Authors:

Abigail Hyejin Lee

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About Paper:

As drug discovery is known to be a labor, time, and cost-intensive process, computational drug repurposing provides a promising approach for identifying new applications of existing therapeutics. From a large-scale in silico drug screening, our lab has identified ciclopirox (CPX), an FDA-approved antifungal agent, as a top candidate for treating urothelial and renal carcinomas. CPX has previously demonstrated anti-tumor activity against other cancers through an iron chelation mechanism, however, its clinical application has been hampered by a limited half-life in vivo and low aqueous solubility. To mitigate these shortcomings, we developed the novel modified CPX-1 (mCPX-1) prodrug, which has structural modifications to improve both solubility and resistance to iron-mediated inactivation. Thus, this study investigates how mCPX-1 impacts cancer cell proliferation and provides resistance to iron-mediated inactivation in vitro as compared to conventional CPX and existing CPX prodrugs. Canine urothelial and human renal cancer cell cultures were first treated with CPX and selected prodrugs in the presence or absence of iron. Relative cell proliferation was then quantified with a Cell Counting Kit (CCK8) assay. Additionally, the impact of CPX on the activation of pathways associated with proliferation, such as the Wnt/β-catenin and Myc pathway, was determined using western blot. Results suggest that mCPX-1 exhibits the most potent anti-tumor activity and greatest resistance to iron-mediated inactivation in both urothelial and renal cancer cells. These findings provide insights on the activity, stability, and mechanism of CPX, and may support future exploration of mCPX-1 for in vivo animal models and ultimately human clinical trials. Keywords: Drug Repurposing; Ciclopirox; Urothelial carcinoma; Renal Carcinoma; Cell Proliferation

Source:

Purdue University / 2024

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Co-authors:

Abigail Hyejin Lee