Drug Resistance Molecular ABCG2 And EGFR Signaling Pathway: Molecular Target Of Glioma Therapy

Part one: ABCG2:Molecular Target in the resistance to chemotherapeutic drugs of Glioma cellsAbstract Objective: ABCG2 (the G2 member of ATP-binding cassette family), which encodes breast cancer resistance protein (BCRP), is regarded as a marker of small population (SP) cells to identify tumor stem cells. This paper aimed to inhabit its resistance to chemotherapeutic drugs.Methods: Gliobastona multiforme (GBM) cells and nude mice burdened with xenografts of GBM were treated with ACNU, NCDP and combination administration respectively. In vitro, MTT assay were performed to evaluate the inhibitory effects upon the proliferation of GBM cells and the apoptotic rate of GBM cells was estimated by flow cytometry (FCM). In vivo, survival times of these nude mice were calculated and the pathology of implanted xenografts ware analyzed.Results: In vitro, the inhibition rate and apoptotic rate of GBM in the group of NCDP+ACNU combination administration were significantly higher than that of only administration of ACNU and control group ( P <0.01). In vivo, the combinated administration of ACNU and NCDP could markedly prolong the lifespans than that of only administration of ACNU (P<0.01).Conclusion: The inhibition of drug resistance gene ABCG2 by NCDP could enhance the cytotoxicity of ACNU and promote apoptosis, consequently prolong lifespans of nude mice bearing tumors.Part two: EGFR Signaling Pathway: Molecular Target of Glioma Therapy【Objective】There is no expression of EGFR in normal tissues and neural stem cells .But high expression of EGFR is observed in glioma, specifically in brain tumor stem cells. The expression quantity of EGFR is related closely to malignant grades of glioma. The EGF (epidermal growth factor) receptor-tyrosine kinase inhibitor Gefitinib can block the cell signaling pathways involved in cell proliferation, survival, and angiogenesis in various cancer cells. We investigated the antitumor effects of Gefitinib alone or in combination with ACNU and nicardipine against Glioblastoma multiforme (GBM) lines.【Methods】Gliobastona multiforme (GBM) cells were treated with Gefitinib,ACNU NCDP and combination administration respectively. MTT assay were performed to evaluate the inhibitory effects upon the proliferation of GBM cells .After treatment with drug, the distribution of Cell Cycle and apoptotic rate of GBM cells was estimated by flow cytometry (FCM).【Result】Gefitinib caused a dose dependent growth arrest at G0–G1 phase ,After treatment with gefitinib,ACNU,ACNU plus gefitinib,ACNU+gefitinib+nicardipine, 4.90±0.90%,33.02±2.00%,51.05±7.16%和66.04±5.22% of GBM cell were annexin V-positive. The inhibition rate and apoptotic rate of GBM in the group of NCDP+ACNU+ Gefitinib combination administration were significantly higher than that of other group(P <0.01).【Conclusion】NCDP and Gefitinib augmented the anti-cancer activity of ACNU . Treatment with NCDP, Gefitinib and ACNU may have potential in the treatment of glioma patients.