The Effects of Traditional Chinese Medicine on P-Glycoprotein–Mediated Multidrug Resistance and Approaches for Studying the Herb–P-Glycoprotein Interactions

Abstract

As a member of the ATP-dependent membrane transport proteins, P-Glycoprotein (P-gp) is known to pump substrates out of cells using an ATP-dependent mechanism. The overexpression of P-gp in tumor cells reduces the intracellular drug concentrations, which decreases the efficacy of extensive antitumor drugs and leads to multidrug resistance (MDR) clinically. The combination of anticancer drugs with P-gp inhibitor has been an attractive and promising strategy to reverse MDR in cancer treatment. However, nonspecific or nonselective distribution of P-gp inhibitors to nontarget organs is one of the most fatal shortcomings in clinical application. Thus, there is an urgent need for effective and nontoxic MDR reversal agents, particularly in P-gp-mediated MDR. Traditional Chinese medicine (TCM) natural products may prove less toxic for use in P-gp inhibition to promote MDR reversal. P-gp modulatory effects have been previously demonstrated using selected TCM, including the flavonoid, alkaloid, terpenoid, coumarin, and quinonoid compounds, and some Chinese medicine extracts. Moreover, the approaches for screening active components from TCM are necessary, and these approaches face challenges. At present, the approaches to study the interaction between TCM and P-gp are divided into in vitro, in vivo, and in silico methods. This review will provide an overview and update on the role of TCM in overcoming P-gp-mediated MDR and the approaches to study the interaction between TCM and P-gp. SIGNIFICANCE STATEMENT This review summarized some traditional Chinese medicines identified to have a modulatory effect on P-gp, including flavonoids, alkaloids, terpenoids, coumarins, quinonoid compounds, and some Chinese medicine extracts, and it introduced possible mechanisms. The approaches to study the interaction between TCM and P-gp are divided into in vitro, in vivo, and in silico methods.

The potential effects and mechanisms of Gegen Qinlian Decoction in oxaliplatin-resistant colorectal cancer based on network pharmacology

“…P-glycoprotein (P-gp) inhibitors, RNA interference, nano drugs, and combination drugs are new strategies against MDR; however, current clinical trials of related transporter protein inhibitors have been unsuccessful and have shown toxic side effects of these drugs ( Mohammad et al., 2020 ; Robey et al., 2018 ; Tian et al., 2012 ). Baicalein is a substrate of P-gp and competitively inhibits P-gp to enhance anticancer activity, and flavonoids and alkaloids also modulate P-gp, the main active component of GQD ( Cao et al., 2020 ; Palko-Labuz et al., 2017 ).…”

Nano Drug Delivery Systems: Effective Therapy Strategies to Overcome Multidrug Resistance in Tumor Cells

“…More and more attention has been paid to the development of new inhibitors from natural products of traditional Chinese medicine (TCM). Some TCM extracts, such as flavonoids, alkaloids, terpenoids, coumarins, and quinones, have been reported to have a good ability of inhibiting P‐gp and reversing MDR [94] …”

A Nanosized Codelivery System Based on Intracellular Stimuli-Triggered Dual-Drug Release for Multilevel Chemotherapy Amplification in Drug-Resistant Breast Cancer

“…In fact, over 90% of chemotherapy failures amidst patients with malignant tumors are related to MDR, resulting in unfavorable prognosis, recrudescent disease, and a decreased subsistence rate [5,6]. Recently, combination therapy of chemo-drugs with P-glycoprotein (P-gp)-targeted small-molecule inhibitors has been considered an advantageous approach in MDR reversal as numerous anticancer agents belong to substrates of P-gp, which is an overexpressed drug-efflux transporter, especially in malignant cells [7]. Unfortunately, although the present three generations of P-gp suppressants, including verapamil, biricodar, and elacridar, can restore the efficacy of chemotherapeutic drugs in vitro and in vivo, they seldom have been approved for clinical use due to some deficiencies, such as improper interactions with therapeutic agents and intolerable systemic adverse effects [8][9][10].…”