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Zhankuic Acids A, B and C from Taiwanofungus Camphoratus Act as Cytotoxicity Enhancers by Regulating P-Glycoprotein in Multi-Drug Resistant Cancer Cells

1
Department of Medicine, College of Medicine, I-Shou University, 8 Yida Road, Kaohsiung 82445, Taiwan
2
Department of Pharmacy, Nantou Hospital, Ministry of Health and Welfare, 478 Fuxing Rd., Nantou City, Nantou County 540, Taiwan
3
Department of Pharmacy, College of Pharmacy, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan
4
School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
5
Department of Pharmacy, College of Pharmacy and Health Care, Tajen University, Pingtung 907, Taiwan
6
Department of Pharmacy, China Medical University Hospital, 2 Yude Road, Taichung 40447, Taiwan
*
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(12), 759; https://doi.org/10.3390/biom9120759
Received: 26 October 2019 / Revised: 18 November 2019 / Accepted: 19 November 2019 / Published: 21 November 2019
: Since P-glycoprotein (P-gp)-related multidrug resistance (MDR) remains the most important unsolved problem in cancer treatment, scientists are attempting to find potential structures from natural resources. The aim of the present study was to elucidate whether the triterpenoids from Taiwanofungus camphoratus could reverse cancer MDR by influencing P-gp efflux pump. Substrates efflux assay and P-gp ATPase activity assay were conducted to reveal the molecular mechanisms of P-gp inhibition, while SRB assay, cell cycle analyses and apoptosis analyses were performed to confirm the cancer MDR modulating effects. The results indicated that Zhankuic acids A, B and C (ZA-A, ZA-B and ZA-C) impacted P-gp efflux function in competitive, noncompetitive and competitive manners, respectively. Furthermore, these triterpenoids all demonstrated inhibitory patterns on both basal P-gp ATPase activity and verapamil-stimulated ATPase activity. In terms of MDR reversal effects, ZA-A sensitized the P-gp over-expressing cell line (ABCB1/Flp-InTM-293) and MDR cancer cell line (KB/VIN) toward clinically used chemotherapeutic drugs, including doxorubicin, paclitaxel and vincristine, exhibiting the best cytotoxicity enhancing ability among investigated triterpenoids. The present study demonstrated that ZA-A, ZA-B and ZA-C, popular triterpenoids from T. camphoratus, effectively modulated the drug efflux transporter P-gp and reversed the cancer MDR issue.
Keywords: multidrug resistance; p-glycoprotein; Taiwanofungus camphoratus; Zhankuic acid multidrug resistance; p-glycoprotein; Taiwanofungus camphoratus; Zhankuic acid
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Teng, Y.-N.; Wang, Y.-H.; Wu, T.-S.; Hung, H.-Y.; Hung, C.-C. Zhankuic Acids A, B and C from Taiwanofungus Camphoratus Act as Cytotoxicity Enhancers by Regulating P-Glycoprotein in Multi-Drug Resistant Cancer Cells. Biomolecules 2019, 9, 759.

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