Homoharringtonine Induces Apoptosis In Gefitinib-Resistant Non-Small Cell Lung Cancer

Lung cancer is one of the most diagnosed cancer type in the world.There are two types of lung cancer,namely small cell lung cancer and non-small cell lung cancer(NSCLC),and NSCLC accounts for 80% of lung cancer populations.Many efficient agents such as PD1 and EGFR specific antibodies and reversible tyrosine kinase inhibitors(TKIs)Gefitinib and Erlotinib benefit a proportion of NSCLC patients,but after 6~12 month treatment,the majority patients may produce drug resistance.EGFR secondary mutation T790 M and IL-6 abrrent expression are responsible for drug resistance but there maybe other unknown reasons.Therefore,EGFR-dependent inhibition treatment maybe not sufficient for patients harboring mutant EGFR.discovering more novel compounds to efficiently overcome the drug resistance and the natural resources is a good drug pool for us.In the present study,a natural compound extracted from Cephalotaxus harringtonia,homoharringtonine(HHT)was used to treat Gefitinib-resistance NSCLC cell lines A549 and H1975 and the possible mechanisms were investigated.We found HHT efficiently inhibited A549 and H1975 cell proliferation,viability and soft-agar colony formation activity in an EGFR-independent manner.We also found that HHT induced cell apoptosis in mitochondria-dependent pathway,and the anti-apoptotic proteins MCL1 and Survivin protein levels decreased on HHT treatment.To further investigate which signal pathway was inhibited by HHT,we found JAK1 and STAT3(Y705)phosphorylations were significantly inhibited.IL-6 is a multifunction cytokine and contributes to NSCLC cell drug resistance.We found HHT inhibited IL-6-induced STAT3 phosphorylation in a dose-and time-dependent manner.As a second line drug for NSCLC treatment,DTX and HHT dispalyed synergistic effect on NSCLC cell treatment,which provide a new strategy for lung cancer treatment.We also evaluated the HHT effect on Gefitinib-resistance H1975 xenograft tumor in nude mice.After 3weeks treatment,HHT exhibited efficient inhibition effects on tumor growth comparing with Gefitinib and vehicle treatment groups.On the molecular level,HHT also inhibited STAT3 phosphorylation by western blot assay and tumor immunofluorescence staining.In a conclusion,HHT inhibited IL-6/JAK/STAT3 signalpathway and therefore induced cell apoptosis so that repressed cancer cell growth and viability and exhibited great potential in Gefitinib-resistance NSCLC treatment.In addition,to improve the delivery of anti-cancer drugs,a star-shaped nanocarrier TAPP-PCL-b-TPGS was designed,synthesize and evaluated.The nanocarrier realized high encapsulation efficiency,controlled release and the combination of chemotherapy and photodynamic therapy,which provided a novel delivery manner for DTX.