Dataset Information

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells.

ABSTRACT: M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.

SUBMITTER: Wu ZX

PROVIDER: S-EPMC7235170 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells.

Wu Zhuo-Xun ZX Peng Zheng Z Yang Yuqi Y Wang Jing-Quan JQ Teng Qiu-Xu QX Lei Zi-Ning ZN Fu Yi-Ge YG Patel Ketankumar K Liu Lili L Lin Lizhu L Zou Chang C Chen Zhe-Sheng ZS

Frontiers in oncology 20200512

M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to i ...[more]

PMID: 32477940

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Project description:Introduction: The overexpression of ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, are two of the major mediators of multidrug resistance (MDR) in cancers. Although multiple ABCB1 and ABCG2 inhibitors have been developed and some have undergone evaluation in clinical trials, none have been clinically approved. The compound, MK-2206, an inhibitor of the protein kinases AKT1/2/3, is undergoing evaluation in multiple clinical trials for the treatment of certain types of cancers, including those resistant to erlotinib. In this in vitro study, we conducted in vitro experiments to determine if MK-2206 attenuates multidrug resistance in cancer cells overexpressing the ABCB1 or ABCG2 transporter. Methodology: The efficacy of MK-2206 (0.03-1 μM), in combination with the ABCB1 transporter sub-strates doxorubicin and paclitaxel, and ABCG2 transporter substrates mitoxantrone, SN-38 and topotecan, were determined in the cancer cell lines, KB-C2 and SW620/Ad300, which overexpress the ABCB1 transporter or H460/MX20 and S1-M1-80, which overexpress the ABCG2 transporter, respectively. The expression level and the localization of ABCG2 transporter on the cancer cells membranes were determined using western blot and immunofluorescence assays, respectively, following the incubation of cells with MK-2206. Finally, the interaction between MK-2206 and human ABCG2 transporter was predicted using computer-aided molecular modeling. Results: MK-2206 significantly increased the efficacy of anticancer compounds that were substrates for the ABCG2 but not the ABCB1 transporter. MK-2206 alone (0.03-1 μM) did not significantly alter the viability of H460/MX20 and S1-M1-80 cancer cells, which overexpress the ABCG2 transporter, compared to cells incubated with vehicle. However, MK-2206 (0.3 and 1 μM) significantly increased the anticancer efficacy of mitoxantrone, SN-38 and topotecan, in H460/MX20 and S1-M1-80 cancer cells, as indicated by a significant decrease in their IC50 values, compared to cells incubated with vehicle. MK-2206 significantly increased the basal activity of the ABCG2 ATPase (EC50 = 0.46 μM) but did not significantly alter its expression level and sub-localization in the membrane. The molecular modeling results suggested that MK-2206 binds to the active pocket of the ABCG2 transporter, by a hydrogen bond, hydrophobic interactions and π-π stacking. Conclusion: These in vitro data indicated that MK-2206 surmounts resistance to mitoxantrone, SN-38 and topotecan in cancer cells overexpressing the ABCG2 transporter. If these results can be translated to humans, it is possible that MK-2206 could be used to surmount MDR in cancer cells overexpressing the ABCG2 transporter.

Project description:The main characteristic of tumor cell resistance is multidrug resistance (MDR). MDR is the principle cause of the decline in clinical efficacy of chemotherapeutic drugs. There are several mechanisms that could cause MDR. Among these, one of the most important mechanisms underlying MDR is the overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) super-family of transporters, which effectively pump out cytotoxic agents and targeted anticancer drugs across the cell membrane. In recent years, studies found that ABC transporters and tyrosine kinase inhibitors (TKIs) interact with each other. TKIs may behave as substrates or inhibitors depending on the expression of specific pumps, drug concentration, their affinity for the transporters and types of co-administered agents. Therefore, we performed in vitro experiments to observe whether olmutinib could reverse MDR in cancer cells overexpressing ABCB1, ABCG2, or ABCC1 transporters. The results showed that olmutinib at 3 ?M significantly reversed drug resistance mediated by ABCG2, but not by ABCB1 and ABCC1, by antagonizing the drug efflux function in ABCG2-overexpressing cells. In addition, olmutinib at reversal concentration affected neither the protein expression level nor the localization of ABCG2. The results observed from the accumulation/efflux study of olmutinib showed that olmutinib reversed ABCG2-mediated MDR with an increasing intracellular drug accumulation due to inhibited drug efflux. We also had consistent results with the ATPase assay that olmutinib stimulated ATPase activity of ABCG2 up to 3.5-fold. Additionally, the molecular interaction between olmutinib and ABCG2 was identified by docking simulation. Olmutinib not only interacts directly with ABCG2 but also works as a competitive inhibitor of the transport protein. In conclusion, olmutinib could reverse ABCG2-mediated MDR. The reversal effect of olmutinib on ABCG2-mediated MDR cells is not due to ABCG2 expression or intracellular localization, but rather related to its interaction with ABCG2 protein resulting in drug efflux inhibition and ATPase stimulation.

Dataset Information

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells.

Publications

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells.

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