Discipline: Biological Sciences
Subcategory: Cancer Research
Ebony Nottingham - Florida Agricultural and Mechanical University
Co-Author(s): Vsanthkumar Sekar,Florida A & M University, Tallahassee ,FL; Ravi Doddapaneni,Florida A & M University, Tallahassee ,FL; Arindam Mondal,Florida A & M University, Tallahassee ,FL; Stephen Safe ,Texas A&M University, College Station, Texas; Mandip Singh , Florida A & M University, Tallahassee ,FL
Background: Erlotinib, an EGFR selective reversible inhibitor, improved response of patients diagnosed with non-small cell lung cancer (NSCLC) with 70% of patients showing significant tumor regression upon treatment. Unfortunately,most patients eventually relapse due to development of resistance. Our research goal is to quantify the effects of combination treatment of Erlotinib with a glycyrrhetinic acid analogs and to improve the oral bioavailability of this treatment using Self-Nano-Emulsifying Drug Delivery Systems (SNEDDs). Methods: NSCLC cell lines HCC827, HCC827 (4µM Erlotinib resistant), HCC827 Cl4 (second site EGFR mutated), HCC827BEAS2B (normal epithelial cells), and H1975 (4µM Erlotinib resistant) were treated in combination with CDODA-Me, CF3CDODA-Me and Erlotinib. The cell viability assays were performed and combination index (CI) values were calculated by isobolographic analysis. SNEDDs were formulated and characterized through in vitro stability studies and in vivo pharmacokinetic studies. Results: CF3CDODA and CDODA-Me improved efficacy for erlotinib in all cell lines with IC50 values of 6.0±2.3 µM, 7.8±1.24 µM, 4.6± 0.85µM and 4.2±1.56µM for HCC827(RESISTANT), H1975(RESISTANT), HCC827CL4 and HCC827 respectively compared to IC50values of erlotinib alone (25±2.6µM, 21±3.4µM, 23±1.8µM, and 8±2.2µM). This was superior when compared to IC50 values of CDODA-Me combination treatment (6.66±1.4µM, 7.32±1.87µM, 12.06±1.05µM, and 5.45±2.1µM respectively). Combination treatment showed strong synergism with a constant concentration of 0.5µM CF3CDODA and CI values of 0.461, 0.548, 0.389, 0.550 for HCC827 4µM, H1975µM, HCC827CL4, and HCC827 respectively and antagonism in HCC827BEAS2B (1.508) cells. This is comparable to the synergism observed at a minimum concentration of 2µM CDODA-Me with CI values of 0.337, 0.67, 0.64, and 0.657 respectively and antagonism CI of 1.175 for HCC827BEAS2B. CF3CDODA Combination therapy showed a 2.5-fold decrease in colony formation in resistant cells making them comparable to wild type. This was comparable to CDODA-Me combination treatment with a 1.46-fold decrease in colony formation. Both combination treatments showed little effect on HCC827BEAS2B. Western Blot analysis showed decreased EGFR and MET phosphorylation indicating their kinase inhibition. SNEDD formulations increased maximum drug plasma concentrations for Erlotinib (281ng/ml to 442ng/ml) and circulating time as well (12hrs – 21hrs). Conclusions: Based on the results of these studies, CDODA-Me and CF3CDODA-Me have shown to overcome erlotinib resistance in non-small cell lung cancer and when combining these treatments with the use of SNEDDS, they have shown to be a promising treatment regimen.Nottingham ERN 2017 ABSTRACT 2.docx
Funder Acknowledgement(s): This study was supported, in part, by a CREST grant awarded to Mandip Sachdeva PhD, Pharmaceutics Section Leader, Florida A & M University, Tallahassee, FL, 32307.
Faculty Advisor: Mandip Sachdeva, firstname.lastname@example.org
Role: All experiment were performed by me with the assistance of my co-authors