A 20(S)‑protopanaxadiol derivative PPD12 reverses ABCB1‑mediated multidrug resistance with oral bioavailability and low toxicity

Wei,Shunfeng; Chen,Wantao; Hu,Lihong; Pan,Jinsong; Wang,Xu

doi:10.3892/ol.2018.9338

A 20(S)‑protopanaxadiol derivative PPD12 reverses ABCB1‑mediated multidrug resistance with oral bioavailability and low toxicity

Authors:
- Shunfeng Wei
- Wantao Chen
- Lihong Hu
- Jinsong Pan
- Xu Wang
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Affiliations: Department of Stomatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China, Department of Oral and Maxillofacial‑Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China, Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China
Published online on: August 21, 2018 https://doi.org/10.3892/ol.2018.9338
Pages: 5891-5899
Copyright: © Wei et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The ATP‑binding cassette subfamily B member 1 (ABCB1) is a transporter that mediates multidrug resistance (MDR) against chemotherapy, which leads to decreased patient survival. To inhibit ABCB1 activity in MDR cancer cells, the authors previously designed and synthesized a derivative from 20(S)‑protopanaxadiol (PPD) PPD12 and verified its efficacy in ABCB1‑overexpressing cancer cells. In the present study, the reversal effect of PPD12 on MDR was further evaluated and its pharmacokinetics and toxicity in vitro and in vivo were investigated. Incubation with PPD12 may significantly ameliorate the drug resistance of KB/VCR cells in a short time and maintain its reversed MDR ability for increasing time periods. In assays on a series of CYP450 activities, PPD12 demonstrated slight inhibition effects on the majority of enzymes. The bioavailability of PPD12 was nearly 100% by oral administration in a mouse model. Single PPD12 oral gavage at either high doses or subchronic low doses, was well tolerated by the mice. In addition, PPD12 at the therapeutic dosage did not significantly increase the toxicity of the chemotherapeutic agent Adriamycin when mice received a combination of the two compounds. In conclusion, PPD12 represents a novel type of ABCB1 inhibitor that has significant bioactivity in terms of MDR, high oral bioavailability and low toxicity.

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