Browsing by Subject "Dimethylaminoparthenolide"

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    DCA and DMAPT as Radiosensitizing Drugs in the Treatment of Pancreatic Cancer
    (Office of the Vice Chancellor for Research, 2013-04-05) Cavazos, Ana; Mendonca, Marc
    Pancreatic cancer is currently one of the deadliest forms of cancer. This is due to high local recurrence and invasiveness. Recurrence is thought to be due in part to the resistance of pancreatic cancer cells. Treatment for pancreatic cancer includes chemotherapy, radiation therapy and surgery. Currently, about 94% of all patients diagnosed with pancreatic cancer die within 5 years of diagnosis. Thus, the focus of this research is to develop a better therapeutic approach to therapy in order to improve the killing of cancer cells and prevent recurrence. We investigated two drugs, Dichloroacetate (DCA) and Dimethylaminoparthenolide (DMAPT, a derivative of Parthenolide). Both DCA and DMAPT were studied for their ability to radiosensitize and help increase radiation induced cell killing in drug treated cancer cells. The experiment involved pancreatic cancer cells (MIA PACA2) being exposed to DMAPT, DCA, and dual treatment, with or without radiation. The cells were then tested for survival rates and doubling times. The hypothesis is that DCA and DMAPT will enhance radiation-induced cell killing of MIA PACA2 cells. The results show that DMAPT and DCA are in fact toxic to the pancreatic cancer cell lines. The dual treatment suppressed cell growth, and increased doubling time of MIA PACA2 cells. Dual treatment also decreased the survival rate of the MIA PACA2 cells (depending on radiation dosage). The data shows that dual treatment of DCA and DMAPT radiation are beneficial in slowing down the spread of pancreatic cancer. Future research will study the mechanisms of radiation sensitization and could help to develop a new technique to treat pancreatic cancer.
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    A water soluble parthenolide analogue suppresses in vivo tumor growth of two tobacco associated cancers, lung and bladder cancer, by targeting NF-κB and generating reactive oxygen species
    (Wiley, 2011-05-15) Shanmugam, Rajasubramaniam; Kusumanchi, Praveen; Appaiah, Hitesh; Cheng, Liang; Crooks, Peter; Neelakantan, Sundar; Peat, Tyler; Klaunig, James; Matthews, William; Nakshatri, Harikrishna; Sweeney, Christopher J
    Dimethylaminoparthenolide (DMAPT) is a water soluble parthenolide analogue with preclinical activity in hematologic malignancies. Using NSCLC cell lines (A549, H522) and an immortalized human bronchial epithelial cell line (BEAS2B) and TCC cell lines (UMUC-3, HT-1197, HT-1376) and a bladder papilloma (RT-4), we aimed to characterize DMAPT's anti-cancer activity in tobacco associated neoplasms. Flow cytometric, electrophorectic mobility gel shift assays (EMSA), and western blot studies measured generation of reactive oxygen species (ROS), inhibition of NFκB DNA binding, and changes in cell cycle distribution and apoptotic proteins. DMAPT generated ROS with subsequent JNK activation and also decreased NFκB DNA binding and anti-apoptotic proteins, TRAF-2 and XIAP. DMAPT induced apoptotic cell death and altered cell cycle distribution with upregulation of p21 and p73 levels in a cell type dependent manner. DMAPT suppressed cyclin D1 in BEAS2B. DMAPT retained NFκB and cell cycle inhibitory activity in the presence of the tobacco carcinogen nitrosamine ketone, 4(methylnitrosamino)-1-(3–pyridyl)-1-butanone (NNK). Using a BrdU accumulation assay, 5 to 20μM of DMAPT was shown to inhibit cellular proliferation of all cell lines by more than 95%. Oral dosing of DMAPT suppressed in vivo A549 and UMUC-3 subcutaneous xenograft growth by 54% (p=0.015) and 63% (p<0.01) respectively and A549 lung metastatic volume by 28% (p=0.043). In total this data demonstrates DMAPT's novel anti-cancer properties in both early and late stage tobacco associated neoplasms as well as its significant in vivo activity. The data provides support for the conduct of clinical trials in TCC and NSCLC.