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A 20(S)-protopanoxadiol derivative overcomes multi-drug resistance by antagonizing ATP-binding cassette subfamily B

Gang Chen1,2, Junhua Liu3, Wantao Chen1,2

  • 1Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P. R. China.

Oncotarget
|January 30, 2016
PubMed

Insights

A new compound, PPD12, effectively overcomes multi-drug resistance (MDR) in cancer cells by inhibiting the ABCB1 transporter. This PPD derivative enhances chemotherapy efficacy, offering a promising strategy for MDR cancer treatment.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Chemotherapy failure in cancer is often due to ATP-binding cassette subfamily B member 1 (ABCB1)-mediated multi-drug resistance (MDR).
  • Developing drugs to overcome ABCB1-mediated MDR remains a significant challenge in cancer treatment.

Purpose of the Study:

  • To investigate the role of novel 20(S)-protopanoxadiol (PPD) derivatives in modulating ABC transporter function.
  • To evaluate the potential of PPD derivative PPD12 in overcoming ABCB1-mediated MDR in cancer cells.

Main Methods:

  • Synthesized and tested PPD derivatives for their ability to sensitize ABCB1-overexpressing cells to anti-cancer drugs.
  • Assessed the effect of PPD12 on intracellular drug accumulation and ABCB1 ATPase activity.
  • Utilized homology modeling to predict PPD12 binding to human ABCB1.
  • Evaluated PPD12 efficacy in a xenograft mouse model.

Main Results:

  • PPD12 significantly sensitized ABCB1-overexpressing cells to anti-cancer substrates, increasing intracellular adriamycin and rhodamine123 accumulation.
  • PPD12 stimulated ABCB1 ATPase activity without affecting ABCB1 mRNA or protein expression, indicating a functional inhibition mechanism.
  • PPD12 demonstrated competitive inhibition, predicted to bind within the ABCB1 hydrophobic cavity.
  • PPD12 enhanced adriamycin efficacy against ABCB1-overexpressing xenografts in vivo.

Conclusions:

  • PPD12 effectively enhances the efficacy of chemotherapeutic agents in ABCB1-overexpressing cancer cells.
  • Combination therapy with PPD12 and conventional chemotherapy presents a potential therapeutic strategy for patients with ABCB1-mediated MDR cancers.
Keywords:
ABCB1apoptosischemotherapymulti-drug resistancepanax ginseng

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