【摘 要】
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Gefitinib is a new molecular targeted antitumor drug and recently used widely in lung cancer treatment in China But when used for an average tenmonth period, patient show resistance to gefitinib and t
【机 构】
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State Key Laboratory of Natural and Biomimetic Drugs,Department of Pharmacology,School of Basic Medi
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Gefitinib is a new molecular targeted antitumor drug and recently used widely in lung cancer treatment in China But when used for an average tenmonth period, patient show resistance to gefitinib and this resistance limit its continued use.Lowmolecularweight heparin (LMWH) has potent inhibitory action on experimental metastasis.In present study, we are trying to find whether LMWH combined with gefitinib could sensitize its antitumor effects and potential relieve its resistance phenomenon in vivo and in vitro.Enoxaparin (one kind of LMWH) combined with gefitinib inhibited the growth of xenograft A5491ucC5 tumors in nude mice and reduced lung colony formation compared with gefitinib alone.Enoxaparin in combination with gefitinib had stronger inhibitory effects on A549 cell migration than either agent used individually.Gefitinib is an EGFRtyrosine kinase inhibitor and have antitumor effects mainly through inhibiting PI3KAkt and MAPKErk1/2 signal pathway.However, this inhibitory effect of gefitinib was shortterm and cancelled when EGFRtyrosine kinase genes occurred resistance mutants.Additional enoxaparin administration resulted in synergistic inhibition of Akt activity in A549 cell than gefitinib alone administration.Then by using whole proteomics analysis (one dimensional SDAPAGE/LCMS) and network construct with Cytoscape database, we clarified the underlying and characteristic molecular mechanisms of this combined treatment, in which dedicator of cytokinesis 1 (DOCK1) was the important node molecule.Western blot verified the additional enoxaparin administrations synergistic inhibition on DOCK1 expression in A549 cells than gefitinib alone administration.Knockdown of DOCK1 in A549 cells confirmed its role in cell migration.Altogether, our data demonstrate that enoxaparin may sensitize gefitinib antitumor and antimigration activity in lung cancer by suppressing DOCK1 expression and AKT activity.
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