Design, Biological Evaluation, and Molecular Modeling of Tetrahydroisoquinoline Derivatives: Discovery of A Potent P-Glycoprotein Ligand Overcoming Multidrug Resistance in Cancer Stem Cells

Abstract

P-Glycoprotein is a well-known membrane transporter responsible for the efflux of an ample spectrum of anticancer drugs. Its relevance in the management of cancer chemotherapy is increased in view of its high expression in cancer stem cells, a population of cancer cells with strong tumor-promoting ability. In the present study, a series of compounds were synthesized through structure modulation of [4′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)­biphenyl-4-ol] (MC70), modifying the phenolic group of the lead compound. Among them, compound 5b emerged for its activity against the transporter (EC50 = 15 nM) and was capable of restoring doxorubicin antiproliferative activity at nontoxic concentration. Its behavior was rationalized through a molecular modeling study consisting of a well-tempered metadynamics simulation, which allowed one to identify the most favorable binding pose, and of a subsequent molecular dynamics run, which indicated a peculiar effect of the compound on the motion pattern of the transporter.

Wnt/IL‐1β/IL‐8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5

“…We cannot exclude a priori that other ABC transporters expressed in MPM IC, such as ABCG2 and ABCB1, another target of Wnt pathway, mediate chemoresistance. Recently, we also found ABCB2, ABCC1, ABCC6 overexpressed in UPN1, UPN4 and UPN6‐derived IC, compared to AC . Cisplatin is a substrate of ABCC1 and ABCC6; pemetrexed is poorly recognized by all these transporters .…”

“…Recently, we also found ABCB2, ABCC1, ABCC6 overexpressed in UPN1, UPN4 and UPN6-derived IC, compared to AC. 40 Cisplatin is a substrate of ABCC1 and ABCC6; pemetrexed is poorly recognized by all these transporters. 41,42 In contrast, ABCB5 is known to induce resistance to carboplatin 22 and to recognize a broad spectrum of chemotherapeutic drugs.…”

MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor

“…These experiments were carried out as described by Riganti et al, with minor modifications [55]. Each cell line (30,000 cells per well) was seeded into a black CulturePlate 96/well plate with a 100 µL medium and allowed to become confluent overnight.…”

“…The determination of cell growth was performed using an MTT assay at 24 or 72 h [55]. On day 1, 10,000 cells/well were seeded into 96-well plates in a volume of 100 µL.…”

Elucidation of the Differences in Cinobufotalin’s Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein

“…Moreover, overexpress of P-gp is one of the main precipitating factors for the emergence of multi-drug resistance through influencing the absorption, distribution, metabolism and excretion of drugs during chemotherapy (Robey et al, 2018). Throughout recent years, many researches have been conducted to found or design new P-gp inhibitors, which can be used in combination therapy for cancers to improve the bioavailability and efficacy of therapeutic compounds or drugs (Ma et al, 2018; Riganti et al, 2018). Hence, it is imperative to define the role of P-gp in cinobufotalin transport, and the results are expected to provide a reference for future clinical research and rational application of cinobufotalin.…”