The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter
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. I...
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MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/5/2463 |
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| author | Silpa Narayanan Nehaben A. Gujarati Jing-Quan Wang Zhuo-Xun Wu Jagadish Koya Qingbin Cui Vijaya L. Korlipara Charles R. Ashby Zhe-Sheng Chen |
| author_facet | Silpa Narayanan Nehaben A. Gujarati Jing-Quan Wang Zhuo-Xun Wu Jagadish Koya Qingbin Cui Vijaya L. Korlipara Charles R. Ashby Zhe-Sheng Chen |
| author_sort | Silpa Narayanan |
| collection | DOAJ |
| description | 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. <i>In vitro</i>, 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, <i>in vitro,</i> 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<sub>50</sub> = 2.3 µM). In conclusion, our study suggests that <i>in vitro</i>, 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. |
| first_indexed | 2024-03-09T06:08:41Z |
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| language | English |
| last_indexed | 2024-03-09T06:08:41Z |
| publishDate | 2021-02-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ad2a492337714defb6f22b848bd4f8702023-12-03T12:00:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01225246310.3390/ijms22052463The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 TransporterSilpa Narayanan0Nehaben A. Gujarati1Jing-Quan Wang2Zhuo-Xun Wu3Jagadish Koya4Qingbin Cui5Vijaya L. Korlipara6Charles R. Ashby7Zhe-Sheng Chen8Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USAThe 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. <i>In vitro</i>, 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, <i>in vitro,</i> 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<sub>50</sub> = 2.3 µM). In conclusion, our study suggests that <i>in vitro</i>, 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.https://www.mdpi.com/1422-0067/22/5/2463benzamideMDRreversal effectATP binding cassetteABCG2 |
| spellingShingle | Silpa Narayanan Nehaben A. Gujarati Jing-Quan Wang Zhuo-Xun Wu Jagadish Koya Qingbin Cui Vijaya L. Korlipara Charles R. Ashby Zhe-Sheng Chen The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter International Journal of Molecular Sciences benzamide MDR reversal effect ATP binding cassette ABCG2 |
| title | The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter |
| title_full | The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter |
| title_fullStr | The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter |
| title_full_unstemmed | The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter |
| title_short | The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter |
| title_sort | novel benzamide derivative vkng 2 restores the efficacy of chemotherapeutic drugs in colon cancer cell lines by inhibiting the abcg2 transporter |
| topic | benzamide MDR reversal effect ATP binding cassette ABCG2 |
| url | https://www.mdpi.com/1422-0067/22/5/2463 |
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