Abstract
BackgroundGlioblastoma (GBM) develops resistance to the advances in chemotherapy leading to poor prognosis and life quality. Consequently, new treatment modalities are needed. Our aims were to investigate the effects of combined noscapine (NOS) and imatinib mesylate (IM) on human GBM in vitro and the role of midkine (MK) in this new combination treatment.MethodsMonolayer and spheroid cultures of T98G human GBM cell line were used to evaluate the effects of IM (10 μM), Nos (10 μM) and their combination on cell proliferation and apoptotic indexes, cell cycle, the levels of antiapoptotic MK, MRP-1, p170, PFGFR-α, EGFR, bcl-2 proteins, apoptotic caspase-3 levels, morphology (SEM) and ultrastructure (TEM) for 72 hrs. Results were statistically analyzed using the Student's t-test.ResultsThe combination group induced highest decrease in cell proliferation and apoptotic indexes, caspase-3 levels, MRP-1 and PDGFR-α levels. The decrease in p170 levels were lower than IM but higher that NOS. The highest increases were in EGFR, MK, bcl-2 and cAMP levels in the combination group. The G0+G1 cell cycle arrest at the end of 72nd hr was the lowest in the combination group. Apoptotic appearence was observed rarely both in the morphologic and ultrastructural evaluation of the combination group. In addition, autophagic vacuoles which were frequently observed in the IM group were observed rarely.ConclusionsThe combination of Nos with IM showed antagonist effect in T98G human GBM cells in vitro. This antagonist effect was correlated highly with MK levels. The effects of NOS on MRP-1, MK and receptor tyrosine kinase levels were firstly demonstrated in our report. In addition, we proposed that MK is one of the modulator in the switch of autophagy to cell death or survival/resistance.
Highlights
Glioblastoma (GBM) develops resistance to the advances in chemotherapy leading to poor prognosis and life quality
We investigated primarily whether Nos could potentiate the cyctotoxicity of imatinib mesylate (IM) in human GBM cells in vitro and secondly we investigated the role of MK as a survival and resistance molecule in this combination treatment
One of them which was reported by Newcomb et al demonstrated that Nos with inhibition concentration 50 (IC50) value as 97 μmol/l inhibited T98G cell proliferation index in 24 hrs, induced M-phase arrest and led to a maximal cell death within 48 hrs [22]
Summary
Glioblastoma (GBM) develops resistance to the advances in chemotherapy leading to poor prognosis and life quality. Various combined therapies of surgery, radiation and chemotherapy are tried in order to cope with resistance and relapse to prolong survival time, the prognosis of patients remains poor. This shortcoming leads investigators to design new antineoplastic agents and to use them alone or in combination with previously-used agents. These advances achieved some success, this process from bench to in vivo and phase trials took considerable time and financial resources, resulting in more deaths.
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