Multidrug Resistance Modulators Research Articles

Evaluation of Novel Benzo-annelated 1,4-dihydropyridines as MDR Modulators in Cancer Cells.

Multidrug resistance (MDR) is the main problem in anticancer therapy today. Causative transmembrane efflux pumps in cancer cells have been reconsidered as promising anticancer target structures to restore anticancer drug sensitivity by various strategies, including MDR modulators. MDR modulators interfere with the efflux pumps and improve the cellular efficiency of chemotherapeutics. So far, only a few candidates have gone through clinical trials with disappointing results because of low specificity and toxic properties. This study aimed to find Novel MDR modulators to effectively combat multidrug resistance in cancer cells. We synthesized various novel benzo-annelated 1,4-dihydropyridines to evaluate them as MDR modulators towards ABCB1 in cancer cells. Synthesized compounds were purified by column chromatography. The MDR modulation of ABCB1 was determined in cellular efflux assays using the flow cytometry technique and cellular fluorescent measurements by the use of each fluorescent substrate. Compounds were yielded in a two-step reaction with structurally varied components. Further, substituent- dependent effects on the determined MDR inhibiting properties towards ABCB1 were discussed. Cellular studies prove that there is no toxicity or restoration of cancer cell sensitivity towards the used anticancer drug. Novel MDR modulators could be identified with favorable methoxy and ester group functions. Their use in both ABCB1 non-expressing and overexpressing cells proves a selective toxicity-increasing effect of the applied anticancer agent in the ABCB1 overexpressing cells, whereas the toxicity effect of the anticancer drug was almost unchanged in the non-expressing cells. These results qualify our novel compounds as perspective anticancer drugs compared to MDR modulators with nonselective toxicity properties.

Isolation and structural characterization of eight new resin glycosides, calyhedins XVI–XXIII, from the rhizomes of Calystegia hederacea

Biological effects attributed to resin glycosides, including cytotoxicity against cancer cells and antibacterial, multidrug resistance-modulating, and antiviral activities have been documented. Penta-glycosides composed of calysolic acid A or calyhedic acid A, which are glycosidic acid components of the crude resin glycoside fraction of Calystegia hederacea, have not yet been isolated from this plant. In this study, eight new resin glycosides, termed calyhedins XVI (1)–XXIII (8), were isolated from the rhizomes of C. hederacea. Compounds 1–8 are penta- or hexa-glycosides with macrolactone structures, and their sugar moieties are partially acylated by five organic acids, including 2S-methylbutyric, (E)-2-methylbut-2-enoic, and 2R-methyl-3R-hydroxybutyric acids. Compounds 1–5 are the first identified macrocyclic resin glycosides with five monosaccharides obtained from this plant, and 2 and 4 are the first to be characterized as containing calyhedic acid A as the glycosidic acid component. Compounds 1–8 were of the four following macrolactone types: one with a 22-membered ring (5), another with a 23-membered ring (6–8), the third with a 27-membered ring (1, 3), and the fourth with a 28-membered ring (2, 4). Compounds 2–8 exhibited cytotoxic activity against HL-60 human promyelocytic leukemia cells comparable to that of the positive control, cisplatin.

Mechanisms involved in the HMGB1 modulation of tumor multidrug resistance (Review).

Tumor multidrug resistance (MDR) remains one of the most challenging barriers to successful cancer treatment. Several previous studies have suggested that high mobility group box 1 (HMGB1) may be a promising therapeutic target for overcoming cancer drug resistance. Emerging evidence has indicated that HMGB1 functions as a 'double‑edged sword' that plays both pro‑ and anti‑tumor roles in the development and progression of multiple types of cancer. HMGB1 has also been found to be a key regulator of several cell death and signaling pathways, and is involved in MDR by mediating cell autophagy and apoptosis, ferroptosis, pyroptosis and multiple signaling pathways. Additionally, HMGB1 is regulated by a variety of non‑coding RNAs (ncRNAs), such as microRNAs, long ncRNAs and circular RNAs that are involved in MDR. Thus far, studies have been conducted to identify strategies with which to overcome HMGB1‑mediated MDR by the targeted silencing of HMGB1 and the targeted interference of HMGB1 expression using drugs and ncRNAs. Therefore, HMGB1 is closely associated with tumor MDR and is a promising therapeutic target.

Effect of interleukin-8 on docetaxel resistance in prostate cancer cells: insights into the role of multidrug resistance 1 protein modulation

<p>Although docetaxel treatment yields a high survival rate for prostate cancer (PCa), resistance eventually develops in many patients. Understanding the underlying mechanisms of docetaxel resistance is essential for improving treatment strategies. Cytokines, which play a role in cell signaling and immune responses, have been implicated in drug resistance mechanisms. The study revealed that interleukin-8 (IL-8) was consistently overexpressed in both docetaxel-resistant PCa cell lines. Thus, the expression levels of cytokines released from docetaxel-sensitive (PC-3- and DU-145) and resistant (PC-3/R-DU-145/R) PCa cells were compared. IL-8 was found to be commonly expressed in resistant cell lines. This finding led to the hypothesis that IL-8 could play a key role in mediating PCa cell resistance to docetaxel. IL-8 siRNA treatment increased docetaxel sensitivity in both resistant cells. To demonstrate the mechanism of IL-8-related resistance, MDR1 expression was evaluated. After IL-8 siRNA treatment MDR1 expression was reduced in both resistant cells suggesting that IL-8 regulates the docetaxel resistance of PCa cells via modulation of multidrug resistance 1 (MDR1). By expanding the knowledge of the cytokines and their effect mechanisms, novel approaches can be developed for the treatment of docetaxel-resistant prostate cancer. Further investigations into the role of IL-8 in docetaxel resistance could offer valuable insights into the development of effective treatment strategies for PCa patients.</p>

Design, Synthesis, and Biological Evaluation of Marine Lissodendrins B Analogues as Modulators of ABCB1-Mediated Multidrug Resistance

Multidrug resistance (MDR) caused by ATP-Binding Cassette Subfamily B Member 1 (ABCB1, P-glycoprotein, P-gp) is a major barrier for the success of chemotherapy in clinics. In this study, we designed and synthesized a total of 19 Lissodendrins B analogues and tested their ABCB1-mediated MDR reversal activity in doxorubicin (DOX)-resistant K562/ADR and MCF-7/ADR cells. Among all derivatives, compounds D1, D2, and D4 with a dimethoxy-substituted tetrahydroisoquinoline fragment possessed potent synergistic effects with DOX and reversed ABCB1-mediated drug resistance. Notably, the most potent compound D1 merits multiple activities, including low cytotoxicity, the strongest synergistic effect, and effectively reversing ABCB1-mediated drug resistance of K562/ADR (RF = 1845.76) and MCF-7/ADR cells (RF = 207.86) to DOX. As a reference substance, compound D1 allows for additional mechanistic studies on ABCB1 inhibition. The synergistic mechanisms were mainly related to the increased intracellular accumulation of DOX via inhibiting the efflux function of ABCB1 rather than from affecting the expression level of ABCB1. These studies suggest that compound D1 and its derivatives might be potential MDR reversal agents acting as ABCB1 inhibitors in clinical therapeutics and provide insight into a design strategy for the development of ABCB1 inhibitors.

Abstract 2846: The mitochondrial dynamics of breast cancer regulate P-glycoprotein expression

Abstract Multidrug efflux transporter ABCB1 (MDR1) encodes P-glycoprotein (P-gp), a well-known transporter that is believed to contribute to the development of multidrug resistance (MDR). Furthermore, P-gp plays an important role in drug disposition, pharmacokinetics, and drug development. Thus, P-gp transporter expression, function, and modulation of MDR in human cancers have been extensively studied. In spite of significant progress in understanding P-gp, ABCB1 regulation and its impact on clinical trials remain unclear. Through sequential exposure of SUM159PT to paclitaxel, we created a paclitaxel resistant triple negative breast cancer cell line SUM159PT-PAC200. We observed a significant increase in the phosphorylation of the mitochondrial fission protein dynamin related protein kinase 1 (Drp1) at Ser616 and its upstream kinase ERK1/2a of Drp1. Through the use of CRISPR-Cas9 technology, we knocked out the gene encoding Drp1 in PAC200. When Drp1 is genetically abated (PAC200 Drp1-/-), paclitaxel resistance is significantly reversed. It was also observed that clonogenicity under paclitaxel pressure was significantly decreased in both the PAC200/Drp1-/- line and the partial KO Drp1-/+ line, compared to the PAC200 line. Parallelly, a significant increase in the expression of P-gp transporters was also observed in the PAC200 cell line. As a surprise, genetically targeting Drp1 in PAC200 cells (i.e., PAC200 Drp1/KO) reduced P-gp expression to virtually undetectable levels. Until now, there has been no description of how Drp1 and P-gp are related. Furthermore, PAC200 Drp1/KO cells showed reduced proliferation, migration, and invasion potential, while their soft agar clonogenic capacities were almost nonexistent, suggesting that Drp1 plays a key role in breast cancer proliferation and dissemination. It appears that modulating or targeting Drp1 might be a useful strategy for modulating P-gp in the development and maintenance of the cancer's MDR phenotype, proliferation, and invasion. Understanding how mitochondrial dynamics determine the transactivation and coordination of drug-resistant P-gp phenotypes would make Drp1 an attractive molecular target for cancer treatment. Citation Format: David Terrero, Saloni Malla, Dayanidhi Raman, Jayachandra Babu, Amit Tiwari. The mitochondrial dynamics of breast cancer regulate P-glycoprotein expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2846.

Vegetal-Derived Bioactive Compounds as Multidrug Resistance Modulators in Colorectal Cancer

Colorectal cancer is one of the leading causes of morbidity and mortality today. Knowledge of its pathogenesis has made it possible to advance the development of different therapeutic strategies. However, the appearance of drug resistance constitutes one of the main causes of treatment failure. Bioactive compounds of vegetable origin are being studied as a new strategy to improve antitumor treatment, due to their ability to regulate the pathways involved in the development of carcinogenesis or processes that are decisive in its evolution, including multidrug resistance. In vitro and in vivo studies of these substances in combination with cytotoxic drugs have shown that they reduce resistance and increase therapeutic efficacy. The objective of this review is to summarize the knowledge that is described in the scientific literature on the antitumor and chemo-sensitizing capacity of vegetable-derived biomolecules such as polyphenols, flavonoids, and terpenes. These compounds may hold a promising future in improving the treatment of colorectal cancer.

Success stories of natural product-derived compounds from plants as multidrug resistance modulators in microorganisms.

Microorganisms evolve resistance to antibiotics as a function of evolution. Antibiotics have accelerated bacterial resistance through mutations and acquired resistance through a combination of factors. In some cases, multiple antibiotic-resistant determinants are encoded in these genes, immediately making the recipient organism a "superbug". Current antimicrobials are no longer effective against infections caused by pathogens that have developed antimicrobial resistance (AMR), and the problem has become a crisis. Microorganisms that acquire resistance to chemotherapy (multidrug resistance) are a major obstacle for successful treatments. Pharmaceutical industries should be highly interested in natural product-derived compounds, as they offer new sources of chemical entities for the development of new drugs. Phytochemical research and recent experimental advances are discussed in this review in relation to the antimicrobial efficacy of selected natural product-derived compounds as well as details of synergistic mechanisms and structures. The present review recognizesand amplifies the importance of compounds with natural origins, which can be used to create safer and more effective antimicrobial drugs by combating microorganisms that are resistant to multiple types of drugs.

Phenolic compounds that modulate Multi Drug Resistance through inhibiting of P-glycoprotein encoded by gene ABCB1

One of the most important challenges in the fight against cancer is acquired drug resistance. P-glycoprotein (P-gp), encoded by the ABCB1 gene in many organs, is one of the important factors involved in the development of drug resistance. P-gp is mainly involved in efflux of toxic substances such as xenobiotics from the cell. In addition to these, it also plays a role the efflux of drugs used in the treatment of cancer, the rate of success in cancer treatment reduces. Phenolic compounds are chemicals that are naturally synthesized in plants and have many biological activities, especially antioxidant and anticancer. In previous studies, it was determined that in addition to their anticancer activities, phenolics modulate the acquired drug resistance by inhibiting the expression and function of P-gp. In this review, phenolic compounds that play a role in breaking multi-drug resistance by inhibiting the activation and expression of P-gp are discussed.

The Tetrahydroisoquinoline Scaffold in ABC Transporter Inhibitors that Act as Multidrug Resistance (MDR) Reversers.

The failure of anticancer chemotherapy is often due to the development of resistance to a variety of anticancer drugs. This phenomenon is called multidrug resistance (MDR) and is related to the overexpression of ABC transporters, such as P-glycoprotein, multidrug resistance- associated protein 1 and breast cancer resistance protein. Over the past few decades, several ABC protein modulators have been discovered and studied as a possible approach to evade MDR and increase the success of anticancer chemotherapy. Nevertheless, the co-administration of pump inhibitors with cytotoxic drugs, which are substrates of the transporters, does not appear to be associated with an improvement in the therapeutic efficacy of antitumor agents. However, more recently discovered MDR reversing agents, such as the two tetrahydroisoquinoline derivatives tariquidar and elacridar, are characterized by high affinity towards the ABC proteins and by reduced negative properties. Consequently, many analogs of these two derivatives have been synthesized, with the aim of optimizing their MDR reversal properties. This review aims to describe the MDR modulators carrying the tetraidroisoquinoline scaffold reported in the literature in the period 2009-2021, highlighting the structural characteristics that confer potency and/or selectivity towards the three ABC transport proteins. Many compounds have been synthesized in the last twelve years showing interesting properties, both in terms of potency and selectivity. Although clear structure-activity relationships can be drawn only by considering strictly related compounds, some of the compounds reviewed could be promising starting points for the design of new ABC protein inhibitors.

Recent Advances on P-Glycoprotein (ABCB1) Transporter Modelling with In Silico Methods

ABC transporters play a critical role in both drug bioavailability and toxicity, and with the discovery of the P-glycoprotein (P-gp), this became even more evident, as it plays an important role in preventing intracellular accumulation of toxic compounds. Over the past 30 years, intensive studies have been conducted to find new therapeutic molecules to reverse the phenomenon of multidrug resistance (MDR) ), that research has found is often associated with overexpression of P-gp, the most extensively studied drug efflux transporter; in MDR, therapeutic drugs are prevented from reaching their targets due to active efflux from the cell. The development of P-gp inhibitors is recognized as a good way to reverse this type of MDR, which has been the subject of extensive studies over the past few decades. Despite the progress made, no effective P-gp inhibitors to reverse multidrug resistance are yet on the market, mainly because of their toxic effects. Computational studies can accelerate this process, and in silico models such as QSAR models that predict the activity of compounds associated with P-gp (or analogous transporters) are of great value in the early stages of drug development, along with molecular modelling methods, which provide a way to explain how these molecules interact with the ABC transporter. This review highlights recent advances in computational P-gp research, spanning the last five years to 2022. Particular attention is given to the use of machine-learning approaches, drug-transporter interactions, and recent discoveries of potential P-gp inhibitors that could act as modulators of multidrug resistance.

Talazoparib Does Not Interact with ABCB1 Transporter or Cytochrome P450s, but Modulates Multidrug Resistance Mediated by ABCC1 and ABCG2: An in Vitro and Ex Vivo Study.

Talazoparib (Talzenna) is a novel poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that is clinically used for the therapy of breast cancer. Furthermore, the drug has shown antitumor activity against different cancer types, including non-small cell lung cancer (NSCLC). In this work, we investigated the possible inhibitory interactions of talazoparib toward selected ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 biotransformation enzymes (CYPs) and evaluated its position in multidrug resistance (MDR). In accumulation studies, talazoparib interacted with the ABCC1 and ABCG2 transporters, but there were no significant effects on ABCB1. Furthermore, incubation assays revealed a negligible capacity of the tested drug to inhibit clinically relevant CYPs. In in vitro drug combination experiments, talazoparib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCC1 and ABCG2 expression, respectively. Importantly, the position of an effective MDR modulator was further confirmed in drug combinations performed in ex vivo NSCLC patients-derived explants, whereas the possible victim role was refuted in comparative proliferation experiments. In addition, talazoparib had no significant effects on the mRNA-level expressions of MDR-related ABC transporters in the MCF-7 cellular model. In summary, our study presents a comprehensive overview on the pharmacokinetic drug-drug interactions (DDI) profile of talazoparib. Moreover, we introduced talazoparib as an efficient MDR antagonist.

Effective use of Silymarin as a promising P-Glycoprotein Inhibitor in the Management of Breast Cancer

Objectives: Chemotherapy has various side effects and toxins, to overcome these problems nanoparticles are formed. Nanoparticles accumulate in tumor cells due to EPR effect. Given the role of P-gp in influencing drug’s pharmacology, methods to overcome P-gp mediated efflux have been investigated. The objectives of present research were to formulate nanoparticles containing DOX and PTX. The present research also includes the potential of flavonoids such as silymarin (SLM) to act as    P-gp inhibitors, enabling increased absorption and inhibition of excretion and modulation of multi-drug resistance. 
 Materials and Methods: Nanoparticles of PLGA and BSA were developed paclitaxel (PTX). Using 23 factorial designs total eight formulations of PTX-PLGA and PTX-BSA nanoparticles were prepared. PLGA (A,) poly vinyl alcohol (PVA) (B) and speed (C) used as independent variants in size of the particles (Y1), efficiency of entrapment (Y2) and % release of drug (Y3) taken as a dependent variable. PTX was successfully applied to the micelles by dissolving.
 Results: The median diameter of PTX-BSA and PTX-PLGA nanoparticles ranged from 104 to 1150 nm and 110 to 1023 nm respectively. The effectiveness of the entrapment and release of in vitro drugs also rely on the solubility of the drug and the polymer in the solvent. The use of software is a systematic tool for optimization, and it helps to reduce the cost of experiments.
 Conclusion: From the experiments it was concluded that the prepared formulation helped to overcome the multiple drug resistance by incorporation of P-gp inhibitor like silymarin.

Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore.

The permeability transition pore in mitochondria (MPTP) and the ATP-binding cassette transporters (АВС transporters) in cell membranes provide the efflux of low-molecular compounds across mitochondrial and cell membranes, respectively. The inhibition of ABC transporters, especially of those related to multi drug resistance (MDR) proteins, is an actively explored approach to enhance intracellular drug accumulation and increase thereby the efficiency of anticancer therapy. Although there is evidence showing the simultaneous effect of some inhibitors on both MDR-related proteins and mitochondrial functions, their influence on MPTP has not been previously studied. We examined the participation of verapamil and quinidine, classified now as the first generation of MDR modulators, and avermectin, which has recently been actively studied as an MDR inhibitor, in the regulation of the MPTP opening. In experiments on rat liver mitochondria, we found that quinidine lowered and verapamil increased the threshold concentrations of calcium ions required for MPTP opening, and that they both decreased the rate of calcium-induced swelling of mitochondria. These effects may be associated with the positive charge of the drugs and their aliphatic properties. Avermectin not only decreased the threshold concentration of calcium ions, but also by itself induced the opening of MPTP and the mitochondrial swelling inhibited by ADP and activated by carboxyatractyloside, the substrate and inhibitor of adenine nucleotide translocase (ANT), which suggests the involvement of ANT in the process. Thus, these data indicate an additional opportunity to evaluate the effectiveness of MDR modulators in the context of their influence on the mitochondrial-dependent apoptosis.

Ingol, ent-atisane, and stachane-type diterpenoids from Euphorbia deightonii with multidrug resistance reversing activity

Nine previously undescribed ingol-type diterpenoid polyesters with eighteen known ingol esters, two ent-atisane, and one stachane diterpenoid were isolated from the methanol extract of Euphorbia deightonii Croizat. The structures were established by extensive spectroscopic analysis involving 1D (1H, 13C J-modulation) and 2D NMR experiments, HRESIMS measurements, and the comparison of the spectroscopic data with reported literature values. The cytotoxic concentrations of 13 isolated compounds were determined, and the compounds were investigated for multidrug resistance modulating activity on an L5178 mouse lymphoma cell line using a rhodamin 123 accumulation assay. Six ingol esters demonstrated the significant inhibition of P-glycoprotein, while the two ent-atisane diterpenoids were found to be inactive. The measured activities allowed to establish some structure–activity relationships. Notably, lower and higher-type diterpenoids simultaneously occurred in E. deightonii.

Abstract 409: Reversal of ABCG2-mediated multidrug resistance by tepotinib in vitro and in vivo

Abstract ABCG2/BCRP transporter-mediated Multidrug resistance (MDR) in cancers has been considered as one of the obstacles to the cancer chemotherapy. Our recent study characterized the MET inhibitor tepotinib as a potent ABCB1 inhibitor. In the present study, we demonstrated the MET inhibitor tepotinib effectively antagonized ABCG2-mediated MDR in vitro and in vivo. In addition, the ABCB1/ABCG2 double-transfected cell model demonstrated that tepotinib can simultaneously inhibit the two MDR transporters. Mechanistically, tepotinib stimulated ABCG2 ATPase activity without altering the protein expression level of ABCG2, MET, or p-MET. Moreover, the MDR reversal effect may be attributed to its reversible inhibition of ABCG2 substrate efflux function, thereby sensitizing the drug-resistant cancer cells to substrate drugs. The molecular docking analysis suggested that tepotinib may directly bind to the drug-binding site of ABCG2, which subsequently block the binding of ABCG2 substrates. Animal study showed that tepotinib significantly increased the intratumor accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect in ABCG2-overexpressing tumors. In conclusion, our study provides a new strategy of repositioning tepotinib as an MDR modulator to antagonize ABCG2-mediated MDR. Citation Format: Zhuoxun Wu, Qiu-Xu Teng, Yuqi Yang, Nikita Acharekar, Jing-Quan Wang, Min He, Sabesan Yoganathan, Jun Lin, Jian Wang, Zhe-Sheng Chen. Reversal of ABCG2-mediated multidrug resistance by tepotinib in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 409.

Ketone-selenoesters as potential anticancer and multidrug resistance modulation agents in 2D and 3D ovarian and breast cancer in vitro models

Long-term treatment of cancer with chemotherapeutics leads to the development of resistant forms that reduce treatment options. The main associated mechanism is the overexpression of transport proteins, particularly P-glycoprotein (P-gp, ABCB1). In this study, we have tested the anticancer and multidrug resistance (MDR) modulation activity of 15 selenocompounds. Out of the tested compounds, K3, K4, and K7 achieved the highest sensitization rate in ovarian carcinoma cells (HOC/ADR) that are resistant to the action of the Adriamycin. These compounds induced oxidation stress, inhibited P-gp transport activity and altered ABC gene expression. To verify the effect of compounds, 3D cell models were used to better mimic in vivo conditions. K4 and K7 triggered the most significant ROS release. All selected selenoesters inhibited P-gp efflux in a dose-dependent manner while simultaneously altering the expression of the ABC genes, especially P-gp in paclitaxel-resistant breast carcinoma cells (MCF-7/PAX). K4, and K7 demonstrated sensitization potential in resistant ovarian spheroids. Additionally, all selected selenoesters achieved a high cytotoxic effect in 3D breast and ovarian models, which was comparable to that in 2D cultures. K7 was the only non-competitive P-gp inhibitor, and therefore appears to have considerable potential for the treatment of drug-resistant cancer.

Anticancer and Overcoming Multidrug Resistance Activities of Potential Phytochemicals

Cancer is a serious healthy issue worldwide and cause death to human. Drug resistance is a key factor for the successful treatment of various types of cancers. Phytochemicals have many pharmacological activities with low side effects. Several phytochemicals have been tested in clinical trials as chemosensitizers or anticancer drugs with low side effects. The molecular mechanism of anticancer and reversing multidrug resistance of phytochemicals by modulating signaling transduction or target gene expression are discussed in this article. In this study, we will review the pharmacological activities of natural compounds from herb with anticancer activities and multidrug resistance modulators including berberine, capsaicin, curcumin, 6-gingerol and piperine.

Isodon rubescens (Hemls.) Hara.: A Comprehensive Review on Traditional Uses, Phytochemistry, and Pharmacological Activities.

Isodon rubescens is a medicinal and food plant, often eaten as a wild vegetable in ancient China, and has been widely used for decades to treat sore throats, tonsillitis, colds and headaches, bronchitis, chronic hepatitis, joint rheumatism, snake and insect bites, and various cancers. This comprehensive and systematic review of the ethnomedicinal uses, phytochemical composition, pharmacological activity, quality control and toxicology of I. rubescens provides updated information for the further development and application in the fields of functional foods and new drugs research. To date, a total of 324 substances have been isolated and identified from the plant, including terpenoids, flavonoids, polyphenols, alkaloids, amino acids, and volatile oils. Among these substances, diterpenoids are the most important and abundant bioactive components. In the past decades pharmacological studies have shown that I. rubescens has significant biological activities, especially in the modulation of antitumor and multidrug resistance. However, most of these studies have been conducted in vitro. In-depth in vivo studies on the quality control of its crude extracts and active ingredients, as well as on metabolite identification are still very limited. Therefore, more well-designed preclinical and clinical studies are needed to confirm the reported therapeutic potential of I. rubescens.

Lazertinib improves the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 overexpression cancer cells in vitro, in vivo, and ex vivo

Multidrug resistance (MDR) is the major cause of chemotherapy failure, which is usually caused by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2. To date, no MDR modulator has been clinically approved. Here, we found that lazertinib (YH25448; a novel third-generation tyrosine kinase inhibitor [TKI]) could enhance the anticancer efficacy of MDR transporter substrate anticancer drugs in vitro，in vivo, and ex vivo. Mechanistically, lazertinib was shown to inhibit the drug efflux activities of ABCB1 and ABCG2 and thus increase the intracellular accumulation of the transporter substrate anticancer drug. Moreover, lazertinib was found to stimulate the ATPase activity of ABCB1/ABCG2 and inhibit the photolabeling of the transporters by 125I-iodoarylazidoprazosin (IAAP). However, lazertinib neither changed the expression or locolization of ABCB1 and ABCG2 nor blocked the signal pathway of Akt or Erk1/2 at a drug concentration effective for MDR reversal. Overall, our results demonstrate that lazertinib effectively reverses ABCB1- or ABCG2-mediated MDR by competitively binding to the ATP-binding site and inhibiting drug efflux function. This is the first report demonstrating the novel combined use of lazertinib and conventional chemotherapeutical drugs to overcome MDR in ABCB1/ABCG2-overexpressing cancer cells.