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

Ying Tzu (hallo)Chang, Charles C.N. Wang, Jiun Yi Wang, Tsui Er Lee, Yung Yi Cheng, Susan L Morris-Natschke, Kuo-Hsiung Lee, Chin Chuan Hung

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Pages252-262
Number of pages11
JournalPhytomedicine
Volume53
DOIs
StatePublished - Feb 1 2019

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Multiple Drug Resistance
P-Glycoprotein
Neoplasms
Cell Line
Doxorubicin
Adenosine Triphosphatases
Rhodamine 123
Sesquiterpenes
Lactones
tenulin
Biological Products
Pharmaceutical Preparations
Cell Survival
Drug Therapy
Therapeutics

Keywords

  • Isotenulin
  • Kinetic mechanism
  • Multidrug resistance
  • P-glycoprotein
  • Sesquiterpene lactone
  • Tenulin

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine

Cite this

Tenulin and isotenulin inhibit P-glycoprotein function and overcome multidrug resistance in cancer cells. / (hallo)Chang, Ying Tzu; Wang, Charles C.N.; Wang, Jiun Yi; Lee, Tsui Er; Cheng, Yung Yi; Morris-Natschke, Susan L; Lee, Kuo-Hsiung; Hung, Chin Chuan.

In: Phytomedicine, Vol. 53, 01.02.2019, p. 252-262.

Research output: Contribution to journalArticle

(hallo)Chang, Ying Tzu ; Wang, Charles C.N. ; Wang, Jiun Yi ; Lee, Tsui Er ; Cheng, Yung Yi ; Morris-Natschke, Susan L ; Lee, Kuo-Hsiung ; Hung, Chin Chuan. / Tenulin and isotenulin inhibit P-glycoprotein function and overcome multidrug resistance in cancer cells. In: Phytomedicine. 2019 ; Vol. 53. pp. 252-262.
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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.",
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T1 - Tenulin and isotenulin inhibit P-glycoprotein function and overcome multidrug resistance in cancer cells

AU - (hallo)Chang, Ying Tzu

AU - Wang, Charles C.N.

AU - Wang, Jiun Yi

AU - Lee, Tsui Er

AU - Cheng, Yung Yi

AU - Morris-Natschke, Susan L

AU - Lee, Kuo-Hsiung

AU - Hung, Chin Chuan

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

KW - Isotenulin

KW - Kinetic mechanism

KW - Multidrug resistance

KW - P-glycoprotein

KW - Sesquiterpene lactone

KW - Tenulin

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