Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma.

Rat C6 glioma is a chemo-resistant experimental brain tumor that is difficult to treat with various drug combinations. Previous studies suggested that imatinib mesylate (Gleevec) is effective in pre-clinical trials for glioblastoma. Also, chlorimipramine (Anafranil) is an anti-depressant drug in use in the clinic and shown to have anti-neoplastic activity. We hypothesized that treatment of resistant C6 glioma with combination of imatinib and chlorimipramine may potentiate cytotoxicity and reverse resistance. C6 glioma was examined both as monolayer and as spheroid cultures. Several experimental designs were examined all of which showed synergistic activity albeit at different time kinetics. Combination treatment resulted in inhibition of cell growth and enhanced cell death as determined by dye exclusion. Further, the combination treatment resulted in significant induction of apoptosis as determined by Annexin V-FITC and PI. Also, there was inhibition of DNA synthesis and cAMP. Altogether, these findings supported the antiproliferative and cytotoxic effects of the combination treatment. Morphological studies were also performed using transmission and scanning electron microscopy. Significant synergistic apoptosis was detected by the combination treatment in both the monolayers and spheroid cultures. There was also a synergistic effect in autophagy by the combination. Several altered morphological features were noted by both the individual compound and enhanced by the combination treatment. The present findings support our hypothesis and demonstrate the potentiation of cytotoxicity by the com-bination of imatinib and chlorimipramine in C6 glioma. Further, the findings suggest the potential clinical application of the combination in the treatment of drug-resistant glioma

Combination of imatinib mesylate with lithium chloride and medroxyprogesterone acetate is highly active in Ishikawa endometrial carcinoma in vitro

Objective: The aim of the study was to investigate whether lithium chloride and medroxyprogesterone acetate can potentiate the cytotoxicity of imatinib mesylate in human endometrial cancer in vitro and the effect of midkine in these therapies

Decreased therapeutic effects of noscapine combined with imatinib mesylate on human glioblastoma in vitro and the effect of midkine

<p>Abstract</p> <p>Background</p> <p>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 <it>in vitro </it>and the role of midkine (MK) in this new combination treatment.</p> <p>Methods</p> <p>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-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.</p> <p>Results</p> <p>The 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 72^ndhr 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.</p> <p>Conclusions</p> <p>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.</p

Evaluation of Light-Emitting Diode (LED-660 Nm) Application over Primary Osteoblast-Like Cells on Titanium Surfaces: An In Vitro Study

Background: The goal of this study was to evaluate the behavior of neonatal rat calvarial osteoblast-like cells cultured on different implant surfaces and exposed once or three times to a 660-nm light-emitting diode (LED)

Drug-Resistant Glioma: Treatment with Imatinib Mesylate and Chlorimipramine

Glioblastoma (GBM) is the most common and malignant primary brain tumor. Despite recent advances in treatment regimens, the prognosis of patients remains poor. Although different combined therapies of surgery, radiation and chemotherapy are being essayed in order to cope with resistance and relapse to prolong survival time and reach complete remission, these have still demonstrated equivocal significant benefit. In chemotherapy era, this shortcoming lead investigators to design new antineoplastic agents. Although most of them reached their aim, one side of the coin shows that this process from bench to in vivo and phase trials take a lot of time and money resulting in more death and the formation and/or incidence of economic crisis. Another side of the coin is lack of stability and/or quality of patients' social life during chemotheraphy due to psychiatric disorders. Two parts of the coin are apart so they are not valuable. Consequently, investigators start to search whether commonly and effectively used non antineoplastic drugs for a long time in clinic has anti-neoplastic effects and/or has ability to potentiate antineoplastic drugs cytotoxicity or not. An antidepressant chlorimipramine (CIMP) has been being involved in these trials and proposed as a promising antineoplastic agent. In addition, investigators chose to experience current antineoplastic agents which their success were proved at specific cancer types for another cancer types such as an antileukemic agent imatinib mesylate (IM) in GBM. This chapter focuses on GBM, and the roles of IM and CIMP in the treatment of GBM

Combination of imatinib mesylate with lithium chloride and medroxyprogesterone acetate is highly active in Ishikawa endometrial carcinoma in vitro

Objective: The aim of the study was to investigate whether lithium chloride and medroxyprogesterone acetate can potentiate the cytotoxicity of imatinib mesylate in human endometrial cancer in vitro and the effect of midkine in these therapies

Lithium chloride has a biphasic effect on prostate cancer stem cells and a proportional effect on midkine levels

WOS: 000385579200110PubMed ID: 27703531Prostate cancer (PCa) is the second most frequent type of cancer in men worldwide and the levels of differentiation growth factor midkine (MK) are increased in PCa. Cancer and/or the treatment process itself may lead to psychiatric disorders. Lithium chloride (LiCl) has anti-manic properties and has been used in cancer therapy; however, it has a queried safety profile. In addition, cancer stem cells are responsible for the heterogeneous phenotype of tumor cells; they are involved in progression, metastasis, recurrence and therapy resistance in various cancer types. The aims of the present study were to investigate the effect of different concentrations of LiCl on PCa stem cells (whether a shift from tumorigenic to non-tumorigenic cells occurs) and to determine if these results can be explained through changes in MK levels. Monolayer and spheroid cultures of human prostate stem cells and non-stem cells were incubated with low (1, 10 mu M) and high (100, 500 mu M) concentrations of LiCl for 72 h. Cell proliferation, apoptotic indices, MK levels and ultrastructure were evaluated. Cells stimulated with low concentrations showed high proliferation, low apoptotic indices, high MK levels and more healthy ultrastructure. Opposite results were obtained at high concentrations. Furthermore, stem cells were more sensitive to stimulation and more resistant to inhibition than non-stem cells. LiCl exhibited concentration-dependent effects on stem cell and non-stem cell groups. MK levels were not involved in the biphasic effect of LiCl; however, they were proportionally affected. To the best of our knowledge, the present study was the first to show the effect of LiCl on PCa stem cells through MK

Effects of scopolamine treatment and consequent convulsion development in c–fos expression in fed, fasted, and refed mice

Fasting, anticholinergics, and seizures affect c-fos activation in the brain. Additionally, antimuscarinic treated fasted animals develop convulsion soon after re-feeding. Therefore, we assessed whether c-fos expression changes in fed, fasting, and refed animals and how scopolamine treatment affects these changes. We further assessed whether there is a change in c-fos expression after convulsions. For this purpose, BALB/c mice fasted for 1, 3, 6, 12, 24 and 48 h periods were used. The animals were treated with saline or scopolamine. Half of the animals treated with saline or scopolamine were given food 20 min after injection. All animals were observed for development of convulsions for 30 min. At the end of this period, the brains of all animals were removed, and the percentage of c-fos active cells in the hypothalamus was determined immunohistochemically. Convulsions occurred within 1-48 h of fasting, after scopolamine treatment and re-feeding. Compared to fed animals, c-fos expression was not significantly changed in those undergoing different fasting periods, but significantly decreased after 12 h fasting. After animals were allowed to eat, c-fos activation significantly increased in the 1, 3, 6 and 12 refed-saline groups and decreased in the 48 refed-saline group. Scopolamine treatment in 1-24 h fasted animals increased c-fos expression, but decreased in 48 h fasted animals. Whereas convulsion development in scopolamine-treated 3, 6, 12 and 24 h refed animals suppressed c-fos expression. These results demonstrate that re-feeding and scopolamine treatment induces neuronal activity in the hypothalamus, while scopolamine induced convulsions after food intake suppressed the c-fos activity

Antagonist activity of the antipsychotic drug lithium chloride and the antileukemic drug imatinib mesylate during glioblastoma treatment in vitro

Objectives: Glioblastoma (GBM), the most common primary tumour of the central nervous system, is characterised by a high malignancy and poor prognosis. The aims of this study were to investigate whether the combination of imatinib mesylate (IM) and lithium chloride (LiCl) exhibited a synergistic effect in treatment and to determine whether midkine (MK) affected the fate of this treatment in vitro