time investigated that out of 10 major limonoids isolated from Azadirachta indica, epoxyazadiradione exhibits most potent anti-cancer activity in both TNBC and ER+ breast cancer cells. Epoxyazadiradione induces apoptosis and inhibits PI3K/Akt-mediated mitochondrial potential, cell viability, migration and angiogenesis. It also inhibits the expression of pro-angiogenic and pro-metastatic genes such as Cox2, OPN, VEGF and MMP-9 in these cells. Furthermore, epoxyazadiradione attenuates PI3K/Akt-mediated AP-1 activation. Our in vivo data revealed that epoxyazadiradione suppresses breast tumor growth and angiogenesis in orthotopic NOD/SCID mice model.


Our findings demonstrate that epoxyazadiradione inhibits PI3K/Akt-dependent mitochondrial depolarisation, induces apoptosis and attenuates cell migration, angiogenesis and breast tumor growth suggesting that this compound may act as a potent therapeutic agent for the management of breast cancer.
Additional file 1: Figure S1. Epoxyazadiradione inhibits breast cancer cell viability. Figure S2. Epoxyazadiradione induces cell death through ROS and AIF independent pathway in MCF-7 cells. Figure S3. Epoxyazadiradione attenuates breast cancer cell migration through downregulation of PI3K/Akt pathway. Table S1. List of antibodies used for western blot and immunofluorescence. Table S2. IC50 of epoxyazadiradione in breast cancer (MDA-MB-231 and MCF-7) cells. (PDF 3912 kb)
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