Biological Evaluation of DSF-1b a Synthetic Carbazole Derivative as an Anti-glioma Drug

  • 花 國書

Student thesis: Master's Thesis


Malignant glioma is considered to be the deadliest cancer type as it is highly invasive and neurologically destructive Despite decades of concerted effort and technological advances in neurosurgery radiotherapy and chemotherapy the therapeutic resistance and tumor recurrence still result in dismal prognosis with a five year survival rate of less than 5% Therefore developing a novel agent for treating malignant glioma is particularly imperative Carbazole a group of aromatic tricyclic compounds naturally occurred in Rutaceae plants has first been extracted in 1872 Its derivatives have been proposed to exert anti-proliferation activity against several types of cancers However the effectiveness and underlying mechanism by which carbazole derivatives inhibit malignant glioma progression remains poorly clarified Here we screened 16 novel synthetic carbazole derivatives for their cytotoxic effects against three glioma cell lines and found DSF-1b to be the most potent compound Using both cell proliferation and direct cell counting we further showed that DSF-1b not only attenuated glioma cell growth but also induced cell death while caused minimal harm to normal glia An interrupted cell cycle that failed to pass G2/M checkpoint was observed in all glioma cell lines However elevated percentage of cells in the sub-G1 phase within 48 hours was detected in U251 and T98G glioma but much less in C6 glioma This observation was consistent with the level of apoptotic hallmarks: caspase activation and chromatin condensation On the other hand Western blotting and immunofluorescent staining showed that C6 glioma underwent autophagy at 24 hours after DSF-1b treatment Interestingly ablation of DSF-1b-induced autophagy did not affect overall C6 glioma survival but induce cell death Besides above-mentioned apoptotic hallmarks were increased in C6 glioma pretreated with 3-MA Furthermore we also found that DSF-1b-induced ER stress was triggered before autophagy indicating ER stress may account for the DSF-1b-induced autophagy In conclusion our data demonstrated that DSF-1b inhibits three glioma cell lines growth by interfering cell cycle progression and inducing apoptosis In case of C6 glioma cell will stay in a non-proliferating stage and alleviate cytotoxic stress by triggering ER stress-associated autophagy
Date of Award2014 Jul 30
Original languageEnglish
SupervisorPo-Wu Gean (Supervisor)

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