A new protoapigenone analog RY10-4 induces apoptosis and suppresses invasion through the PI3K/Akt pathway in human breast cancer
ABSTRACT 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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ABSTRACT: Protoapigenone (Pa) is a flavone aglycone with a p-quinol structure in its B-ring. It was first discovered in Thelypteris torresiana, a native fern in Taiwan. Recent studies highlighted that protoapigenone and some of its derivatives show very potent anticancer activity against several types of tumors, using both in vitro and in vivo models. Despite the growing body of evidence on the selective anticancer potential of protoapigenone and its derivatives, no data are available on their pharmacokinetical properties. In our present research, albumin binding properties of Pa and seven different 1'-O-alkyl protoapigenone derivatives were analyzed as well as their biochemical effects on HepG2 tumor cell line in comparison with the flavone apigenin. Our results are in good accordance with the data of previous investigations of 1'-O-alkylated derivatives of protoapigenone (with the exception of isopropyl and allyl derivatives) showing similar or higher antitumor effects than Pa. Furthermore structural changes in Pa cause a very remarkable influence on plasma albumin binding affinity of the derivatives. Our investigation proves that parallel with changes of lipophilic character and extent of plasma protein binding properties of Pa derivatives a consequent alteration occurs in their pharmacokinetic behavior without losing the pharmacodynamic effect. Based on our study a better understanding of the structural and biochemical behavior of different chemically modified flavonoid derivatives could be achieved making further design of in vivo experiments feasible.Journal of photochemistry and photobiology. B, Biology 04/2013; 124C:20-26. DOI:10.1016/j.jphotobiol.2013.04.002 · 2.80 Impact Factor
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ABSTRACT: In this study, isoegomaketone(IK) was isolated from Perilla frutescens(L.), a Chinese herbal. The effects of IK were examined by cell viability assay, colony formation assay, xenograft tumor assay and western blotting in HCC cells. We found that IK inhibited cell viability, and its administration decreased tumor volume and weight profoundly. The presence of IK(10nmol/l) produced a dramatic decrease of pAkt, while total Akt level was not affected. The data suggested that IK from perilla suppressed HCC tumor growth via blocking PI3K/Akt signaling pathway.African Journal of Traditional, Complementary and Alternative Medicines 01/2012; 10(2):251-7. · 0.56 Impact Factor
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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.Toxicology and Applied Pharmacology 04/2013; DOI:10.1016/j.taap.2013.04.011 · 3.63 Impact Factor