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  1. Article ; Online: ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines

    Chung-Pu Wu / Cheng-Yu Hung / Ya-Ju Hsieh / Megumi Murakami / Yang-Hui Huang / Tsung-Yao Su / Tai-Ho Hung / Jau-Song Yu / Yu-Shan Wu / Suresh V. Ambudkar

    Cells, Vol 12, Iss 1056, p

    2023  Volume 1056

    Abstract: Constitutive activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts ...

    Abstract Constitutive activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts cancer cell proliferation via G2/M cell cycle arrest, the resistance mechanisms to HS-173 have not been investigated. In this study, we investigated the susceptibility of HS-173 to efflux mediated by the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most well-known ATP-binding cassette (ABC) transporters associated with the development of cancer multidrug resistance (MDR). We found that the overexpression of ABCB1 or ABCG2 significantly reduced the efficacy of HS-173 in human cancer cells. Our data show that the intracellular accumulation of HS-173 was substantially reduced by ABCB1 and ABCG2, affecting G2/M arrest and apoptosis induced by HS-173. More importantly, the efficacy of HS-173 in multidrug-resistant cancer cells could be recovered by inhibiting the drug-efflux function of ABCB1 and ABCG2. Taken together, our study has demonstrated that HS-173 is a substrate for both ABCB1 and ABCG2, resulting in decreased intracellular concentration of this drug, which may have implications for its clinical use.
    Keywords multidrug resistance ; ABCB1 ; ABCG2 ; PI3K ; HS-173 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Hydroxygenkwanin Improves the Efficacy of Cytotoxic Drugs in ABCG2-Overexpressing Multidrug-Resistant Cancer Cells

    Yan-Qing Li / Megumi Murakami / Yang-Hui Huang / Tai-Ho Hung / Shun-Ping Wang / Yu-Shan Wu / Suresh V. Ambudkar / Chung-Pu Wu

    International Journal of Molecular Sciences, Vol 23, Iss 12763, p

    2022  Volume 12763

    Abstract: Hydroxygenkwanin, a flavonoid isolated from the leaves of the Daphne genkwa plant, is known to have pharmacological properties; however, its modulatory effect on multidrug resistance, which is (MDR) mediated by ATP-binding cassette (ABC) drug ... ...

    Abstract Hydroxygenkwanin, a flavonoid isolated from the leaves of the Daphne genkwa plant, is known to have pharmacological properties; however, its modulatory effect on multidrug resistance, which is (MDR) mediated by ATP-binding cassette (ABC) drug transporters, has not been investigated. In this study, we examine the interaction between hydroxygenkwanin, ABCB1, and ABCG2, which are two of the most well-characterized ABC transporters known to contribute to clinical MDR in cancer patients. Hydroxygenkwanin is not an efflux substrate of either ABCB1 or ABCG2. We discovered that, in a concentration-dependent manner, hydroxygenkwanin significantly reverses ABCG2-mediated resistance to multiple cytotoxic anticancer drugs in ABCG2-overexpressing multidrug-resistant cancer cells. Although it inhibited the drug transport function of ABCG2, it had no significant effect on the protein expression of this transporter in cancer cells. Experimental data showing that hydroxygenkwanin stimulates the ATPase activity of ABCG2, and in silico docking analysis of hydroxygenkwanin binding to the inward-open conformation of human ABCG2, further indicate that hydroxygenkwanin sensitizes ABCG2-overexpressing cancer cells by binding to the substrate-binding pocket of ABCG2 and attenuating the transport function of ABCG2. This study demonstrates the potential use of hydroxygenkwanin as an effective inhibitor of ABCG2 in drug combination therapy trials for patients with tumors expressing higher levels of ABCG2.
    Keywords ABC-transporter ; multidrug resistance ; chemosensitizer ; natural products ; ABCG2 ; hydroxygenkwanin ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 610
    Language English
    Publishing date 2022-10-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: ABCB1 limits the cytotoxic activity of TAK-243, an inhibitor of the ubiquitin-activating enzyme UBA1

    Zhuoxun Wu / Yuqi Yang / Zining Lei / Silpa Narayanan / Jingquan Wang / Qiuxu Teng / Megumi Murakami / Suresh V. Ambudkar / Fengfeng Ping / Zhesheng Chen

    Frontiers in Bioscience-Landmark, Vol 27, Iss 1, p

    2022  Volume 005

    Abstract: Background: One of the major concerns of cancer therapy is the emergence of multidrug resistance (MDR). The MDR-associated ATP-binding cassette sub-family B member 1 (ABCB1) transporter is established to mediate resistance against numerous anticancer ... ...

    Abstract Background: One of the major concerns of cancer therapy is the emergence of multidrug resistance (MDR). The MDR-associated ATP-binding cassette sub-family B member 1 (ABCB1) transporter is established to mediate resistance against numerous anticancer drugs. In this study, we demonstrated that the Ubiquitin-like modifier activating enzyme 1 (UBA1) inhibitor TAK-243 is transported by the ABCB1. Methods: MTT assay was performed to evaluate the cytotoxicity of TAK-243. Western blot was carried out to investigate if TAK-243 affect to ABCB1 protein expression in cancer cells. High Performance Liquid Chromatography (HPLC) and ATPase assay were carried out to confirm TAK-243 as an ABCB1 substrate. [3H]-paclitaxel accumulation assay was used to determine the MDR reversal effect of TAK-243. Computational docking analysis was performed to investigate the drug-transporter binding position. Results: The cytotoxicity profile showed that TAK-243 was less effective in ABCB1-overexpressing cells than in the parental cells, but pharmacological inhibition or knockout the gene of ABCB1 was able to reverse TAK-243 resistance. Furthermore, TAK-243 potently stimulated ABCB1 ATPase activity and the HPLC analysis revealed that TAK-243 accumulation was significantly reduced in ABCB1-overexpressing cells. Finally, the computational docking analysis indicates a high binding affinity between TAK-243 and human ABCB1 transporter. Conclusions: Our in vitro data characterized TAK-243 as a substrate of ABCB1, which may predict limited anticancer effect of this compound in drug resistant tumors.
    Keywords ubiquitin-activating enzyme ; tak-243 ; multidrug resistance ; abcb1 ; in vitro cytotoxicity ; Biochemistry ; QD415-436 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher IMR Press
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Branebrutinib (BMS-986195), a Bruton’s Tyrosine Kinase Inhibitor, Resensitizes P-Glycoprotein-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Agents

    Chung-Pu Wu / Megumi Murakami / Yu-Shan Wu / Ya-Chen Chi / Sung-Han Hsiao / Yang-Hui Huang / Tai-Ho Hung / Suresh V. Ambudkar

    Frontiers in Cell and Developmental Biology, Vol

    2021  Volume 9

    Abstract: The overexpression of P-glycoprotein (P-gp/ABCB1), an ATP-binding cassette (ABC) drug transporter, often contributes to the development of multidrug resistance (MDR) in cancer cells. P-gp mediates the ATP hydrolysis-dependent efflux of a wide range of ... ...

    Abstract The overexpression of P-glycoprotein (P-gp/ABCB1), an ATP-binding cassette (ABC) drug transporter, often contributes to the development of multidrug resistance (MDR) in cancer cells. P-gp mediates the ATP hydrolysis-dependent efflux of a wide range of chemotherapeutic agents out of cancer cells, thereby reducing the intracellular drug accumulation and decreasing the chemosensitivity of these multidrug-resistant cancer cells. Studies with tyrosine kinase inhibitors (TKIs) in P-gp-overexpressing cells have shown that certain TKIs could reverse MDR mediated by P-gp, while some TKIs are transported by P-gp. In the present work, we explored the prospect of repositioning branebrutinib (BMS-986195), a highly selective inhibitor of Bruton’s tyrosine kinase (BTK), to resensitize P-gp-overexpressing multidrug-resistant cancer cells to chemotherapeutic agents. Our results demonstrated that branebrutinib is capable of reversing P-gp-mediated MDR at sub-toxic concentrations, most likely by directly inhibiting the drug transport function of P-gp. Our findings were supported by the result of branebrutinib stimulating the ATPase activity of P-gp in a concentration-dependent manner and the in silico study of branebrutinib binding to the substrate-binding pocket of P-gp. In addition, we found that branebrutinib is equally cytotoxic to drug-sensitive parental cell lines and the respective P-gp-overexpressing multidrug-resistant variants, suggesting that it is unlikely that the overexpression of P-gp in cancer cells plays a significant role in reduced susceptibility or resistance to branebrutinib. In summary, we discovered an additional pharmacological action of branebrutinib against the activity of P-gp, which should be investigated further in future drug combination studies.
    Keywords multidrug resistance ; chemotherapy ; P-glycoprotein ; ABCB1 ; branebrutinib ; BMS-986195 ; Biology (General) ; QH301-705.5
    Subject code 500
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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