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10-Phenyltriazoyl Artemisinin is a Novel P-glycoprotein Inhibitor that Suppresses the Overexpression and Function of P-glycoprotein

Author(s):

Dong-Hwan Lee*, Md. Hasanuzzaman*, Daeho Kwon, Hye-Young Choi, So Myoung Kim, Dong Jin Kim, Dong Ju Kang, Tae-Ho Hwang, Hyung-Hoi Kim, Ho Jung Shin, Jae-Gook Shin, Sangtae Oh, Seokjoon Lee and So Won Kim   Pages 1 - 8 ( 8 )

Abstract:


Background: The effect of drugs on ATP-binding cassette transporters, especially permeability-glycoprotein (P-gp), is an important consideration during new anti-cancer drug development.

Objective: In this context, the effects of a newly synthesized artemisinin derivative, 10-(4-phenyl-1H-1,2,3-triazol)-artemisinin (5a), were evaluated on P-gp expression and function.

Methods: Reverse transcript polymerase chain reaction and immunoblotting techniques were used to determine the effect of 5a on P-gp expression in LS174T cells. In addition, the ability of 5a to work as either a substrate or an inhibitor of P-gp was investigated through different methods.

Results: The results revealed that 5a acts as a novel P-gp inhibitor that dually suppresses the overexpression and function of P-glycoprotein. Co-treatment of LS174T cell line, human colon adenocarcinoma cell line, with 5a and paclitaxel recovered the anticancer effect of paclitaxel by controlling the acquired drug resistance pathway. The overexpression of P-gp induced by rifampin and paclitaxel in a colorectal cell line was suppressed by 5a which could be a novel inhibitory substrate inhibiting the transport of paclitaxel by P-gp.

Conclusion: The results revealed that 5a can be classified as a type B P-gp inhibitor (with both substrate and inhibitor activities) with an additional function of suppressing P-gp overexpression. The results might be clinically useful in the development of anticancer drugs against cancers with multidrug resistance.

Keywords:

Artemisinin, Triazolyl artemisinin, P-glycoprotein, Rifampin, Paclitaxel

Affiliation:

Hallym Institute for Clinical Medicine, Hallym University Medical Center, Anyang, 14066, Department of Pharmacy, Noakhali Science and Technology University, Sonapur, Noakhali 3814, Department of Microbiology, Catholic Kwandong University College of Medicine, Gangneung 25601, Department of Pharmacology, Catholic Kwandong University College of Medicine, Gangneung 25601, Department of Pharmacology, Catholic Kwandong University College of Medicine, Gangneung 25601, Approval and Review Team, Medical Device Safety Bureau, Ministry of Food and Drug Safety, Cheongju 28159, Department of Pharmacology, Catholic Kwandong University College of Medicine, Gangneung 25601, Gene and Cell Therapy Research Center for Vessel-associated Diseases, Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Department of Laboratory Medicine, (Bio)Medical Research Institute, School of Medicine, Pusan National University, Pusan National University Hospital, Busan 4924, SPMED Co., Ltd., 111 Hyoyeol-ro, Buk-gu, Busan 46508, Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan 47392, Department of Basic Science, Catholic Kwandong University College of Medicine, Gangneung 25601, Department of Pharmacology, Catholic Kwandong University College of Medicine, Gangneung 25601, Department of Pharmacology, Catholic Kwandong University College of Medicine, Gangneung 25601



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