| Cancer seriously threatens human lives health. Glioma is one of the most common and malignant cancers. The glioma occupies 78% in the adult central nervous system (CNS) cancers. Most suffers are teenagers with high recurrence rate and low cure rate. Chemotherapeutic is the main way of clinical treatments for brain cancer. More and more efforts are carried out to explore and develop novel compounds that will prevent and treat malignant tumors. Thiazolidinones are a kind of active compounds, which has received considerable attention for its broad-spectrum anti-tumor activity and low toxicity. Therefore, it is critical and urgent to develop novel thiazolidinones compounds and study the anticancer mechanism to improve the treatment of human cancer.Objective:This project aims to evaluate the anticancer effect of Thiazolidinones (HBPT) on tumor-bearing mice, investigate its possible mechanism in cellular, sub-cellular aspects, and to evaluate its acute toxicity.Methods:SRB assay was applied to study the antitumor activities of thiazolidinone compound HBPT in U87MG cells in vitro. Acute toxicity was applied to appraise (evaluate) the safety of HBPT. Tumor treatment efficiency of HBPT was measured by U87MG tumor model in vivo. Alteration of apoptosis and cell cycle arrest induced by HBPT was detected using flow cytometer (FCM). Action of HBPT on tubulin was determined by immunofluorescence and microtubules kit. The kinase assay was applied to screen the possible targets.Results:1. The SRB suggested that thiazolidinones compounds (HBPT) exhibited obvious antiproliferative activity in U87MG cells with IC50 at about 20μM. The results of tumor bearing mice show that HBPT has high experimental therapeutic activity in inhibiting the tumor growth. The inhibition rates induced by 40 and 60 mg/kg HBPT were 63.61% and 73.16% in 2 weeks, respectively (P< 0.01).2. There was no significant difference of blood system and organs between HBPT treatments groups and solvent group, and there was also no loss of body weight treated with HBPT compared with solvent group. HBPT showed superiority compared with positive control TMZ.3. The flow cytometer results indicated that most of U87MG cells treated with HBPT were arrested at G2/M phase and then were initiated into apoptosis. By TEM observation, HBPT treated in U87MG cells induced autophagy, which protected U87MG cells in the treated process. Western blot results showed that intracellular expression of autophagy-related protein level was increased.4. The results of immunofluorescence and microtubules kit indicated that HBPT can inhibit microtubule polymerization in concentration and time dependent manners. The kinases screening show that HBPT do not regard any kineses as targets.5. The acute toxicity testing approved that HBPT had no obvious acute toxicity, and the maximum tolerated drug dose was 400mg/kg and 60mg/kg with administration by oral and intravenous injection respectively.Conclusion:HBPT was a potent agent against U87MG tumor cells in vivo and in vitro without blood and organs action, as well as no visible acute toxicity. HBPT could inhibit microtubule polymerization, arrest tumor cells at G2/M phase and induce apoptosis. Autophagy were observed in HBPT-treated U87MG cells, which display protective effect in HBPT treatment in vitro. HBPT did not regard kinases as targets in the tumor treatment. |
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