CM082 Enhances the Efficacy of Chemotherapeutic Drugs by Inhibiting the Drug Efflux Function of ABCG2

Xu, Lejia; Huang, Jiwei; Xi, Yun; Zheng, Zongheng; To, Kenneth K.W.; Chen, Zhen; Wang, Fang; Zhang, Yongming; Fu, Liwu

doi:10.1016/j.omto.2019.12.007

Cited by 9 publications

(8 citation statements)

References 36 publications

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“…VKNG-2 did not significantly alter the anticancer efficacy of mitoxantrone or SN-38 in the parental S1 colon cancer cells that do not overexpress the ABCG2 transporter. This finding is congruent with previous studies reporting that the efficacy of certain anticancer drugs in parental cancer cell lines that do not express the ABCG2 transporter is not altered by compounds that decrease the efflux and/or expression of the ABCG2 transporter [ 45 , 46 , 47 ]. However, in the S1-M1-80 colon cancer cells, 1 or 5 µM of VKNG-2 significantly increased the efficacy (i.e., decreased resistance) of the ABCG2 substrates, mitoxantrone and SN-38, in comparison with the cells incubated with the vehicle similar to FTC, as previously reported [ 48 ], suggesting that one of the mechanisms by which VKNG-2 reverses ABCG2-mediated drug resistance is by inhibiting the ABCG2 transporter.…”

Section: Discussionsupporting

confidence: 92%

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

Narayanan

Gujarati

Wang

et al. 2021

IJMS

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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. In vitro, 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, in vitro, 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 (EC50 = 2.3 µM). In conclusion, our study suggests that in vitro, 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.

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Section: Discussionsupporting

confidence: 92%

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

Narayanan

Gujarati

Wang

et al. 2021

IJMS

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“…40,41 Therefore, a large number of investigations have been undertaken in an effort to search for effective reversal agents targeting ABCG2 to overcome MDR. [42][43][44][45] In the present study, we investigated the possibility of using CC-671, a dual inhibitor of TTK/CLK2, to reverse ABCG2-mediated MDR.…”

Section: Discussionmentioning

confidence: 99%

“…ABCG2 has long been characterized as a major MDR contributor that can pump out a wide range of anticancer drugs including mitoxantrone, doxorubicin, topotecan, and some tyrosine kinase inhibitors 40,41 . Therefore, a large number of investigations have been undertaken in an effort to search for effective reversal agents targeting ABCG2 to overcome MDR 42‐45 . In the present study, we investigated the possibility of using CC‐671, a dual inhibitor of TTK/CLK2, to reverse ABCG2‐mediated MDR.…”

Section: Discussionmentioning

confidence: 99%

Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells

Yang

Wang

et al. 2020

Cancer Science

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One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2‐mediated MDR. CC‐671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC‐671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2‐overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC‐671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC‐671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC‐671 has high binding affinity to the drug‐binding site of ABCG2. In conclusion, we reveal the interaction between CC‐671 and ABCG2, providing a rationale for the potential combined use of CC‐671 with ABCG2 substrate to overcome MDR.

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“…10 Enhanced chemotherapeutic drug efficacy has also been shown by inhibition of the drug efflux function of ABCG2, a potential ATP-binding cassette transporter. 11 Several pharmacodynamic and pharmacokinetic studies and/or phase I clinical trials of vorolanib, alone or combined with other targeted therapy or chemotherapeutic agents, 12 have been performed in advanced RCC and lung cancer. 10,[12][13][14][15] A randomized phase 2/3, double-blinded, multi-center trial of vorolanib and everolimus in patients with pretreated metastatic RCC is ongoing.…”

Section: Introductionmentioning

confidence: 99%

Vorolanib, a novel tyrosine receptor kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity

Liang

Yuan

Shen

et al. 2022

Molecular Therapy - Oncolytics

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CM082 Enhances the Efficacy of Chemotherapeutic Drugs by Inhibiting the Drug Efflux Function of ABCG2

Cited by 9 publications

References 36 publications

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

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

Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells

Vorolanib, a novel tyrosine receptor kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity

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