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Tenulin and isotenulin inhibit P-glycoprotein function and overcome multidrug resistance in cancer cells.

ABSTRACT: BACKGROUND:Multidrug resistance (MDR) in cancer is one of the main obstacles in treatment with chemotherapy. Drug efflux through P-glycoprotein is the major mechanism involved in MDR. A potential strategy to provide the best possible clinical outcomes is to develop P-glycoprotein (P-gp) inhibitors from natural products. PURPOSE:The present study investigated the effects of the natural sesquiterpene lactone tenulin and its derivative isotenulin on human P-gp; the mechanisms of kinetic interactions were also explored. METHODS:The human P-gp (ABCB1/Flp-In™-293) stable expression cells were established by using the Flp-In™ system. The effects of tenulin and isotenulin on cell viability were evaluated by SRB assays in established cell lines, sensitive cancer cell line (HeLaS3), and resistant cancer cell line (KB-vin). The transporter inhibition ability was evaluated by calcein-AM uptake assays. The P-gp inhibition kinetics of tenulin and isotenulin were evaluated by rhodamine123 and doxorubicin efflux assays. The ATPase activity was evaluated with the Pgp-Glo™ Assay System. RESULTS:Tenulin and isotenulin significantly inhibited the P-gp efflux function by stimulating P-gp ATPase activity. Tenulin and isotenulin interacted with the effluxes of rhodamine 123 and doxorubicin through a competitive and noncompetitive mechanism, respectively. The combinations of tenulin and isotenulin with chemotherapeutic drugs significantly resensitized MDR cancer cells. CONCLUSION:These results suggested that tenulin and isotenulin are potential candidates to be developed for synergistic treatment of MDR cancers.

SUBMITTER: Chang YT

PROVIDER: S-EPMC6421864 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Tenulin and isotenulin inhibit P-glycoprotein function and overcome multidrug resistance in cancer cells.

Chang Ying-Tzu YT Wang Charles C N CCN Wang Jiun-Yi JY Lee Tsui-Er TE Cheng Yung-Yi YY Morris-Natschke Susan L SL Lee Kuo-Hsiung KH Hung Chin-Chuan CC

Phytomedicine : international journal of phytotherapy and phytopharmacology 20180905

<h4>Background</h4>Multidrug resistance (MDR) in cancer is one of the main obstacles in treatment with chemotherapy. Drug efflux through P-glycoprotein is the major mechanism involved in MDR. A potential strategy to provide the best possible clinical outcomes is to develop P-glycoprotein (P-gp) inhibitors from natural products.<h4>Purpose</h4>The present study investigated the effects of the natural sesquiterpene lactone tenulin and its derivative isotenulin on human P-gp; the mechanisms of kine ...[more]

PMID: 30668405

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Project description:Multidrug resistance (MDR) to chemotherapeutic drugs remains one of the major impediments to the treatment of cancer. Discovery and development of drugs that can prevent and reverse the acquisition of multidrug resistance constitute a foremost challenge in cancer therapeutics. In this work, we screened a library of 1,127 compounds with known targets for their ability to overcome Pgp-mediated multidrug resistance in cancer cell lines. We identified four compounds (CHIR-124, Elesclomol, Tyrphostin-9 and Brefeldin A) that inhibited the growth of two pairs of parental and Pgp-overexpressing multidrug-resistant cell lines with similar potency irrespective of their Pgp status. Mechanistically, CHIR-124 (a potent inhibitor of Chk1 kinase) inhibited Pgp activity in both multidrug-resistant cell lines (KB-V1 and A2780-Pac-Res) as determined through cell-based Pgp-efflux assays. Other three inhibitors on the contrary, were effective in Pgp-overexpressing resistant cells without increasing the cellular accumulation of a Pgp substrate, indicating that they overcome resistance by avoiding efflux through Pgp. None of these compounds modulated the expression of Pgp in resistant cell lines. PIK-75, a PI3 Kinase inhibitor, was also determined to inhibit Pgp activity, despite being equally potent in only one of the two pairs of resistant and parental cell lines. Strong binding of both CHIR-124 and PIK-75 to Pgp was predicted through docking studies and both compounds inhibited Pgp in a biochemical assay. The inhibition of Pgp causes accumulation of these compounds in the cells where they can modulate the function of their target proteins and thereby inhibit cell proliferation. In conclusion, we have identified compounds with various cellular targets that overcome multidrug resistance in Pgp-overexpressing cell lines through mechanisms that include Pgp inhibition and efflux evasion. These compounds, therefore, can avoid challenges associated with the co-administration of Pgp inhibitors with chemotherapeutic or targeted drugs such as additive toxicities and differing pharmacokinetic properties.

Dataset Information

Tenulin and isotenulin inhibit P-glycoprotein function and overcome multidrug resistance in cancer cells.

Publications

Tenulin and isotenulin inhibit P-glycoprotein function and overcome multidrug resistance in cancer cells.

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