FGF2 promotes the chemotherapy resistance in colon cancer cells through activating PI3K/Akt signaling pathway

Background:To investigate the role of fibroblast growth factor 2(FGF2)in chemotherapy resistance of colon cancer.Methods:An HCT116/5-fluorouracil(5-FU)-resistant cell line was established,and FGF2 levels were detected in a sensitive cell group(HCT116)and a resistant cell group(HCT1116-R)using different methods.Fibroblast growth factor 2 levels in the medium were determined by enzyme-linked immunoassay.The protein expressions of FGF2,fibroblast growth factor receptor 1(FGFR1),and phospho-FGFR1 were assessed by Western blotting,and FGF2 mRNA levels were detected by quantitative real-time polymerase chain reaction.Fibroblast growth factor 2 recombinant protein was added to sensitive cells,and FGFR inhibitor AZD4547 was added to resistant cells,and the cell survival rate was determined using the cell counting kit-8 method and the protein expressions of PI3K(phosphatidylinositol 3 kinase),p-PI3K(phospho-PI3K),Akt(protein kinase B),p-Akt(phospho-Akt),mammalian target of rapamycin(mTOR),p-mTOR(phospho-mTOR),Bad(Bcl-xL/Bcl-2-associated death promoter),NF-κB(nuclear factorκB),GSK-3(glycogen synthase kinase-3),FKHR(forkhead box protein O1),and PTEN(phosphatase and tensin homolog deleted on chromosome ten)were detected by Western blotting.Results:Fibroblast growth factor 2 protein and mRNA expression levels in the HCT116-R group were significantly higher than those in the HCT116 group.Fibroblast growth factor 2 increased the survival rate of HCT116 cells;improved tolerance to 5-FU;upregulated p-PI3K,p-Akt,and p-mTOR;and downregulated Bad.The FGFR inhibitor AZD4547 decreased cell survival rate and tolerance to 5-FU;downregulated p-PI3K,p-Akt,and p-mTOR expression;and upregulated Bad.Conclusions:Fibroblast growth factor 2 promotes chemotherapy tolerance in colon cancer cells by activating the Akt/mTOR and Akt/Bad signaling pathways downstream of PI3K.

Transduction of mesenchymal stem cells with multidrug resistance gene provides protection for bone marrow toxicity after being transplanted into a nude mice model

Background Myelosuppression is the main dose-related toxicity of many chemotherapeutic drugs. The human multidrug resistance （mdrl） gene is well-known for its ability to confering drug resistance. In this study, we meant to transplant the placenta mesenchymal stem cells （P-MSCs） moderated by mdrl gene into a nude mice model radiated by γ-Co60 and to explore the chemoprotection for bone marrow （BM） toxicity. Methods Human P-MSCs were isolated from trypsin-digested term placentas and then transduced by with reconstructed retroviral vector containing mdrl gene and green fluorescent protein （GFP） reporter gene. The integration and expression of mdrl gene was observed indirectedly by the expression of GFP. A nude mice model was constructed after irradiation with a sublethal dosage of γ-Co60. These irradiated mice were transplanted with mdrl-MSCs through the caudal vein and then received paclitaxel （PAC） intraperitoneal chemotherapy. The Peripheral peripheral blood （PB） of the nude mice was collected, and the PB cells counts and values were determined using an automatic analyzer. Results After PAC treatment, mdrl-MSCs transplanted mice showed markedly improved survival upon compared to MSCs transplanted mice （85.7% vs. 57.1%）. White blood cell （WBC） and red blood cell （RBC） counts as well as the hemoglobin （Hb） values were significantly increased in PAC treated mdrl-MSCs mice compared to PAC treated control mice when PAC chemotherapy had been finished （all P 〈0.05）, but the difference was not found in the plateltes （PLT） count （P 〉0.05）.

Near infrared light triggered nitric oxide releasing platform based on upconversion nanoparticles for synergistic therapy of cancer stem-like cells

Near infrared(NIR) light-driven nitric oxide(NO) release nano-platform based on upconversion nanoparticles(UCNPs) and light sensitive NO precursor Roussin's black salt(RBS) was fabricated to generate NO upon 808 nm irradiation. The application of 808 nm laser as the excitation source could achieve better penetration depth and avoid overheating problem. The combination of UCNPs and RBS could realize the on-demand release of NO at desired time and location by simply controlling the output of NIR laser.Cellular uptake results showed that more nanoparticles were internalized in cancer stem-like cells(CSCs)rather than non-CSCs. Therefore, a synergistic cancer therapy strategy to eradicate both CSCs and nonCSCs simultaneously was developed. Traditional chemo-drug could inhibit non-CSCs but has low killing efficiency in CSCs. However, we found that the combination of NO and chemotherapy could efficiently inhibit CSCs in bulk cells, including inhibiting mammosphere formation ability, decreasing CD44^+/CD24^- subpopulation and reducing tumorigenic ability. The mechanism studies confirmed that NO could not only induce apoptosis but also increase drug sensitivity by declining drug efflux in CSCs. This UCNPsbased platform may provide a new combinatorial strategy of NO and chemotherapy to improve cancer treatment.