• Chetomin as a Potent Hsp90 Inhibitor

      Leibou, Stav; Lu, Sumin; Debbab, Abdssamad; Chadli, Ahmed; Georgia Cancer Center (2017-03)
      Molecular chaperones have been the focus of intense research for their important role in cancer cell homeostasis. Heat shock protein 90 (Hsp90) promotes metastasis, evasion of apoptosis, and proliferative angiogenesis in tumors through preserving the stability and functionality of its client proteins [1]. While the first generation of Hsp90 inhibitors has proven effective in hindering Hsp90 function, they have shown low clinical efficacy in part due to the induction of anti-apoptotic proteins Hsp27, Hsp40, and Hsp70 [2,3]. It is therefore our objective to develop novel efficacious Hsp90 inhibitors without these detrimental effects. During our screen for novel Hsp90 inhibitors, we found that the natural product, Chetomin, is a potent inhibitor of the Hsp90 machine chaperoning activity. Our in vitro data using human and murine mammary carcinoma cell lines suggest that Chetomin is effective in causing degradation of several known Hsp90 physiological client proteins that are crucial to cancer cell proliferation and survival. While the molecular mechanism by which Chetomin inhibits the Hsp90 function is still unclear, our data suggests that Chetomin is highly efficacious in killing cancer cells without induction of the anti-apoptotic proteins as does the first generation of Hsp90 inhibitors making Chetomin a promising new therapeutic agent.
    • Investigating the Effects of DNA Damaging Agents on Survival in Hob1 Knockout Strains of Schizosaccharomyces Pombe

      Hashmi, Natasha; Department of Biological Sciences (2016-03)
      An important aspect of cancer research investigates why one tumor is resistant to chemotherapy while another tumor is sensitive to chemotherapy. The gene BIN1 when expressed renders chemoresistant cancer cells sensitive to DNA damaging agents in mammals. To better understand the extent of the chemosensitivity when BIN1 is expressed we are going to utilize the fission yeast, Schizosaccharomyces pombe. S. pombe has a functional homolog of BIN1 called HOB1 (Homolog Of Bin1). We have exposed both wild type and hob1Δ yeast strains to a wild variety of DNA damaging agents at various concentrations and accessed their survival rates. By comparing the sensitivities of wild type yeast to yeast lacking a function Hob1 protein we can have a better understanding of the role mammalian Bin1 protein plays in rendering cancer cells chemosensitive.