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Browsing by Author "Wikel, James H."
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Item Identification of new chemical entities targeting APE1 for the prevention of chemotherapy-induced peripheral neuropathy (CIPN)(ASPET, 2016-01-01) Kelley, Mark R.; Wikel, James H.; Guo, Chunlu; Pollok, Karen E.; Bailey, Barbara J.; Wireman, Randy; Fishel, Melissa L.; Vasko, Michael R.; Department of Pediatrics, School of MedicineChemotherapy-induced peripheral neuropathy (CIPN) is a potentially debilitating side effect of a number of chemotherapeutic agents that does not have any FDA-approved interventions or prevention strategies. Although the cellular mechanisms mediating CIPN remain to be determined, several lines of evidence support the notion that DNA damage may be a causative factor in neuropathy induced by a number of cancer therapies. Therapies including platinum agents and ionizing radiation cause DNA damage in sensory neurons and augmenting key steps in the base excision repair (BER) pathway reverses this damage. Neuronal protection is provided by overexpressing APE1 as well as using a first generation targeted APE1 small molecule E3330 (also called APX3330). Accordingly, we determined whether novel second-generation APE1 targeted molecules would be protective against neurotoxicity-induced by cisplatin or oxaliplatin while not diminishing the anti-tumor effect of the platins. We determined using our ex vivo model of sensory neurons in culture measuring various endpoints of neurotoxicity that APX2009 is an effective small molecule that is neuroprotective against cisplatin and oxaliplatin-induced toxicity of sensory neurons. APX2009 also demonstrated a strong tumor cell killing effect in tumor cells. Additionally, the enhanced tumor cell killing was further shown in a more robust 3D pancreatic tumor model. Together, these data suggest that APX2009 is effective in preventing or reversing platinum-induced CIPN, while not affecting the anti-cancer activity of platins.Item Ref-1/APE1 Inhibition with Novel Small Molecules Blocks Ocular Neovascularization(ASPET, 2018-10) Sardar Pasha, Sheik Pran Babu; Sishtla, Kamakshi; Sulaiman, Rania S.; Park, Bomina; Shetty, Trupti; Shah, Fenil; Fishel, Melissa L.; Wikel, James H.; Kelley, Mark R.; Corson, Timothy W.; Ophthalmology, School of MedicineOcular neovascular diseases like wet age-related macular degeneration are a major cause of blindness. Novel therapies are greatly needed for these diseases. One appealing antiangiogenic target is reduction-oxidation factor 1–apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1). This protein can act as a redox-sensitive transcriptional activator for nuclear factor (NF)-κB and other proangiogenic transcription factors. An existing inhibitor of Ref-1’s function, APX3330, previously showed antiangiogenic effects. Here, we developed improved APX3330 derivatives and assessed their antiangiogenic activity. We synthesized APX2009 and APX2014 and demonstrated enhanced inhibition of Ref-1 function in a DNA-binding assay compared with APX3330. Both compounds were antiproliferative against human retinal microvascular endothelial cells (HRECs; GI50 APX2009: 1.1 μM, APX2014: 110 nM) and macaque choroidal endothelial cells (Rf/6a; GI50 APX2009: 26 μM, APX2014: 5.0 μM). Both compounds significantly reduced the ability of HRECs and Rf/6a cells to form tubes at mid-nanomolar concentrations compared with control, and both significantly inhibited HREC and Rf/6a cell migration in a scratch wound assay, reducing NF-κB activation and downstream targets. Ex vivo, APX2009 and APX2014 inhibited choroidal sprouting at low micromolar and high nanomolar concentrations, respectively. In the laser-induced choroidal neovascularization mouse model, intraperitoneal APX2009 treatment significantly decreased lesion volume by 4-fold compared with vehicle (P < 0.0001, ANOVA with Dunnett’s post-hoc tests), without obvious intraocular or systemic toxicity. Thus, Ref-1 inhibition with APX2009 and APX2014 blocks ocular angiogenesis in vitro and ex vivo, and APX2009 is an effective systemic therapy for choroidal neovascularization in vivo, establishing Ref-1 inhibition as a promising therapeutic approach for ocular neovascularization.