Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Gupta, Pranav; Zhang, Yun-Kai; Zhang, Xiaoyu; Wang, Yijun; Lu, Kimberly; Hall, Timothy L.; Peng, Richard; Yang, Dong‐Hua; Xie, Ni; Chen, Zhe‐Sheng

doi:10.1159/000487578

Cited by 53 publications

(33 citation statements)

References 44 publications

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“…The results of the accumulation and efflux experiments were congruent with the reversal effects of VS-4718 shown in anti-cancer efficacy testing when co-administered with substrate-drugs, suggesting that VS-4718 may increase the accumulation of substrate-drugs in ABCB1- and ABCG2-overexpressing cancer cells by inhibiting the ABCB1- and ABCG2-mediated efflux activity, which led to the decline of IC 50 of substrate-drugs and finally attenuated the ABC transporter-mediated MDR. The results are also consistent with studies of our other small-molecule reversal reagents (Zhang et al, 2017 , 2018 ; Gupta et al, 2018 ).…”

Section: Discussionsupporting

confidence: 92%

VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters

Yang

Cai

et al. 2018

Front. Pharmacol.

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Overexpression of ATP-binding cassette (ABC) transporters is one of the most important mechanisms responsible for multi-drug resistance (MDR). VS-4718, a tyrosine kinase inhibitor targeting focal adhesion kinase (FAK) with a potential anticancer effect, is currently evaluated in clinical trials. In this study, we investigated whether VS-4718 could reverse MDR mediated by ABC transporters, including ABCB1, ABCG2, and ABCC1. The results showed that VS-4718 significantly reversed ABCB1- and ABCG2-mediated MDR, but not MDR mediated by ABCC1. Treatment of VS-4718 did not alter the protein level and subcellular localization of ABCB1 or ABCG2. Mechanism studies indicated that the reversal effects of VS-4718 were related to attenuation of the efflux activity of ABCB1 and ABCG2 transporters. ATPase analysis indicated that VS-4718 stimulated the ATPase activity of ABCB1 and ABCG2. Docking study showed that VS-4718 interacted with the substrate-binding sites of both ABCB1 and ABCG2, suggesting that VS-4718 may affect the activity of ABCB1 and ABCG2 competitively. This study provided a novel insight for MDR cancer treatment. It indicated that combination of VS-4718 with antineoplastic drugs could attenuate MDR mediated by ABCB1 or ABCG2 in ABCB1- or ABCG2-overexpressing cancer cells.

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Section: Discussionsupporting

confidence: 92%

VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters

Yang

Cai

et al. 2018

Front. Pharmacol.

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“…CC-671 obtained a docking score of −12.318 kcal/mol. Furthermore, the docking score of CC-671 is comparable to other reported ABCG2 reversal agents such as selonsertib (−11.094 kcal/mol), 56 voruciclib (−10.304 kcal/mol), 57 and ZM323881 (−11.509 kcal/mol). 58 Of note, the molecular docking is not meant to be an accurate affinity predictor, thereby the bound conformation might not represent the actual binding situation 59 and is therefore used as a reference in this study.…”

Section: Cc-671 Showed High Binding Affinity With Abcg2 In Moleculasupporting

confidence: 66%

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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“…It has been reported that the ATPase activity of P-gp was increased by voruciclib at low to moderate concentrations (not exceeding 7 μM) but was inhibited by CCT129202 [58], although both compounds were categorized as inhibitors/substrates [24]. Together with a recent report indicating that ATP binding to P-gp, but not inducing hydrolysis, promotes release of the substrate [26], these findings indicate that the variance in ATPase activity showing hydrolysis by ABC transporters may be a response to a ligand binding to ABC transporters but does not necessarily indicate inhibition or activation by this ligand.…”

Section: Discussionmentioning

confidence: 99%

“…The ATPase activity of P-gp and BCRP in crude membranes of High-Five insect cells was measured in the presence of BAY-1082439 (0 to 40 μM) by PREDEASY ATPase Kits with modified protocols, as previously described [23,24].…”

Section: Atpase Activity Assaymentioning

confidence: 99%

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

Zhang

Wang

et al. 2020

Mol Cancer

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Background: PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment. Methods: The effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP. Results: By inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb, the ATP-binding cassette transporters P-gp/ ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently. Conclusions: The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.

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Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Cited by 53 publications

References 44 publications

VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters

VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters

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

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

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