The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter

• Published in: International journal of molecular sciences Vol. 22; no. 5; p. 2463
• Main Authors: Narayanan, Silpa, Gujarati, Nehaben A, Wang, Jing-Quan, Wu, Zhuo-Xun, Koya, Jagadish, Cui, Qingbin, Korlipara, Vijaya L, Ashby, Jr, Charles R, Chen, Zhe-Sheng
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 28.02.2021; MDPI AG
• Subjects: ABCG2; Antineoplastic Agents - pharmacology; ATP binding cassette; ATP Binding Cassette Transporter, Subfamily G, Member 2 - antagonists & inhibitors; benzamide; Benzamides - chemistry; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Humans; Irinotecan - pharmacology; MDR; Mitoxantrone - pharmacology; Neoplasm Proteins - antagonists & inhibitors; reversal effect; Topoisomerase I Inhibitors - pharmacology; Tumor Cells, Cultured; benzamide; reversal effect; MDR; ATP binding cassette; ABCG2
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22052463

The overexpression of ATP-binding cassette transporter, ABCG2, plays an important role in mediating multidrug resistance (MDR) in certain types of cancer cells. ABCG2-mediated MDR can significantly attenuate or abrogate the efficacy of anticancer drugs by increasing their efflux from cancer cells. In this study, we determined the efficacy of the novel benzamide derivative, VKNG-2, to overcome MDR due to the overexpression of the ABCG2 transporter in the colon cancer cell line, S1-M1-80. , 5 μM of VKNG-2 reversed the resistance of S1-M1-80 cell line to mitoxantrone (70-fold increase in efficacy) or SN-38 (112-fold increase in efficacy). In contrast, 5 μM of VKNG-2 did not significantly alter either the expression of ABCG2, AKT, and PI3K p110β protein or the subcellular localization of the ABCG2 protein compared to colon cancer cells incubated with the vehicle. Molecular docking data indicated that VKNG-2 had a high docking score (-10.2 kcal/mol) for the ABCG2 transporter substrate-drug binding site whereas it had a low affinity on ABCB1 and ABCC1 transporters. Finally, VKNG-2 produced a significant concentration-dependent increase in ATPase activity (EC = 2.3 µM). In conclusion, our study suggests that , VKNG-2 reverses the resistance of S1-M1-80, a cancer cell line resistant to mitoxantrone and SN-38, by inhibiting the efflux function of the ABCG2 transporter.