Decreased therapeutic effects of noscapine combined with imatinib mesylate on human glioblastoma in vitro and the effect of midkine.
PRIMARY RESEARCH Open Access Decreased therapeutic effects of noscapine combined with imatinib mesylate on human glioblastoma in vitro and the effect of midkine
Mine Erguven1*, Ayhan Bilir2, Nuray Yazihan3, Ezgi Ermis4, Akin Sabanci5, Esin Aktas6, Yavuz Aras7 and Vehbi Alpman8
Abstract
Background: Glioblastoma (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.
Methods: Monolayer 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-a, 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.
Results: The combination group induced highest decrease in cell proliferation and apoptotic indexes, caspase-3 levels, MRP-1 and PDGFR-a 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.
Conclusions: The 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.
Background
Glioblastoma (GBM) is the most common and malignant primary brain tumor. Although 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. The majority of the patients die within a year of diagnosis and the five-year-survival of patients worldwide with glioma is only 10% [1]. In the chemotherapy era, this shortcoming leads investigators to design new antineoplastic agents and to use them alone or in combination with previously-used agents. Although 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. Consequently, investigators started to search whether or not, commonly and effectively used non-antineoplastic drugs long-used in clinic had antineoplastic effects and/or ability to potentiate antineoplastic drug cytotoxicity [2,3]. A plant alkaloid with well-known antitussive effects Noscapine (Nos) was investigated in these trials and Nos was proposed as a promising antineoplastic agent.
The anticancer action of * Correspondence: mine.erguven@gmail.com 1Yeni Yüzyıl University, Faculty of Medicine, Department of Biochemistry, Istanbul, Turkey Full list of author information is available at the end of the article Erguven et al. Cancer Cell International 2011, 11:18 http://www.cancerci.com/content/11/1/18 © 2011 Erguven et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.