Browsing by Author "Bapat, Aditi"

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    Going Ape as an Approach to Cancer Therapeutics
    (2009-09) Bapat, Aditi; Fishel, Melissa L.; Kelley, Mark R.
    The DNA base excision repair (BER) pathway repairs alkylation and oxidative DNA damage caused by endogenous and exogenous agents, including chemotherapeutic agents. Upon removal of the damaged base AP endonuclease 1 (Ape1), a critical component of the pathway cleaves the abasic site to facilitate repair. Ape1 is a multifunctional protein which plays a role not only in DNA repair but it also functions as a reduction–oxidation factor, known as Ref-1 in the literature, to increase the DNA binding ability of several transcription factors involved in different growth signaling pathways. Elevated levels of Ape1 have been linked to resistance to chemotherapy, poor prognosis, and poor survival. Reducing the amount of Ape1 protein in cancer cells and tumors using RNA interference and anti-sense oligonucleotide technology sensitizes mammalian tumor cells to a variety of laboratory and chemotherapeutic agents. Therefore, selective inhibition of Ape1's DNA repair activity is a promising avenue to develop novel cancer therapeutics.
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    Semi-automated high-throughput fluorescent intercalator displacement-based discovery of cytotoxic DNA binding agents from a large compound library
    (2010-03) Glass, LaTeca S.; Bapat, Aditi; Kelley, Mark R.; Georgiadis, Millie M.; Long, Eric C.
    High-throughput fluorescent intercalator displacement (HT–FID) was adapted to the semi-automated screening of a commercial compound library containing 60,000 molecules resulting in the discovery of cytotoxic DNA-targeted agents. Although commercial libraries are routinely screened in drug discovery efforts, the DNA binding potential of the compounds they contain has largely been overlooked. HT–FID led to the rapid identification of a number of compounds for which DNA binding properties were validated through demonstration of concentration-dependent DNA binding and increased thermal melting of A/T- or G/C-rich DNA sequences. Selected compounds were assayed further for cell proliferation inhibition in glioblastoma cells. Seven distinct compounds emerged from this screening procedure that represent structures unknown previously to be capable of targeting DNA leading to cell death. These agents may represent structures worthy of further modification to optimally explore their potential as cytotoxic anti-cancer agents. In addition, the general screening strategy described may find broader impact toward the rapid discovery of DNA targeted agents with biological activity.