A new protoapigenone analog RY10-4 induces apoptosis and suppresses invasion through the PI3K/Akt pathway in human breast cancer

Key Laboratory of Natural Medicinal Chemistry and Resources Evaluation of Hubei Province, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Cancer letters (Impact Factor: 5.62). 05/2012; 324(2):210-20. DOI: 10.1016/j.canlet.2012.05.025
Source: PubMed


RY10-4, a novel protoapigenone analog, shows potent cytotoxicity against a broad spectrum of human cancer cells. Here we investigate its anti-tumor activity on breast cancer. The results indicated that RY10-4 suppressed proliferation, arrested cell cycle, induced apoptosis and inhibited invasion in MDA-MB-231, MCF-7 and SKBR3 breast cancer cells. Western blot analysis showed that RY10-4 down-regulated the PI3K/Akt signaling pathway and inhibited doxorubicin-induced p-Akt. Moreover, it effectively suppressed tumor growth in mice without major side effects. Therefore, RY10-4 had potential anti-tumor activity, and could be used as a lead to design more potent derivatives.

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    • "Furthermore, selective toxicity against a multidrug resistant (MDR) cancer cell line [11] and antiviral activity against Ebstein–Barr virus (EBV) [12] was published . During the last 2 years the biochemical effectiveness of two further, synthetic protoapigenone analogs RY10-4 and WYC0209 has been also verified [13] [14] [15]. Probably the most interesting , recent finding concerning the mode of action of protoapigenone and WYC0209 is that they can inhibit ataxia telangiectasiamutated and Rad3-related (ATR) signaling both in vitro and in vivo [16]. "
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    ABSTRACT: Protoapigenone is a unique flavonoid and enriched in many ferns, showing potent antitumor activity against a broad spectrum of human cancer cell lines. RY10-4, a modified version of protoapigenone, manifested better anti-proliferation activity in human breast cancer cell line MCF-7. The cytotoxicity of RY10-4 against MCF-7 cells exhibited in both time- and concentration-dependent manners. Here we investigated a novel effect of RY10-4 mediated autophagy in autophagy defect MCF-7 cells. Employing immunofluorescence assay for microtubule-associated protein light-chain 3 (LC3), monodansylcadaverine staining, western blotting analyses for LC3 and p62 as well as ultrastructural analysis by transmission electron microscopy, we showed that RY10-4 induced autophagy in MCF-7 cells but protoapigenone did not. Meanwhile, inhibition of autophagy by pharmacological and genetic approaches significantly increased the viability of RY10-4 treated cells, suggested that the autophagy induced by RY10-4 played as a promotion mechanism for cell death. Further studies revealed that RY10-4 suppressed activation of mTOR and p70S6K via Akt/mTOR pathway. Our results provided new insights for the mechanism of RY10-4 induced cell death and the cause of RY10-4 showing better antitumor activity than protoapigenone, and supported further evidences for RY10-4 as a lead to design promising antitumor agent.
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