Date on Master's Thesis/Doctoral Dissertation

12-2019

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Gupta, Ramesh

Committee Co-Chair (if applicable)

Chesney, Jason

Committee Member

Chesney, Jason

Committee Member

Yan, Jun

Committee Member

Luzzio, Frederick

Committee Member

Aqil, Farrukh

Author's Keywords

withaferin A; paclitaxel; efficacy; synergistic; toxicity, pharmacokinetics

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide and in the United States. Despite recent advancements in treatment approaches, chemoresistance and metastasis remain a major therapeutic challenge. Withaferin A (WFA), a plant-derived compound has recently emerged as a promising antitumor agent. In the present study, we explored the therapeutic potential of WFA against advanced NSCLC. Briefly, WFA was evaluated for its efficacy, toxicity and pharmacokinetic properties against advanced NSCLC using in vitro and in vivo models. Two human NSCLC cell lines, H1299 and A549 were used in cell culture to determine the anticancer properties of WFA. Repeat dose toxicity and pharmacokinetics were evaluated in male SD rats. Our findings show that WFA alone displayed time- and concentration-dependent cytotoxicity on NSCLC cells. Importantly, the combinations of WFA and paclitaxel (PAC) resulted in significant synergistic antiproliferative activity against H1299 and A549 cells. In addition, WFA was active against drug resistant TR-A549 cells in cell culture and xenografts. Mechanistically, WFA induced apoptosis, inhibited MDR1, EMT and regulated multiple pathways critical for the growth, migration and invasion of NSCLC cells. Further, WFA was well tolerated in male rats following 28 days oral dosing in male SD rats. A single intravenous bolus dose of WFA resulted in rapid distribution and clearance from rat plasma with a half-life In vitro, WFA displayed high plasma protein binding and rapid clearance from rat liver microsomes. Together, these data provide a strong rationale for further investigations to demonstrate the clinical efficacy of WFA against NSCLC.

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