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Cancer nanomedicine is defined as the application of nanotechnology and nanomaterials for the formulation of cancer therapeutics that can overcome the impediments and restrictions of traditional chemotherapeutics. Multidrug resistance (MDR) in cancer cells can be defined as a decrease or abrogation in the efficacy of anticancer drugs that have different molecular structures and mechanisms of action and is one of the primary causes of therapeutic failure. There have been successes in the development of cancer nanomedicine to overcome MDR; however, relatively few of these formulations have been approved by the United States Food and Drug Administration for the treatment of cancer. This is primarily due to the paucity of knowledge about nanotechnology and the fundamental biology of cancer cells. Here, we discuss the advances, types of nanomedicines, and the challenges regarding the translation of in vitro to in vivo results and their relevance to effective therapies.

Chemotherapy is one of the important methods to treat cancer, and the emergence of multidrug resistance (MDR) is one major cause for the failure of cancer chemotherapy. Almost all anti-tumor drugs develop drug resistance over a period of time of application in cancer patients, reducing their effects on killing cancer cells. Chemoresistance can lead to a rapid recurrence of cancers and ultimately patient death. MDR may be induced by multiple mechanisms, which are associated with a complex process of multiple genes, factors, pathways, and multiple steps, and today the MDR-associated mechanisms are largely unknown. In this paper, from the aspects of protein–protein interactions, alternative splicing (AS) in pre-mRNA, non-coding RNA (ncRNA) mediation, genome mutations, variance in cell functions, and influence from the tumor microenvironment, we summarize the molecular mechanisms associated with MDR in cancers. In the end, prospects for the exploration of antitumor drugs that can reverse MDR are briefly discussed from the angle of drug systems with improved targeting properties, biocompatibility, availability, and other advantages. Multiple mechanisms associated with MDR in cancers. On the levels of regulatory by anti-tumor drugs, signaling pathways, gene mutations and miRNAs, etc., MDR in cancers could be induced. Clarification of these regulations will unveil potential targets for cancer treatment by combined chemotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on breast cancer resistance protein (BCRP) and p-glycoprotein (P-gp) were synthesized. A cyclopropyl-containing quinazolinamine 22 was identified as a dual BCRP and P-gp inhibitor, while azide-containing quinazolinamine 33 showed BCRP inhibitory activity. These lead compounds were further investigated in a battery of mechanistic experiments. Compound 22 changed the localization of BCRP and P-gp in cells, thus inhibiting the efflux of anticancer drugs by the two ATP-binding cassette (ABC) transporters. In addition, both 22 and 33 significantly stimulated the ATP hydrolysis of the BCRP transporter, indicating that they can be competitive substrates of the BCRP transporter, and thereby increase the accumulation of mitoxantrone in BCRP-overexpressing H460/MX20 cells. Azide derivative 33, exhibited a greater inhibitory effect on BCRP after UV activation and can serve as a valuable probe for investigating the interactions of quinazolinamine derivatives with BCRP. Notably, the dual BCRP and P-gp inhibitors 4–5, 22–24, 27, and BCRP inhibitor 33 showed improved metabolic stability compared to Ko143. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein (P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5- a ]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp, WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel (PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4 (CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft (PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy. Preclinical studies reveal that WS-716 is a highly potent, specific and orally active P-glycoprotein inhibitor and increases sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]

Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR. Tepotinib antagonizes multidrug resistance (MDR) by inhibiting the efflux function of ABCG2 transporter, thereby increasing the intracellular substrate drug concentration, and enhancing its cytotoxic effect in MDR cancer cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1/P-gp) is a major cause of cancer chemotherapy failure, but the regulation mechanisms are largely unknown. Methods: Based on single gene knockout, we studied the regulation of CDK6-PI3K axis on ABCB1-mediated MDR in human cancer cells. CRISPR/Cas9 technique was performed in KB-C2 cells to knockout cdk6 or cdk4 gene. Western blot, RT-PCR and transcriptome analysis were performed to investigate target gene deletion and expression of critical signaling factors. The effect of cdk4 or cdk6 deficiency on cell apoptosis and the cell cycle was analyzed using flow cytometry. In vivo studies were performed to study the sensitivity of KB-C2 tumors to doxorubicin, tumor growth and metastasis. Results: Deficiency of cdk6 led to remarkable downregulation of ABCB1 expression and reversal of ABCB1-mediated MDR. Transcriptomic analysis revealed that CDK6 knockout regulated a series of signaling factors, among them, PI3K 110α and 110β, KRAS and MAPK10 were downregulated, and FOS-promoting cell autophagy and CXCL1-regulating multiple factors were upregulated. Notably, PI3K 110α/110β deficiency in-return downregulated CDK6 and the CDK6-PI3K axis synergizes in regulating ABCB1 expression, which strengthened the regulation of ABCB1 over single regulation by either CDK6 or PI3K 110α/110β. High frequency of alternative splicing (AS) of premature ABCB1 mRNA induced by CDK6, CDK4 or PI3K 110α/110β level change was confirmed to alter the ABCB1 level, among them 10 common skipped exon (SE) events were found. In vivo experiments demonstrated that loss of cdk6 remarkably increased the sensitivity of KB-C2 tumors to doxorubicin by increasing drug accumulation of the tumors, resulting in remarkable inhibition of tumor growth and metastasis, as well as KB-C2 survival in the nude mice. Conclusions: CDK6-PI3K as a new target signaling axis to reverse ABCB1-mediated MDR is reported for the first time in cancers. Pathways leading to inhibition of cancer cell proliferation were revealed to be accompanied by CDK6 deficiency. [ABSTRACT FROM AUTHOR]

The efficacy of cancer chemotherapy can be attenuated or abrogated by multidrug resistance (MDR) in cancer cells. In this study, we determined the effect of the CDK4/6 inhibitor, ribociclib (or LEE011), on P-glycoprotein (P-gp)-mediated MDR in the human epidermoid carcinoma MDR cell line, KB-C2, which is widely used for studying P-gp-mediated MDR in cancers. The incubation of KB-C2 cells with ribociclib (3–9 µM) increased the efficacy of colchicine, a substrate for P-gp. The cell expression of P-gp was down-regulated at both translation and transcription levels. Furthermore, ribociclib produced a 3.5-fold increase in the basal activity of P-gp ATPase, and the concentration required to increase basal activity by 50% (EC50) was 0.04 μM. Docking studies indicated that ribociclib interacted with the drug-substrate binding site of P-gp. The short-term and long-term intracellular accumulation of doxorubicin greatly increased in the KB-C2 cells co-cultured with ribociclib, indicating ribociclib inhibited the drug efflux activity of P-gp. The results of our study indicate that LEE011 may be a potential agent for combined therapy of the cancers with P-gp mediated MDR. [ABSTRACT FROM AUTHOR]

Palbociclib was approved by the United States Food and Drug Administration for use, in combination with letrozole, as a first-line treatment for estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) postmenopausal metastatic breast cancer. However, recent studies show that palbociclib may be an inhibitor of the ABCB1 transporter, although this remains to be elucidated. Therefore, we conducted experiments to determine the interaction of palbociclib with the ABCB1 transporter. Our in vitro results indicated that the efficacy of palbociclib was significantly decreased in the ABCB1-overexpressing cell lines. Furthermore, the resistance of ABCB1-overexpressing cells to palbociclib was reversed by 3 μM of the ABCB1 inhibitor, verapamil. Moreover, the incubation of ABCB1-overexpressing KB-C2 and SW620/Ad300 cells with up to 5 μM of palbociclib for 72 h, significantly upregulated the protein expression of ABCB1. The incubation with 3 µM of palbociclib for 2h significantly increased the intracellular accumulation of [3H]-paclitaxel, a substrate of ABCB1, in ABCB1 overexpressing KB-C2 cells but not in the corresponding non-resistant parental KB-3-1 cell line. However, the incubation of KB-C2 cells with 3 μM of palbociclib for 72 h decreased the intracellular accumulation of [3H]-paclitaxel due to an increase in the expression of the ABCB1 protein. Palbociclib produced a concentration-dependent increase in the basal ATPase activity of the ABCB1 transporter (EC50 = 4.73 μM). Molecular docking data indicated that palbociclib had a high binding affinity for the ABCB1 transporter at the substrate binding site, suggesting that palbociclib may compete with other ABCB1 substrates for the substrate binding site of the ABCB1. Overall, our results indicate that palbociclib is a substrate for the ABCB1 transporter and that its in vitro anticancer efficacy is significantly decreased in cancer cells overexpressing the ABCB1. [ABSTRACT FROM AUTHOR]

To investigate the collateral sensitivity (CS) of ABCB1-positive multidrug resistant (MDR) colorectal cancer cells to the survivin inhibitor MX106–4C and the mechanism. Biochemical assays (MTT, ATPase, drug accumulation/efflux, Western blot, RT-qPCR, immunofluorescence, flow cytometry) and bioinformatic analyses (mRNA-sequencing, reversed-phase protein array) were performed to investigate the hypersensitivity of ABCB1 overexpressing colorectal cancer cells to MX106–4C and the mechanisms. Synergism assay, long-term selection, and 3D tumor spheroid test were used to evaluate the anti-cancer efficacy of MX106–4C. MX106–4C selectively killed ABCB1-positive colorectal cancer cells, which could be reversed by an ABCB1 inhibitor, knockout of ABCB1, or loss-of-function ABCB1 mutation, indicating an ABCB1 expression and function-dependent mechanism. MX106–4C's selective toxicity was associated with cell cycle arrest and apoptosis through ABCB1-dependent survivin inhibition and activation on caspases-3/7 as well as modulation on p21-CDK4/6-pRb pathway. MX106–4C had good selectivity against ABCB1-positive colorectal cancer cells and retained this in multicellular tumor spheroids. In addition, MX106–4C could exert a synergistic anti-cancer effect with doxorubicin or re-sensitize ABCB1-positive cancer cells to doxorubicin by reducing ABCB1 expression in the cell population via long-term exposure. MX106–4C selectively kills ABCB1-positive MDR colorectal cancer cells via a novel ABCB1-dependent survivin inhibition mechanism, providing a clue for designing CS compound as an alternative strategy to overcome ABCB1-mediated colorectal cancer MDR. [Display omitted] [ABSTRACT FROM AUTHOR]

The KRAS-G12C inhibitor ARS-1620, is a novel specific covalent inhibitor of KRAS-G12C, possessing a strong targeting inhibitory effect on KRAS-G12C mutant tumors. Overexpression of ATP-binding cassette super-family B member 1 (ABCB1/P-gp) is one of the pivotal factors contributing to multidrug resistance (MDR), and its association with KRAS mutations has been extensively studied. However, the investigations about the connection between the inhibitors of mutant KRAS and the level of ABC transporters are still missing. In this study, we investigated the potential drug resistance mechanism of ARS-1620 associated with ABCB1. The desensitization effect of ARS-1620 was remarkably intensified in both drug-induced ABCB1-overexpressing cancer cells and ABCB1-transfected cells as confirmed by cell viability assay results. This desensitization of ARS-1620 could be completely reversed when co-treated with an ABCB1 reversal agent. In mechanism-based studies, [3H] -paclitaxel accumulation assay revealed that ARS-1620 could be competitively pumped out by ABCB1. Additionally, it was found that ARS-1620 remarkably stimulated ATPase activity of ABCB1, and the HPLC drug accumulation assay displayed that ARS-1620 was actively transported out of ABCB1-overexpressing cancer cells. ARS-1620 acquired a high docking score in computer molecular docking analysis, implying ARS-1620 could intensely interact with ABCB1 transporters. Taken all together, these data indicated that ARS-1620 is a substrate for ABCB1, and the potential influence of ARS-1620-related cancer therapy on ABCB1-overexpressing cancer cells should be considered in future clinical applications. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the leading female malignancies which accounts for the highest mortality rate among gynecologic cancers. Surgical cytoreduction followed by chemotherapy is the mainstay of treatment. However, patients with recurrent ovarian cancer are likely to exhibit resistance to chemotherapy due to reduced sensitivity to chemotherapeutic drugs. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been extensively studied as multidrug resistance (MDR) mediators since they are responsible for the efflux of various anticancer drugs. Multidrug resistance protein 7 (MRP7, or ABCC10) was discovered in 2001 and revealed to transport chemotherapeutic drugs. Till now, only limited knowledge was obtained regarding its roles in ovarian cancer. In this study, we established an MRP7-overexpressing ovarian cancer cell line SKOV3/MRP7 via transfecting recombinant MRP7 plasmids. The SKOV3/MRP7 cell line was resistant to multiple anticancer drugs including paclitaxel, docetaxel, vincristine and vinorelbine with a maximum of 8-fold resistance. Biological function of MRP7 protein was further determined by efflux-accumulation assays. Additionally, MTT results showed that the drug resistance of the SKOV3/MRP7 cells was reversed by cepharanthine, a known inhibitor of MRP7. Moreover, we also found that the overexpression of MRP7 enhanced the migration and epithelial-mesenchymal transition (EMT) induction. In conclusion, we established an in vitro model of MDR in ovarian cancer and suggested MRP7 overexpression as the leading mechanism of chemoresistance in this cell line. Our results demonstrated the potential relationship between MRP7 and ovarian cancer MDR. [ABSTRACT FROM AUTHOR]

The ATP‐binding cassette (ABC) transporter superfamily is one of the largest membrane protein families existing in wide spectrum of organisms from prokaryotes to human. ABC transporters are also known as efflux pumps because they mediate the cross‐membrane transportation of various endo‐ and xenobiotic molecules energized by ATP hydrolysis. Therefore, ABC transporters have been considered closely to multidrug resistance (MDR) in cancer, where the efflux of structurally distinct chemotherapeutic drugs causes reduced itherapeutic efficacy. Besides, ABC transporters also play other critical biological roles in cancer such as signal transduction. During the past decades, extensive efforts have been made in understanding the structure‐function relationship, transportation profile of ABC transporters, as well as the possibility to overcome MDR via targeting these transporters. In this review, we discuss the most recent knowledge regarding ABC transporters and cancer drug resistance in order to provide insights for the development of more effective therapies. [ABSTRACT FROM AUTHOR]

Antibiotic resistance or microbial drug resistance is emerging as a serious threat to human healthcare globally, and the multidrug-resistant (MDR) strains are imposing major hurdles to the progression of drug discovery programs. Newer antibiotic-resistance mechanisms in microbes contribute to the inefficacy of the existing drugs along with the prolonged illness and escalating expenditures. The injudicious usage of the conventional and commonly available antibiotics in human health, hygiene, veterinary and agricultural practices is proving to be a major driver for evolution, persistence and spread of antibiotic-resistance at a frightening rate. The drying pipeline of new and potent antibiotics is adding to the severity. Therefore, novel and effective new drugs and innovative therapies to treat MDR infections are urgently needed. Apart from the different natural and synthetic drugs being tested, plant secondary metabolites or phytochemicals are proving efficient in combating the drug-resistant strains. Various phytochemicals from classes including alkaloids, phenols, coumarins, terpenes have been successfully demonstrated their inhibitory potential against the drug-resistant pathogens. Several phytochemicals have proved effective against the molecular determinants responsible for attaining the drug resistance in pathogens like membrane proteins, biofilms, efflux pumps and bacterial cell communications. However, translational success rate needs to be improved, but the trends are encouraging. This review highlights current knowledge and developments associated challenges and future prospects for the successful application of phytochemicals in combating antibiotic resistance and the resistant microbial pathogens. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a common malignancy with the third highest incidence and second highest mortality rate among all cancers in the world. Chemotherapy resistance in colorectal cancer is an essential factor leading to the high mortality rate. The ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) confers multidrug resistance (MDR) to a range of chemotherapeutic agents by decreasing their intracellular content. The development of novel ABCG2 inhibitors has emerged as a tractable strategy to circumvent drug resistance. In this study, an ABCG2-knockout colorectal cancer cell line was established to assist inhibitor screening. Additionally, we found that ataxia-telangiectasia mutated (ATM) kinase inhibitor AZ32 could sensitize ABCG2-overexpressing colorectal cancer cells to ABCG2 substrate chemotherapeutic drugs mitoxantrone and doxorubicin by retaining them inside cells. Western blot assay showed that AZ32 did not alter the expression of ABCG2. Moreover, molecule docking analysis predicted that AZ32 stably located in the transmembrane domain of ABCG2. In conclusion, our result demonstrated that AZ32 could potently reverse ABCG2-mediated MDR in colorectal cancer. [ABSTRACT FROM AUTHOR]

Betulin is a lupane-type pentacyclic triterpene, which is isolated from birch bark. It has a broad spectrum of biological and pharmacological properties, such as anti-inflammatory, anti-tumor, anti-viral, and anti-bacterial activity. Herein, we explored the factors that may result in betulin resistance, especially with respect to its interaction with ATP-binding cassette subfamily C member 1 (ABCC1). ABCC1 is an important member of the ATP-binding cassette (ABC) transporter family, which is central to mediating multidrug resistance (MDR) in naturally derived anticancer agents. An MTT-based cell viability assay showed that ABCC1 overexpression has the ability to desensitize both cancer cell line and gene-transfected cell line to betulin and that this betulin-induced resistance can be antagonized by a known ABCC1 inhibitor MK571 at 25 μM. Additionally, betulin upregulates the ABCC1 protein expression level in both concentration-dependent and time-dependent manners, also blocks the transport function mediated by ABCC1. Subsequently, a high affinity score of betulin was achieved in a computational docking analysis, demonstrating a strong interaction of betulin with ABCC1. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Irinotecan is widely used as a chemotherapeutic drug to treat CRC. However, the mechanisms of acquired resistance to irinotecan in CRC remain inconclusive. In the present study, we established a novel irinotecan-resistant human colon cell line to investigate the underlying mechanism(s) of irinotecan resistance, particularly the overexpression of ABC transporters. The irinotecan-resistant S1-IR20 cell line was established by exposing irinotecan to human S1 colon cancer cells. MTT cytotoxicity assay was carried out to determine the drug resistance profile of S1-IR20 cells. The drug-resistant cells showed about 47-fold resistance to irinotecan and cross-resistance to ABCG2 substrates in comparison with S1 cells. By Western blot analysis, S1-IR20 cells showed significant increase of ABCG2, but not ABCB1 or ABCC1 in protein expression level as compared to that of parental S1 cells. The immunofluorescence assay showed that the overexpressed ABCG2 transporter is localized on the cell membrane of S1-IR20 cells, suggesting an active efflux function of the ABCG2 transporter. This finding was further confirmed by reversal studies that inhibiting efflux function of ABCG2 was able to completely abolish drug resistance to irinotecan as well as other ABCG2 substrates in S1-IR20 cells. In conclusion, our work established an in vitro model of irinotecan resistance in CRC and suggested ABCG2 overexpression as one of the underlying mechanisms of acquired resistance to irinotecan. This novel resistant cell line may enable future studies to overcome drug resistance in vitro and improve CRC treatment in vivo. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐glycoprotein (P‐gp/ABCB1) has been most well‐established. The clinical co‐administration of P‐gp drug efflux inhibitors, in combination with anticancer drugs which are P‐gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P‐gp‐mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P‐gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure–activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P‐gp inhibitors in the past 5 years. The development of P‐gp inhibitors will increase our knowledge of the mechanisms and functions of P‐gp‐mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P‐gp transporter overexpression has been implicated in MDR. [ABSTRACT FROM AUTHOR]

The efficacy of anti-cancer drugs in patients can be attenuated by the development of multi-drug resistance (MDR) due to ATP-binding cassette (ABC) transporters overexpression. In this in vitro study, we determined the reversal efficacy of the epidermal growth factor receptor (EFGR) inhibitor, saptinib, in SW620 and SW720/Ad300 colon cancer cells and HEK293/ABCB1 cells which overexpress the ABCB1 transporter. Sapitinib significantly increased the efficacy of paclitaxel and doxorubicin in ABCB1 overexpressing cells without altering the expression or the subcellular location of the ABCB1 transporter. Sapitinib significantly increased the accumulation of [3H]-paclitaxel in SW620/AD300 cells probably by stimulating ATPase activity which could competitively inhibit the uptake of [3H]-paclitaxel. Furthermore, sapitinib inhibited the growth of resistant multicellular tumor spheroids (MCTS). The docking study indicated that sapitinib interacted with the efflux site of ABCB1 transporter by π-π interaction and two hydrogen bonds. In conclusion, our study suggests that sapitinib surmounts MDR mediated by ABCB1 transporter in cancer cells. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) of tumor cells to chemotherapeutic agents is the main reason for the failure of cancer chemotherapy. Overexpression of ABCB1 transporter that actively pumps various drugs out of the cells has been considered a major contributing factor for MDR. Over the past decade, many antimicrobial peptides with antitumor activity have been identified or synthesized, and some antitumor peptides have entered the clinical practice. In this study, we report that peptide HX-12C has the effect of reversing ABCB1-mediated chemotherapy resistance. In ABCB1-overexpressing cells, nontoxic dose of peptide HX-12C inhibited drug resistance and increased the effective intracellular concentration of paclitaxel and other ABCB1 substrate drugs. The mechanism study showed that peptide HX-12C stimulated ABCB1 ATPase activity without changing the expression level and localization patterns of ABCB1. Molecular docking predicted the binding modes between peptide HX-12C and ABCB1. Overall, we found that peptide HX-12C reverses ABCB1-mediated MDR through interacting with ABCB1 and blocking its function without affecting the transporter's expression and cellular localization. Our findings suggest that this antimicrobial peptide may be used as a novel prospective cancer therapeutic strategy in combination with conventional anticancer agents. [ABSTRACT FROM AUTHOR]

One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2‐mediated MDR. CC‐671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC‐671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2‐overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC‐671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC‐671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC‐671 has high binding affinity to the drug‐binding site of ABCG2. In conclusion, we reveal the interaction between CC‐671 and ABCG2, providing a rationale for the potential combined use of CC‐671 with ABCG2 substrate to overcome MDR. [ABSTRACT FROM AUTHOR]

Sitravatinib, also called MGCD516 or MG-516, is a broad-spectrum tyrosine kinase inhibitor (TKI) under phase III clinical evaluation. Herein, we explored the activity of sitravatinib toward multidrug resistance (MDR) by emphasizing its inhibitory effect on ATP-binding cassette super-family G member 2 (ABCG2). ABCG2 is a member of ATP-binding cassette (ABC) transporter family and plays a critical role in mediating MDR. Sitravatinb received an outstanding docking score for binding to the human ABCG2 model (PDB code: 6ETI) among thirty screened TKIs. Also, an MTT assay indicated that sitravatinib at 3 μM had the ability to restore the antineoplastic effect of various ABCG2 substrates in both drug-selected and gene-transfected ABCG2-overexpressing cell lines. In further tritium-labeled mitoxantrone transportation study, sitravatinib at 3 μM blocked the efflux function mediated by ABCG2 and as a result, increased the intracellular concentration of anticancer drugs. Interestingly, sitravatinib at 3 μM altered neither protein expression nor subcellular localization of ABCG2. An ATPase assay demonstrated that ATPase activity of ABCG2 was inhibited in a concentration-dependent manner with sitravatinib; thus, the energy source to pump out compounds was interfered. Collectively, the results of this study open new avenues for sitravatinib working as an ABCG2 inhibitor which restores the antineoplastic activity of anticancer drugs known to be ABCG2 substrates. [ABSTRACT FROM AUTHOR]

M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR. [ABSTRACT FROM AUTHOR]

Failure of cancer chemotherapy is mostly due to multidrug resistance (MDR). Overcoming MDR mediated by overexpression of ATP binding cassette (ABC) transporters in cancer cells remains a big challenge. In this study, we explore whether NVP-TAE684, a novel ALK inhibitor which has the potential to inhibit the function of ABC transport, could reverse ABC transporter-mediated MDR. MTT assay was carried out to determine cell viability and reversal effect of NVP-TAE684 in parental and drug resistant cells. Drug accumulation and efflux assay was performed to examine the effect of NVP-TAE684 on the cellular accumulation and efflux of chemotherapeutic drugs. The ATPase activity of ABCG2 transporter in the presence or absence of NVP-TAE684 was conducted to determine the impact of NVP-TAE684 on ATP hydrolysis. Western blot analysis and immunofluorescence assay were used to investigate protein molecules related to MDR. In addition, the interaction between NVP-TAE684 and ABCG2 transporter was investigated via in silico analysis. MTT assay showed that NVP-TAE684 significantly decreased MDR caused byABCG2-, but not ABCC1-transporter. Drug accumulation and efflux tests indicated that the effect of NVP-TAE684 in decreasing MDR was due to the inhibition of efflux function of ABCG2 transporter. However, NVP-TAE684 did not alter the expression or change the subcellular localization of ABCG2 protein. Furthermore, ATPase activity analysis indicated that NVP-TAE684 could stimulate ABCG2 ATPase activity. Molecular in silico analysis showed that NVP-TAE684 interacts with the substrate binding sites of the ABCG2 transporter. Taken together, our study indicates that NVP-TAE684 could reduce the resistance of MDR cells to chemotherapeutic agents, which provides a promising strategy to overcome MDR. [ABSTRACT FROM AUTHOR]

Background: PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment. Methods: The effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP. Results: By inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb, the ATP-binding cassette transporters P-gp/ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently. Conclusions: The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges. [ABSTRACT FROM AUTHOR]

Overexpression of ABC transporters in cancer cells is an underlying mechanism of multidrug resistance (MDR), leading to insensitive response to chemotherapeutic strategies. Thus, MDR is often results in treatment failure in the clinic. In this study, we found midostaurin, a Food and Drug Administration (FDA)-approved anti-leukemia drug, can antagonize ATP-binding cassette subfamily B member 1 (ABCB1)-mediated MDR. Our results indicated that midostaurin has the capacity to antagonize ABCB1-mediated MDR, while no significant reversal effect was found on ATP-binding cassette subfamily G member 2 (ABCG2)-mediated MDR. Our subsequent resistance mechanism studies showed that midostaurin directly inhibited the efflux function of the ABCB1 transporter without alteration of the expression level or the subcellular localization of ABCB1 transporter. In addition, midostaurin inhibited the ATPase activity of ABCB1 transporter in a dose-dependent manner. Moreover, our in silico docking study predicted that midostaurin could interact with the substrate-binding sites of ABCB1 transporter. This novel finding could provide a promising treatment strategy that co-administrating midostaurin with anticancer drugs in the clinic could overcome MDR and improve the efficiency of cancer treatment. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is one of the leading causes of treatment failure in cancer chemotherapy. One major mechanism of MDR is the overexpressing of ABC transporters, whose inhibitors hold promising potential in antagonizing MDR. Glesatinib is a dual inhibitor of c-Met and SMO that is under phase II clinical trial for non-small cell lung cancer. In this work, we report the reversal effects of glesatinib to P-glycoprotein (P-gp) mediated MDR. Glesatinib can sensitize paclitaxel, doxorubicin, colchicine resistance to P-gp overexpressing KB-C2, SW620/Ad300, and P-gp transfected Hek293/ABCB1 cells, while has no effect to their corresponding parental cells and negative control drug cisplatin. Glesatinib suppressed the efflux function of P-gp to [3H]-paclitaxel and it didn't impact both the expression and cellular localization of P-gp based on Western blot and immunofluorescent analysis. Furthermore, glesatinib can stimulate ATPase in a dose-dependent manner. The docking study indicated that glesatinib interacted with human P-gp through several hydrogen bonds. Taken together, c-Met/SMO inhibitor glesatinib can antagonize P-gp mediated MDR by inhibiting its cell membrane transporting functions, suggesting new application in clinical trials. [ABSTRACT FROM AUTHOR]

Multidrug resistance mediated by the overexpression of ABC transporters is a major challenge in cancer chemotherapy. Here, we report the synthesis of an organoruthenium complex, RuF, that was designed to surmount multidrug resistance by combining ABCG2 inhibition and cancer cell cytotoxicity, yielding synergistic efficacy. [ABSTRACT FROM AUTHOR]

Abstract The successful treatment of cancer has significantly improved as a result of targeted therapy and immunotherapy. However, during chemotherapy, cancer cells evolve and can acquire "multidrug resistance" (MDR), which significantly limits the efficacy of cancer treatment and impacts patient survival and quality of life. Among the approaches to reverse MDR, modulating reactive oxidative species (ROS) may represent a strategy to kill MDR cancer cells that are mechanistically diverse. ROS in cancer cells play a central role in regulating and inducing apoptosis, thereby modulating cancer cells proliferation, survival and drug resistance. The levels of ROS and the activity of scavenging/anti-oxidant enzymes in drug resistant cancer cells are typically increased compared to non-MDR cancer and normal cells. Consequently, MDR cancer cells may be more susceptible to alterations in ROS levels. Numerous studies suggest that compounds modulating cellular ROS levels can enhance MDR cancer cell death and sensitize MDR cancer cells to certain chemotherapeutic drugs. In the current review, we discuss the critical and targetable redox-regulating enzymes, including mitochondrial electron transport chain (ETC) complexes, NADPH oxidases (NOXs), enzymes related to glutathione metabolism, glutamate/cystine antiporter xCT, thioredoxin reductases (TrxRs), nuclear factor erythroid 2-related factor 2 (Nrf2), and their roles in regulating cellular ROS levels, drug resistance as well as their clinical significance. We also discuss and summarize the findings in the past decade regarding the efficacy of ROS modulators for the treatment of MDR cancer alone or as sensitizing compounds. Compounds that are efficacious in modulating ROS generation represent a prominent class of drug candidates that warrants evaluation in clinical trials for patients harboring MDR cancers. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (ATO) is used as a chemotherapeutic agent for the treatment of acute promyelocytic leukemia. However, increasing drug resistance is reducing its efficacy. Therefore, a better understanding of ATO resistance mechanism is required. In this study, we established an ATO-resistant human epidermoid carcinoma cell line, KB/ATO, from its parental KB-3-1 cells. In addition to ATO, KB/ATO cells also exhibited cross-resistance to other anticancer drugs such as cisplatin, antimony potassium tartrate, and 6-mercaptopurine. The arsenic accumulation in KB/ATO cells was significantly lower than that in KB-3-1 cells. Further analysis indicated that neither application of P-glycoprotein inhibitor, breast cancer resistant protein (BCRP) inhibitor, or multidrug resistance protein 1 (MRP1) inhibitor could eliminate ATO resistance. We found that the expression level of ABCB6 was increased in KB/ATO cells. In conclusion, ABCB6 could be an important factor for ATO resistance in KB/ATO cells. The ABCB6 level may serve as a predictive biomarker for the effectiveness of ATO therapy. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is the phenomenon in which cancer cells simultaneously develop resistance to a broad spectrum of structurally and mechanistically unrelated drugs. MDR severely hinders the effective treatment of cancer and is the major cause of chemotherapy failure. ATP-binding cassette (ABC) transporters are extensively expressed in various body tissues, and actively transport endogenous and exogenous substrates through biological membranes. Overexpression of ABC transporters is frequently observed in MDR cancer cells, which promotes efflux of chemotherapeutic drugs and reduces their intracellular accumulation. Increasing evidence suggests that ABC transporters regulate tumor immune microenvironment (TIME) by transporting various cytokines, thus controlling anti-tumor immunity and sensitivity to anticancer drugs. On the other hand, the expression of various ABC transporters is regulated by cytokines and other immune signaling molecules. Targeted inhibition of ABC transporter expression or function can enhance the efficacy of immune checkpoint inhibitors by promoting anticancer immune microenvironment. This review provides an update on the recent research progress in this field. [ABSTRACT FROM AUTHOR]

Multidrug resistance is a key determinant of cancer chemotherapy failure. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment. To reveal the functional mechanisms of ABC transporters in drug resistance, extensive studies have been conducted from identifying drug binding sites to elucidating structural dynamics. In this review article, we examined the recent crystal structures of ABC proteins to depict the functionally important structural elements, such as domains, conserved motifs, and critical amino acids that are involved in ATP-binding and drug efflux. We inspected the drug-binding sites on ABC proteins and the molecular mechanisms of various substrate interactions with the drug binding pocket. While our continuous battle against drug resistance is far from over, new approaches and technologies have emerged to push forward our frontier. Most recent developments in anti-MDR strategies include P-gp inhibitors, RNA-interference, nano-medicines, and delivering combination strategies. With the advent of the ‘Omics’ era – genomics, epigenomics, transcriptomics, proteomics, and metabolomics – these disciplines play an important role in fighting the battle against chemoresistance by further unraveling the molecular mechanisms of drug resistance and shed light on medical therapies that specifically target MDR. [ABSTRACT FROM AUTHOR]

ATP-binding cassette (ABC) transporters represent one of the largest and oldest families of membrane proteins in all extant phyla from prokaryotes to humans, which couple the energy derived from ATP hydrolysis essentially to translocate, among various substrates, toxic compounds across the membrane. The fundamental functions of these multiple transporter proteins include: (1) conserved mechanisms related to nutrition and pathogenesis in bacteria, (2) spore formation in fungi, and (3) signal transduction, protein secretion and antigen presentation in eukaryotes. Moreover, one of the major causes of multidrug resistance (MDR) and chemotherapeutic failure in cancer therapy is believed to be the ABC transporter-mediated active efflux of a multitude of structurally and mechanistically distinct cytotoxic compounds across membranes. It has been postulated that ABC transporter inhibitors known as chemosensitizers may be used in combination with standard chemotherapeutic agents to enhance their therapeutic efficacy. The current paper reviews the advance in the past decade in this important domain of cancer chemoresistance and summarizes the development of new compounds and the re-evaluation of compounds originally designed for other targets as transport inhibitors of ATP-dependent drug efflux pumps. [ABSTRACT FROM AUTHOR]

Background and Purpose The transporter, multidrug resistance protein 1 ( MRP1, ABCC1), plays a critical role in the development of multidrug resistance ( MDR). Ibrutinib is an inhibitor of Bruton's tyrosine kinase. Here we investigated the reversal effect of ibrutinib on MRP1-mediated MDR. Experimental Approach Cytotoxicity was determined by MTT assay. The expression of protein was detected by Western blot. RT-PCR and Q-PCR were performed to detect the expression of MRP1 mRNA. The intracellular accumulation and efflux of substrates for MRP1 were measured by scintillation counter and flow cytometry. HEK293/ MRP1 cell xenografts in nude mice were established to study the effects of ibrutinib in vivo. Key Results Ibrutinib significantly enhanced the cytotoxicity of MRP1 substrates in HEK293/ MRP1 and HL60/ Adr cells overexpressing MRP1. Furthermore, ibrutinib increased the accumulation of substrates in these MRP1-overexpressing cells by inhibiting the drug efflux function of MRP1. However, mRNA and protein expression of MRP1 remained unaltered after treatment with ibrutinib in MRP1-overexpressing cells. In vivo, ibrutinib enhanced the efficacy of vincristine to inhibit the growth of HEK293/ MRP1 tumour xenografts in nude mice. Importantly, ibrutinib also enhances the cytotoxicity of vincristine in primary cultures of leukaemia blasts, derived from patients. Conclusions and Implications Our results indicated that ibrutinib significantly increased the efficacy of the chemotherapeutic agents which were MRP1 substrates, in MRP1-overexpressing cells, in vitro, in vivo and ex vivo. These findings will lead to further studies on the effects of a combination of ibrutinib with chemotherapeutic agents in cancer patients overexpressing MRP1. [ABSTRACT FROM AUTHOR]

ABSTRACT:  Aim: This study aimed to investigate the mechanism of reversal of multidrug resistance mediated by ABC transporters with tivozanib (AV-951 and KRN-951). Tivozanib is a potent inhibitor of VEGF-1, -2 and -3 receptors. Materials & methods: ABCB1- and ABCG2-overexpressing cell lines were treated with respective substrate antineoplastic agents in the presence or absence of tivozanib. Results: The results indicate that tivozanib can significantly reverse ABCB1-mediated resistance to paclitaxel, vinblastine and colchicine, as well as ABCG2-mediated resistance to mitoxantrone, SN-38 and doxorubicin. Drug efflux assays showed that tivozanib increased the intracellular accumulation of substrates by inhibiting the ABCB1 and ABCG2 efflux activity. Furthermore, at a higher concentration, tivozanib inhibited the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2. Conclusion: We conclude that tivozanib at noncytotoxic concentrations has the previously unknown activity of reversing multidrug resistance mediated by ABCB1 and ABCG2 transporters. [ABSTRACT FROM AUTHOR]

ATP-binding cassette ( ABC) transmembrane proteins evidently decrease the intracellular accumulation of substrate chemotherapeutic drugs by extruding them against a concentration gradient, thereby inducing drug resistance. Here we reported the effect of WHI-P154, an irreversible inhibitor of Janus kinase 3 and epidermal growth factor receptor tyrosine kinases, on reversing ABC transporters-mediated drug resistance. We found that WHI-P154 significantly enhanced the sensitivity of ABCG2-overexpressing cells to its substrates. WHI-P154 moderately sensitized ABCB1-overexpressing KB-C2 cells to its substrates whereas showed no sensitizing effect on ABCC1-, ABCC2 or ABCC10-mediated drug resistance. Moreover, WHI-P154 produced a significant increase in the intracellular accumulation of [³H]-mitoxantrone in ABCG2-overexpressing cells. The expression levels nor the localization of the ABCG2 protein was altered after treatment of ABCG2-overexpressing cells with WHI-P154. Further studies indicated that WHI-P154 enhanced the ATPase activity of ABCG2 at low concentrations (<10 μM). Additionally, a docking model predicted the binding conformation of WHI-P154 within the transmembrane region of homology-modeled human ABCG2 transporter. Collectively, these findings highlighted WHI-P154 could significantly reverse ABCG2-mediated multidrug drug resistance by directly blocking the efflux function. [ABSTRACT FROM AUTHOR]

Abstract: Multidrug resistance protein 7 (MRP7, ABCC10) is a recently identified member of the ATP-binding cassette (ABC) transporter family, which adequately confers resistance to a diverse group of antineoplastic agents, including taxanes, vinca alkaloids and nucleoside analogs among others. Clinical studies indicate an increased MRP7 expression in non-small cell lung carcinomas (NSCLC) compared to a normal healthy lung tissue. Recent studies revealed increased paclitaxel sensitivity in the Mrp7−/− mouse model compared to their wild-type counterparts. This demonstrates that MRP7 is a key contributor in developing drug resistance. Recently our group reported that PD173074, a specific fibroblast growth factor receptor (FGFR) inhibitor, could significantly reverse P-glycoprotein-mediated MDR. However, whether PD173074 can interact with and inhibit other MRP members is unknown. In the present study, we investigated the ability of PD173074 to reverse MRP7-mediated MDR. We found that PD173074, at non-toxic concentration, could significantly increase the cellular sensitivity to MRP7 substrates. Mechanistic studies indicated that PD173074 (1μmol/L) significantly increased the intracellular accumulation and in-turn decreased the efflux of paclitaxel by inhibiting the transport activity without altering expression levels of the MRP7 protein, thereby representing a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients. [Copyright &y& Elsevier]

Saracatinib, a highly selective, dual Src/Abl kinase inhibitor, is currently in a Phase II clinical trial for the treatment of ovarian cancer. In our study, we investigated the effect of saracatinib on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters in vitro and in vivo. Our results showed that saracatinib significantly enhanced the cytotoxicity of ABCB1 substrate drugs in ABCB1 overexpressing HeLa/v200, MCF-7/adr and HEK293/ABCB1 cells, an effect that was stronger than that of gefitinib, whereas it had no effect on the cytotoxicity of the substrates in ABCC1 overexpressing HL-60/adr cells and its parental sensitive cells. Additionally, saracatinib significantly increased the doxorubicin (Dox) and Rho 123 accumulation in HeLa/v200 and MCF-7/adr cells, whereas it had no effect on HeLa and MCF-7 cells. Furthermore, saracatinib stimulated the ATPase activity and inhibited photolabeling of ABCB1 with [125I]-iodoarylazidoprazosin in a concentration-dependent manner. In addition, the homology modeling predicted the binding conformation of saracatinib within the large hydrophobic drug-binding cavity of human ABCB1. However, neither the expression level of ABCB1 nor the phosphorylation level of Akt was altered at the reversal concentrations of saracatinib. Importantly, saracatinib significantly enhanced the effect of paclitaxel against ABCB1-overexpressing HeLa/v200 cancer cell xenografts in nude mice. In conclusion, saracatinib reverses ABCB1-mediated MDR in vitro and in vivo by directly inhibiting ABCB1 transport function, without altering ABCB1 expression or AKT phosphorylation. These findings may be helpful to attenuate the effect of MDR by combining saracatinib with other chemotherapeutic drugs in the clinic. [ABSTRACT FROM AUTHOR]

The resistance of tumor cells to a broad range of anticancer agents continues to be a problem for the success of cancer chemotherapy. Multidrug resistance (MDR) is due in part to three drug transporter proteins: ABCB1/P-glycoprotein (P-gp), ABCC1/multidrug resistance protein 1 (MRP1) and ABCG2/breast cancer resistance protein (BCRP). These transporters are part of the ATP-binding cassette (ABC) superfamily, whose members function as ATP-dependent drug-efflux pumps. Their activity can be blocked by various drugs such as verapamil (calcium channel blocker) and cyclosporin A (immunosuppressive agent), etc. These compounds are called MDR modulators or reversals. This review highlights several marine natural products with reversal effect on multidrug resistance in cancer, including agosterol A, ecteinascidin 743, sipholane triterpenoids, bryostatin 1, and welwitindolinones. [ABSTRACT FROM AUTHOR]

Abstract: Tyrosine kinases (TKs) are involved in key signaling events/pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Deregulated activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to inhibit specific kinases whose constitutive activity results in specific cancer types. These TKIs have been found to demonstrate effective anticancer activity and some of them have been approved by the Food and Drug Administration for clinical use or are in clinical trials. However, these targeted therapeutic agents are also transported by ATP-binding cassette (ABC) transporters, resulting in altered pharmacokinetics or development of resistance to these drugs in cancer patients. This review covers the recent findings on the interactions of clinically important TKIs with ABC drug transporters. Future research efforts in the development of novel TKIs with specific targets, seeking improved activity, should consider these underlying causes of resistance to TKIs in cancer cells. [Copyright &y& Elsevier]

The ATP-binding cassette (ABC) transporters are a superfamily of membrane proteins that are best known for their ability to transport a wide variety of exogenous and endogenous substances across membranes against a concentration gradient via ATP hydrolysis. There are seven subfamilies of human ABC transporters, one of the largest being the 'C' subfamily (gene symbol ABCC). Nine ABCC subfamily members, the so-called multidrug resistance proteins (MRPs) 1-9, have been implicated in mediating multidrug resistance in tumor cells to varying degrees as the efflux extrude chemotherapeutic compounds (or their metabolites) from malignant cells. Some of the MRPs are also known to either influence drug disposition in normal tissues or modulate the elimination of drugs (or their metabolites) via hepatobiliary or renal excretory pathways. In addition, the cellular efflux of physiologically important organic anions such as leukotriene C4 and cAMP is mediated by one or more of the MRPs. Finally, mutations in several MRPs are associated with human genetic disorders. In this minireview, the current biochemical and physiological knowledge of MRP1-MRP9 in cancer chemotherapy and human genetic disease is summarized. The mutations in MRP2/ABCC2 leading to conjugated hyperbilirubinemia (Dubin-Johnson syndrome) and in MRP6/ABCC6 leading to the connective tissue disorder Pseudoxanthoma elasticum are also discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: Multidrug resistance or chemoresistance is a phenomenon where cells exhibit resistance to drugs that are pharmacologically and structurally distinct. ABCG2, a member of ABC transporter superfamily has been widely reported to be a principal cause of MDR in various cancers via pumping out various antineoplastic drugs. VKNG-1, a phenyltetrazole analogue selectively inhibits the ABCG2 transporter and reverses resistance to standard anticancer drugs both in vitro and in vivo in ABCG2-overexpressing colon cancers. This study presents the importance of VKNG-1 as a modulator of the ABCG2 transporter. In cancer patients, a combination of VKNG-1 and ABCG2 substrate drugs could be a beneficial treatment option for cells with high ABCG2 expression. The emergence of multidrug resistance (MDR) to chemotherapeutic drugs is a major problem in the therapy of cancer. Knowledge of the mechanisms of drug resistance in cancer is necessary for developing efficacious therapies. ATP-binding cassette (ABC) transporters are transmembrane proteins that efflux chemotherapeutic drugs from cancer cells, thereby producing MDR. Our research efforts have led to the discovery of VKNG-1, a compound that selectively inhibits the ABCG2 transporter and reverses resistanctabe to standard anticancer drugs both in vitro and in vivo. VKNG-1, at 6 µM, selectively inhibited ABCG2 transporter and sensitized ABCG2-overexpressing drug-resistant cancer cells to the ABCG2 substrate anticancer drugs mitoxantrone, SN-38, and doxorubicin in ABCG2-overexpressing colon cancers. VKNG- 1 reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the mRNA and protein levels. Moreover, VKNG-1 inhibits the level of phosphorylated protein kinase B (PKB/p-AKT), and B-cell lymphoma-2 (Bcl-2) protein which may overcome resistance to anticancer drugs. However, the in vitro translocation of ABCG2 protein did not occur in the presence of 6 µM of VKNG-1. In addition, VKNG-1 enhanced the anticancer efficacy of irinotecan in ABCG2- overexpressing mouse tumor xenografts. Overall, our results suggest that VKNG-1 may, in combination with certain anticancer drugs, represent a treatment to overcome ABCG2-mediated MDR colon cancers. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) remains a major obstacle towards curative treatment of cancer. Despite considerable progress in delineating the basis of intrinsic and acquired MDR, the underlying molecular mechanisms remain to be elucidated. Emerging evidences suggest that dysregulation in endolysosomal compartments is involved in mediating MDR through multiple mechanisms, such as alterations in endosomes, lysosomes and autophagosomes, that traffic and biodegrade the molecular cargo through macropinocytosis, autophagy and endocytosis. For example, altered lysosomal pH, in combination with transcription factor EB (TFEB)-mediated lysosomal biogenesis, increases the sequestration of hydrophobic anti-cancer drugs that are weak bases, thereby producing an insufficient and off-target accumulation of anti-cancer drugs in MDR cancer cells. Thus, the use of well-tolerated, alkalinizing compounds that selectively block Vacuolar H⁺-ATPase (V-ATPase) may be an important strategy to overcome MDR in cancer cells and increase chemotherapeutic efficacy. Other mechanisms of endolysosomal-mediated drug resistance include increases in the expression of lysosomal proteases and cathepsins that are involved in mediating carcinogenesis and chemoresistance. Therefore, blocking the trafficking and maturation of lysosomal proteases or direct inhibition of cathepsin activity in the cytosol may represent novel therapeutic modalities to overcome MDR. Furthermore, endolysosomal compartments involved in catabolic pathways, such as macropinocytosis and autophagy, are also shown to be involved in the development of MDR. Here, we review the role of endolysosomal trafficking in MDR development and discuss how targeting endolysosomal pathways could emerge as a new therapeutic strategy to overcome chemoresistance in cancer. [ABSTRACT FROM AUTHOR]

OTS964 is a potent T-LAK cell-originated protein kinase (TOPK) inhibitor. Herein, we investigated the interaction of OTS964 and multidrug resistance (MDR)-associated ATP-binding cassette sub-family G member 2 (ABCG2). The cell viability assay indicated that the effect of OTS964 is limited in cancer drug-resistant and transfected cells overexpressing ABCG2. We found that the known ABCG2 transporter inhibitor has the ability to sensitize ABCG2-overexpressing cells to OTS964. In mechanism-based studies, OTS964 shows inhibitory effect on the efflux function mediated by ABCG2, and in turn, affects the pharmacokinetic profile of other ABCG2 substrate-drugs. Furthermore, OTS964 upregulates ABCG2 protein expression, resulting in enhanced resistance to ABCG2 substrate-drugs. The ATPase assay demonstrated that OTS964 stimulates ATPase activity of ABCG2 in a concentration-dependent manner. The computational molecular docking analysis combined with results from ATPase assay suggested that OTS964 interacts with drug-binding pocket of ABCG2 and has substrate-like behaviors. Thus, OTS964 is an MDR-susceptible agent due to its interactions with ABCG2, and overexpression of ABCG2 transporter may attenuate its therapeutic effect in cancer cells. [ABSTRACT FROM AUTHOR]

The emergence of multidrug resistance (MDR) has been a major issue for effective cancer chemotherapy as well as targeted therapy. One prominent factor that causes MDR is the overexpression of ABCB1 transporter. In the present study, we revealed that the Aurora kinase inhibitor GSK-1070916 is a substrate of ABCB1. GSK-1070916 is a newly developed inhibitor that is currently under clinical investigation. The cytotoxicity assay showed that overexpression of ABCB1 significantly hindered the anticancer effect of GSK-1070916 and the drug resistance can be abolished by the addition of an ABCB1 inhibitor. GSK-1070916 concentration-dependently stimulated ABCB1 ATPase activity. The HPLC drug accumulation assay suggested that the ABCB1-overexpressing cells had lower levels of intracellular GSK-1070916 compared with the parental cells. GSK-1070916 also showed high binding affinity to ABCB1 substrate-binding site in the computational docking analysis. In conclusion, our study provides strong evidence that ABCB1 can confer resistance to GSK-1070916, which should be taken into consideration in clinical setting. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy with complex heterogenous genetic and biological nature. Thus, prognostic prediction and targeted therapies might contribute to better chemotherapeutic response. However, the emergence of multidrug resistance (MDR) markedly impedes chemotherapeutic efficacy and dictates poor prognosis. Therefore, prior evaluation of chemoresistance is of great importance in therapeutic decision making and prognosis. In recent years, preclinical studies on chemoresistance have unveiled a compendium of underlying molecular basis, which facilitated the development of targetable small molecules. Furthermore, routing genomic sequencing has identified various genomic aberrations driving cellular response during the course of therapeutic treatment through adaptive mechanisms of drug resistance, some of which serve as prognostic biomarkers in risk stratification. However, the underlying mechanisms of MDR have challenged the certainty of the prognostic significance of some mutations. This review aims to provide a comprehensive understanding of the role of MDR in therapeutic decision making and prognostic prediction in AML. We present an updated genetic landscape of the predominant mechanisms of drug resistance with novel targeted therapies and potential prognostic biomarkers from preclinical and clinical chemoresistance studies in AML. We particularly highlight the unfolded protein response (UPR) that has emerged as a critical regulatory pathway in chemoresistance of AML with promising therapeutic horizon. Futhermore, we outline the most prevalent mutations associated with mechanisms of chemoresistance and delineate the future directions to improve the current prognostic tools. The molecular analysis of chemoresistance integrated with genetic profiling will facilitate decision making towards personalized prognostic prediction and enhanced therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: ABC transporters comprise a large group of ATP binding plasma membrane proteins, classified into subfamilies A-G, that transport substrates out of cells to maintain homeostasis. Prolonged exposure to chemotherapeutic drugs leads to increased expression of ABC transporters in cancer cells, resulting in increased efflux and decreased efficacy of anti-neoplastic agents. We found that BMS-599626, at 300 nM, inhibited the function of ABCG2, thereby increasing the efficacy of substrate chemotherapeutic drugs in wild-type as well as mutant ABCG2 overexpressing cells. In addition, BMS-599626 did not alter the expression or intracellular localization of ABCG2 but produced its reversal effect by decreasing efflux and increasing the intracellular accumulation of substrate chemotherapeutic drugs. Finally, BMS-5999626 also inhibited ABCG2 mediated ATP hydrolysis. Overall, our results show that administration of BMS-599626 along with chemotherapeutic drugs can improve the efficacy of chemotherapy in ABC transporter overexpressing cancer cells. Multidrug resistance (MDR) associated with the overexpression of ABC transporters is one of the key causes of chemotherapy failure. Various compounds blocking the function and/or downregulating the expression of these transporters have been developed over the last few decades. However, their potency and toxicity have always been a concern. In this report, we found that BMS-599626 is a highly potent inhibitor of the ABCG2 transporter, inhibiting its efflux function at 300 nM. Our study repositioned BMS-599626, a highly selective pan-HER kinase inhibitor, as a chemosensitizer in ABCG2-overexpressing cell lines. As shown by the cytotoxicity assay results, BMS-599626, at noncytotoxic concentrations, sensitizes ABCG2-overexpressing cells to topotecan and mitoxantrone, two well-known substrates of ABCG2. The results of our radioactive drug accumulation experiment show that the ABCG2-overexpressing cells, treated with BMS-599626, had an increase in the accumulation of substrate chemotherapeutic drugs, as compared to their parental subline cells. Moreover, BMS-599626 did not change the protein expression or cell surface localization of ABCG2 and inhibited its ATPase activity. Our in-silico docking study also supports the interaction of BMS-599626 with the substrate-binding site of ABCG2. Taken together, these results suggest that administration of chemotherapeutic drugs, along with nanomolar concentrations (300 nM) of BMS-599626, may be effective against ABCG2-mediated MDR in clinical settings. [ABSTRACT FROM AUTHOR]