2. Academic Validation
  3. Tenulin and isotenulin inhibit P-glycoprotein function and overcome multidrug resistance in cancer cells

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

  • Phytomedicine. 2019 Feb:53:252-262. doi: 10.1016/j.phymed.2018.09.008.
Ying-Tzu Chang 1,  Charles C N Wang 2,  Jiun-Yi Wang 3,  Tsui-Er Lee 4,  Yung-Yi Cheng 5,  Susan L Morris-Natschke 6,  Kuo-Hsiung Lee 7,  Chin-Chuan Hung 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, College of Pharmacy, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan, ROC.
  • 2 Department of Bioinformatics and Medical Engineering, Asia University. 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan, ROC.
  • 3 Department of Healthcare Administration, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan, ROC.
  • 4 Office of Physical Education, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan, ROC.
  • 5 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan, ROC.
  • 6 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
  • 7 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.; Chinese Medicine Research and Development Center, China Medical University and Hospital, 2 Yude Road, Taichung 40447, Taiwan, ROC.
  • 8 Department of Pharmacy, College of Pharmacy, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan, ROC; Department of Pharmacy, China Medical University Hospital, 2 Yude Road, Taichung 40447, Taiwan, ROC. Electronic address: cchung@mail.cmu.edu.tw.
PMID: 30668405 DOI: 10.1016/j.phymed.2018.09.008
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.

Keywords

Isotenulin; Kinetic mechanism; Multidrug resistance; P-glycoprotein; Sesquiterpene lactone; Tenulin.

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