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Highlights: Nanoferroptosis: a novel cell death process using various nanoparticles. Therapeutic potential of nanoferroptosis inducers in cancer. Synergistic approach of nanoferroptosis with immunotherapy, sonodynamic and photodynamic therapy. As a new form of regulated cell death, ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells. The molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of cells. Due to their high loading and structural tunability, nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active targeting. This review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and metastasis. Additionally, we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are cell‐derived nanosized vesicles that mediate cell‐to‐cell communication via transporting bioactive molecules and thus are critically involved in various physiological and pathological conditions. EVs contribute to different aspects of cancer progression, such as cancer growth, angiogenesis, metastasis, immune evasion, and drug resistance. EVs induce the resistance of cancer cells to chemotherapy, radiotherapy, targeted therapy, antiangiogenesis therapy, and immunotherapy by transferring specific cargos that affect drug efflux and regulate signaling pathways associated with epithelial‐mesenchymal transition, autophagy, metabolism, and cancer stemness. In addition, EVs modulate the reciprocal interaction between cancer cells and noncancer cells in the tumor microenvironment (TME) to develop therapy resistance. EVs are detectable in many biofluids of cancer patients, and thus are regarded as novel biomarkers for monitoring therapy response and predicting prognosis. Moreover, EVs are suggested as promising targets and engineered as nanovehicles to deliver drugs for overcoming drug resistance in cancer therapy. In this review, the biological roles of EVs and their mechanisms of action in cancer drug resistance are summarized. The preclinical studies on using EVs in monitoring and overcoming cancer drug resistance are also discussed. [ABSTRACT FROM AUTHOR]

Background: There is a lack of research on the molecular interaction of the enhancers of rudimentary homolog (ERH) in bladder cancer (BC) cells. This study aimed to determine the interacting proteins of ERH in human T24 cells. Methods: First, the ERH gene was overexpressed in human T24 cells. Coimmunoprecipitation (co-IP) and shotgun mass spectrometry (MS) analyses were performed to obtain a list of proteins that interact with ERH. Subsequently, bioinformatic analyses with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein–protein interaction (PPI) studies were performed to analyze the ERH-interactive protein list (ERH-IPL). Then, we selected one of the interacting proteins, EIF2α for verification. An immunofluorescence colocalization assay was performed to validate the co-expression of the selected protein, and the binding sites of the two proteins were predicted by ZDOCK technology. Finally, PCR analysis on the downstream molecules of the interacting protein was performed for verification. Results: ERH protein was successfully overexpressed in human T24 cells. We obtained a list of 205 proteins that might directly or indirectly interact with the ERH protein by mass spectrometric analysis. The bioinformatic analysis showed that ERH-interacting proteins were related to "ribonucleoprotein complex", "ATPase activity", "nuclear speck", and "translation factor activity, RNA binding". We further identified one of the key genes, EIF2S1, and confirmed that the corresponding protein EIF2α is co-expressed and may bind with ERH in human T24 cells. The mRNA levels of molecules ATF4 and CHOP were found to be upregulated by ERH. Conclusion: ERH protein affects "ribonucleoprotein complex", "ATPase activity", "nuclear speck", and "translation factor activity, RNA binding". The ERH protein can interact with EIF2α and regulate the EIF2α-ATF4/CHOP signaling pathway in human T24 cells. [ABSTRACT FROM AUTHOR]

Cancer is a major public health problem worldwide. Studies on oncogenes and tumor-targeted therapies have become an important part of cancer treatment development. In this review, we summarize and systematically introduce the gene enhancer of rudimentary homolog (ERH), which encodes a highly conserved small molecule protein. ERH mainly exists as a protein partner in human cells. It is involved in pyrimidine metabolism and protein complexes, acts as a transcriptional repressor, and participates in cell cycle regulation. Moreover, it is involved in DNA damage repair, mRNA splicing, the process of microRNA hairpins as well as erythroid differentiation. There are many related studies on the role of ERH in cancer cells; however, there are none on tumor-targeted therapeutic drugs or related therapies based on the expression of ERH. This study will provide possible directions for oncologists to further their research studies in this field. [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]

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]

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]

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]

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]

In this study, we investigated the efficacy of methyl-cantharidimide (MCA), a cantharidin (CTD) analog, as an anticancer drug, in cancer cells overexpressing either ABCB1 or ABCG2 transporters and in cisplatin-resistant cancer cells. The results indicated that: (i) MCA was efficacious in the ABCB1-overexpressing cell line, KB-C2, and the ABCB1-gene-transfected cell line, HEK293/ABCB1 (IC50 from 6.37 to 8.44 mM); (ii) MCA was also efficacious in the ABCG2-overexpressing cell line, NCI-H460/MX20, and the ABCG2-gene-transfected cell lines, HEK293/ABCG2-482-R2, HEK293/ABCG2-482-G2, and the HEK293/ABCG2-482-T7 cell lines (IC50 from 6.37 to 9.70 mM); (iii) MCA was efficacious in the cisplatin resistant cancer cell lines, KCP-4 and BEL-7404/CP20 (IC50 values from 7.05 to 8.16 mM); (iv) MCA (up to 16 mM) induced apoptosis in both BEL-7404 and BEL-7404/CP20 cancer cells; (v) MCA arrested both BEL-7404 and BEL-7404/CP20 cancer cells in the G0/G1 phase of the cell cycle; (vi) MCA (8 mM) upregulated the expression level of the protein, unc-5 netrin receptor B (UNC5B) in HepG2 and BEL-7404 cancer cells. Overall, our results indicated that MCA's efficacy in ABCB1- and ABCG2-overexpressing and cisplatin resistant cancer cells is due to the induction of apoptosis and cell cycle arrest in the G0/G1 phase. [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]

Chemoresistance, whether intrinsic or acquired, is a major obstacle in the treatment of cancer. The resistance of cancer cells to chemotherapeutic drugs can result from various mechanisms. Over the last decade, it has been reported that 1ong noncoding RNAs (lncRNAs) can mediate carcinogenesis and drug resistance/sensitivity in cancer cells. This article reviews, in detail, recent studies regarding the roles of lncRNAs in mediating drug resistance. [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]

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]

Purpose: Specific tyrosine kinase inhibitors were recently reported to modulate the activity of ABC transporters, leading to an increase in the intracellular concentration of their substrate drugs. In this study, we determine whether PD173074, a specific fibroblast growth factor receptor (FGFR) inhibitor, could reverse ABC transporter-mediated multidrug resistance. Methods: 3-(4,5-Dimethylthiazol-yl)-2,5-diphenyllapatinibrazolium bromide assay was used to determine the effect of PD173074 on reversal of ABC transporter-mediated multidrug resistance (MDR). In addition, [H]-paclitaxel accumulation/efflux assay, western blotting analysis, ATPase, and photoaffinity labeling assays were done to study the interaction of PD173074 on ABC transporters. Results: PD173074 significantly sensitized both ABCB1-transfected and drug-selected cell lines overexpressing this transporter to substrate anticancer drugs colchicine, paclitaxel, and vincristine. This effect of PD173074 is specific to ABCB1, as no significant interaction was detected with other ABC transporters such as ABCC1 and ABCG2. The observed reversal effect seems to be primarily due to the decreased active efflux of [H]-paclitaxel in ABCB1 overexpressing cells observed in efflux assay. In addition, no significant change in the ABCB1 expression was observed when ABCB1 overexpressing cells were exposed to 5 μM PD173074 for up to 3 days, thereby further suggesting its role in modulating the function of the transporter. In addition, PD173074 stimulated the ATPase activity of ABCB1 in a concentration-dependent manner, indicating a direct interaction with the transporter. Interestingly, PD173074 did not inhibit photolabeling of ABCB1 with [I]-iodoarylazidoprazosin (IAAP), showing that it binds at a site different from that of IAAP in the drug-binding pocket. Conclusions: Here, we report for the first time, PD173074, an inhibitor of the FGFR, to selectively reverse ABCB1 transporter-mediated MDR by directly blocking the efflux function of the transporter. [ABSTRACT FROM AUTHOR]

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]

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]

Lung cancer is the primary cause of cancer-related death worldwide, and development of novel lung cancer preventive and therapeutic agents are urgently needed. Brassica nigra (black mustard) seeds are commonly consumed in several Asian and African countries. Mustard seeds previously exhibited significant anticancer activities against several cancer types. In the present study, we have investigated various cellular and molecular mechanisms of anticancer effects of an ethanolic extract of B. nigra seeds against A549 and H1299 human non-small cell lung cancer cell lines. B. nigra extract showed a substantial growth-inhibitory effect as it reduced the viability and clonogenic survival of A549 and H1299 cells in a concentration-dependent manner. B. nigra extract induced cellular apoptosis in a time- and concentration-dependent fashion as evidenced from increased caspase-3 activity. Furthermore, treatment of both A549 and H1299 cells with B. nigra extract alone or in combination with camptothecin induced DNA double-strand breaks as evidenced by upregulation of γH2A histone family member X, Fanconi anemia group D2 protein, Fanconi anemia group J protein, ataxia-telangiectesia mutated and Rad3-related protein. Based on cell cycle analysis, B. nigra extract significantly arrested A549 and H1299 cells at S and G2/M phases. Additionally, B. nigra extract suppressed the migratory and invasive properties of both cell lines, downregulated the expression of matrix metalloproteinase-2 (MMP2), MMP9, and Snail and upregulated the expression of E-cadherin at mRNA and protein levels. Taken together, these findings indicate that B. nigra seed extract may have an important anticancer potential against human lung cancer which could be mediated through simultaneous and differential regulation of proliferation, apoptosis, DNA damage, cell cycle, migration, and invasion. [ABSTRACT FROM AUTHOR]

The overexpressing ABCB1 transporter is one of the key factors leading to multidrug resistance (MDR). Thus, many ABCB1 inhibitors have been found to be able to overcome ABCB1-mediated MDR. However, some inhibitors also work as a substrate of ABCB1, which indicates that in order to achieve an effective reversal dosage, a higher concentration is needed to overcome the pumped function of ABCB1, which may concurrently increase the toxicity. WYE-354 is an effective and specific mTOR (mammalian target of rapamycin) inhibitor, which recently has been reported to reverse ABCB1-mediated MDR. In the current study, 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cell viability and reversal effect of WYE-354 in parental and drug-resistant cells. Drug accumulation was performed to examine the effect of WYE-354 on the cellular accumulation of chemotherapeutic drugs. The ATPase (adenosine triphosphatase) activity of the ABCB1 transporter in the presence or absence of WYE-354 was conducted in order to determine the impact of WYE-354 on ATP hydrolysis. Western blot analysis and immunofluorescence assay were used to investigate the protein molecules related to MDR. In addition, the interaction between the WYE-354 and ABCB1 transporter was investigated via in silico analysis. We demonstrated that WYE-354 is a substrate of ABCB1, that the overexpression of the ABCB1 transporter decreases the efficacy of WYE-354, and that the resistant WYE-354 can be reversed by an ABCB1 inhibitor at a pharmacological achievable concentration. Furthermore, WYE-354 increased the intracellular accumulation of paclitaxel in the ABCB1-mediated MDR cell line, without affecting the corresponding parental cell line, which indicated that WYE-354 could compete with other chemotherapeutic drugs for the ABCB1 transporter substrate binding site. In addition, WYE-354 received a high score in the docking analysis, indicating a strong interaction between WYE-354 and the ABCB1 transporter. The results of the ATPase analysis showed that WYE-354 could stimulate ABCB1 ATPase activity. Treatment with WYE-354 did not affect the protein expression or subcellular localization of the ABCB1. This study provides evidence that WYE-354 is a substrate of the ABCB1 transporter, implicating that WYE-354 should be avoided for use in ABCB1-mediated MDR cancer. [ABSTRACT FROM AUTHOR]

The overexpression of ABC transporters induced by anticancer drugs has been found to be the main cause of multidrug resistance. It is actually also a strategy by which cancer cells escape being killed. Tetrandrine is a natural product extracted from the stem of Tinospora crispa. In this study, tetrandrine showed synergistic cytotoxic activity in combinational use with chemotherapeutic drugs, such as Doxorubicin, Vincristine, and Paclitaxel, in both drug-induced and MDR1 gene-transfected cancer cells that over-expressed ABCB1/P-glycoprotein. Tetrandrine stimulated P-glycoprotein ATPase activity, decreased the efflux of [3H]-Paclitaxel and increased the intracellular accumulation of [3H]-Paclitaxel in KB-C2 cells. Furthermore, SW620/Ad300 and KB-C2 cells pretreated with 1 μM tetrandrine for 72 h decreased P-glycoprotein expression without changing its cellular localization. This was demonstrated through Western blotting and immunofluorescence analysis. Interestingly, down-regulation of P-glycoprotein expression was not correlated with gene transcription, as the MDR1 mRNA level exhibited a slight fluctuation in SW620/Ad300 and KB-C2 cells at 0, 24, 48, and 72 h treatment time points. In addition, molecular docking analysis predicted that tetrandrine had inhibitory potential with the ABCB1 transporter. Our results suggested that tetrandrine can antagonize MDR in both drug-selected and MDR1 gene-transfected cancer cells by down regulating the expression of the ABCB1 transporter, followed by increasing the intracellular concentration of chemotherapeutic agents. The combinational therapy using tetrandrine and other anticancer drugs could promote the treatment efficiency of drugs that are substrates of ABCB1. [ABSTRACT FROM AUTHOR]

ABCB1 is one of the major drug efflux transporters that is known to cause multidrug resistance (MDR) in cancer patients receiving chemotherapy for the treatment of solid tumors and hematological malignancies. Inhibition of ABCB1 efflux function is important for maintaining the intracellular concentration of chemotherapeutic drugs. Here, we evaluated ciprofloxacin for its ability to reverse MDR caused by the overexpression of ABCB1. Cytotoxicity of ciprofloxacin was determined by the MTT assay. The chemosensitizing effects of ciprofloxacin were determined in combination with ABCB1 substrates. The intracellular accumulation and efflux of ABCB1 substrates was measured by a scintillation counter, and protein expression was determined by the Western blotting. Vanadate-sensitive ATPase assay was performed to determine the effect of ciprofloxacin on the ATPase activity of ABCB1, and docking analysis was done to determine the interaction of ciprofloxacin with ABCB1. Ciprofloxacin significantly potentiated the cytotoxic effects of ABCB1 substrates in ABCB1-overexpressing cells. Furthermore, ciprofloxacin increased the intracellular accumulation and decreased the efflux of [3H]-paclitaxel without altering the expression of ABCB1. Ciprofloxacin stimulated the ATPase activity of ABCB1 in a concentration-dependent manner. Our findings showed that ciprofloxacin potently inhibits the ABCB1 efflux function and it has potential to be developed as a combination anticancer therapy. [ABSTRACT FROM AUTHOR]

Mechanisms of different types of nano-intrabodies that exert functions on the target antigens residing on the cell membrane or distributed in the cytoplasm, ER, or cell nucleus. • Intrabodies can be used to treat cancers. • Intrabodies can be transferred to or expressed in living cells. • The intrabody technology and other gene suppression techniques were briefly compared. • Recent advances in the research of intrabodies for treating cancers are summarized. Conventional antibodies used for cancer therapies can only target the extracellular epitopes of tumor-associated antigens (TAAs); however, they struggle to enter cancer cells to interact with intracellular TAAs. Intrabodies are the engineered single-chain antibodies that can be transferred to the living cells or expressed within the cells and target the intracellular TAAs, owing to their nanosizes, enhanced motility and specific and potent binding affinities for the TAAs. Intrabody-based technology is a supplement to the current gene silencing technologies that can regulate a variety of biochemical processes and cellular functions and could be applicable for clinical treatment of tumors. Here, we review the development and current status of the intrabodies for the targeted treatment of cancers. [ABSTRACT FROM AUTHOR]

Overexpression of ABCB1 transporters plays a crucial role in mediating multidrug resistance (MDR). Therefore, it is important to inhibit ABCB1 activity in order to maintain an effective intracellular level of chemotherapeutic drugs. Tepotinib is a MET tyrosine kinase inhibitor with potential anticancer effect and it is currently in clinical trials. In this study, we investigated whether tepotinib could antagonize ABC transporters-mediated MDR. Our results suggest that tepotinib significantly reversed ABCB1-mediated MDR but not ABCG2- or ABCC1-mediated MDR. Mechanistic studies show that tepotinib significantly reversed ABCB1-mediated MDR by attenuating the efflux activity of ABCB1 transporter. The ATPase assay showed that tepotinib inhibited the ATPase activity of ABCB1 in a concentration-dependent manner. Furthermore, treatment with tepotinib did not change protein expression or subcellular localization of ABCB1. Docking analysis indicated that tepotinib interacted with the drug-binding site of the ABCB1 transporter. Our study provides a potential chemotherapeutic strategy of co-administrating tepotinib with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect. [ABSTRACT FROM AUTHOR]

• ITH- 6 inhibits proliferation of colon cancer cell lines in vitro. • ITH- 6 inhibits G2/M phase and tubulin polymerization in the mitotic phase. • ITH- 6 induces apoptosis and ROS production in colon cancer cells. • ITH- 6 inhibits GSH levels in colon cancer cells. • ITH- 6 could be a potential anti-cancer drug for colorectal cancer treatment. Colorectal cancer is the third leading cause of cancer related deaths in the United States. Currently, Irinotecan, a topoisomerase I inhibitor, is an approved anti-cancer drug for the treatment of patients with advanced or recurrent colorectal cancer. Considering low response rate and events of high toxicity caused by irinotecan, we evaluated a series of thirteen thiazolyl hydrazone derivatives of 1-indanone for their potential antineoplastic activity and four compounds showed promising anti-cancer activity against most of the tested colon cancer cell lines with IC 50 values ranging from 0.41 ± 0.19 to 6.85 ± 1.44 μM. It is noteworthy that the compound, N -Indan-1-ylidene-N'-(4-Biphenyl-4-yl-thiazol-2-yl)-hydrazine (ITH- 6) is found to be more effective than irinotecan against colon cancer cells, HT-29, COLO 205, and KM 12. Mechanistic studies reveal that ITH- 6 arrests these cancer cell lines in G2/M phase of the cell cycle, induces apoptosis and causes an increase in ROS level with a significant reduction in the GSH level. The mechanism of inhibition relates to the inhibition of tubulin polymerization in the mitotic phase. These findings suggest that ITH- 6 is a novel drug candidate for the treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Abstract Overexpression of ATP-binding cassette (ABC) transporters is one of the most important mechanisms responsible for the development of multidrug resistance (MDR). Selonsertib, a serine/threonine kinase inhibitor, targets apoptosis signal-regulating kinase 1 (ASK1) and is now in phase III clinical trial for the treatment of non-alcoholic steatohepatitis (NASH). In this study, we investigated whether selonsertib could reverse MDR-mediated by ABC transporters, including ABCB1, ABCG2, ABCC1 and ABCC10. The results showed that selonsertib significantly reversed ABCB1- and ABCG2-mediated MDR, but not MDR-mediated by ABCC1 or ABCC10. Mechanism studies indicated that the reversal effect of selonsertib was related to the attenuation of the efflux activity of ABCB1 and ABCG2 transporters, without the protein level decrease or change in the subcellular localization of ABCB1 or ABCG2. Selonsertib stimulated the ATPase activity of ABCB1 and ABCG2 in a concentration-dependent manner, and in silico docking study showed selonsertib could interact with the substrate-binding sites of both ABCB1 and ABCG2. This study provides a clue into a novel treatment strategy, which includes a combination of selonsertib with antineoplastic drugs to attenuate MDR-mediated by ABCB1 or ABCG2 in cancer cells overexpressing these transporters. Highlights • Selonsertib, a selective ASK1 inhibitor, significantly overcome MDR in cancer. • Selonsertib stimulates the ATPase activity of ABCB1 and ABCG2. • Selonsertib interacts with the substrate-binding sites of both ABCB1 and ABCG2. • The combination of selonsertib with anticancer drugs could be a novel treatment strategy to evade MDR in cancer. [ABSTRACT FROM AUTHOR]

The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Numerous mechanisms have been recognized that cause MDR, but one of the most important mechanisms is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters, through which the efflux of various anticancer drugs against their concentration gradients is powered by ATP. In recent years, small molecular tyrosine kinase inhibitors (TKIs) have been developed for treatment in various human cancers overexpressing epidermal growth factor receptor (EGFR). At the same time, some TKIs have been shown to be capable of inhibiting ABC transporter-mediated MDR. Dacomitinib (PF-00299804) is a second generation, irreversible TKI, which has shown positive anticancer activities in some preclinical and clinical trials. As many TKIs are substrates or inhibitors of ABC transporters, this study investigates whether dacomitinib could interact with ABC subfamily members that mediate MDR, including ABCB1 (P-gp), ABCG2 (BCRP) and ABCC1 (MRP1). The results showed that dacomitinib at 1.0 μM significantly reversed drug resistance mediated by ABCB1 and ABCG2, but not ABCC1, doing so by antagonizing the drug efflux function in ABCB1- and ABCG2-overexpressing cell lines. The reversal effect on ABCB1-overexpressing cells is more potent than that on ABCG2-overexpressing cells. In addition, dacomitinib at reversal concentration affected neither the protein expression level nor the localization of ABCB1 and ABCG2. Therefore, the mechanisms of this modulating effect are likely to be the following: first, as an inhibitor of ABCB1 or ABCG2 transporters, dacomitinib binds to drug-substrate site in transmembrane domains (TMD) stably in a noncompetitive manner; or second, dacomitinib inhibits ATPase activity and maintains the stability of TMD conformation in a concentration-dependent manner thereby inhibiting the drug efflux function of ABCB1 or ABCG2 transporter. This study provides a useful combinational therapeutic strategy with dacomitinib and substrates of ABCB1 and/or ABCG2 transporters in ABCB1- or ABCG2-overexpressing cancers. [ABSTRACT FROM AUTHOR]

The anti-apoptotic protein survivin is highly expressed in cancer cells but has a very low expression in fully differentiated adult cells. Overexpression of survivin is positively correlated with cancer cell resistance to chemotherapy and radiotherapy, cancer cell metastasis, and poor patient prognosis. Therefore, selective targeting survivin represents an attractive strategy for the development of anticancer therapeutics. Herein, we reported the extensive structural modification of our recently discovered selective survivin inhibitor UC-112 and the synthesis of thirty-three new analogs. The structure-activity relationship (SAR) study indicated that replacement of the benzyloxy moeity in UC-112 with an indole moiety was preferred to other moieties. Among these UC-112 analogs, 10f , 10h , 10k , 10n showed the most potent antiproliferative activities. Interestingly, they were more potent against the P-glycoprotein overexpressing cancer cell lines compared with the parental cancer cell lines. Mechanistic studies confirmed that new analogs maintained their unique selectivity against survivin among the IAP family members. In vivo study using 10f in a human A375 melanoma xenograft model revealed that it effectively inhibited melanoma tumor growth without observable acute toxicity. Collectively, this study strongly supports the further preclinical development of selective survivin inhibitors based on the UC-112 scaffold. [ABSTRACT FROM AUTHOR]

[Display omitted] Drug resistance is the major obstacle that undermines effective cancer treatment. Recently, the application of gas signaling molecules, e.g., carbon monoxide (CO), in overcoming drug resistance has gained significant attention. Growing evidence showed that CO could inhibit mitochondria respiratory effect and glycolysis, two major ATP production pathways in cancer cells, and suppress angiogenesis and inhibit the activity of cystathionine β-synthase that is important in regulating cancer cells homeostasis, leading to synergistic effects when combined with cisplatin, doxorubicin, or phototherapy, etc. in certain resistant cancer cells. In the current review, we attempted to have a summary of these research conducted in the past decade using CO in treating drug resistant cancers, and have a detailed interpretation of the underlying mechanisms. The critical challenges will be discussed and potential solutions will also be provided. The information collected in this work will hopefully evoke more effects in using CO for the treatment of drug resistant cancers. [ABSTRACT FROM AUTHOR]

Abstract: Multidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report that telatinib, a small molecule tyrosine kinase inhibitor, enhances the anticancer activity of ABCG2 substrate anticancer drugs by inhibiting ABCG2 efflux transporter activity. Co-incubation of ABCG2-overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cellular viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1μM did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1μM significantly enhanced the intracellular accumulation of [3H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1μM significantly reduced the rate of [3H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [3H]-E217βG in ABCG2 overexpressing membrane vesicles. Telatinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that telatinib might be a substrate of ABCG2. Binding interactions of telatinib were found to be in transmembrane region of homology modeled human ABCG2. In addition, telatinib (15mg/kg) with doxorubicin (1.8mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. These results, provided that they can be translated to humans, suggesting that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2. [Copyright &y& Elsevier]

Abstract: High intrinsic or acquired expression of membrane spanning, adenosine triphosphate binding cassette (ABC) transporter proteins, such as P-glycoprotein (P-gp), in cancers represents a major impediment to chemotherapy, with accelerated drug efflux leading to multi-drug resistance (MDR). Although ABC transporter inhibitors offer the prospect of reversing the MDR phenotype, no inhibitors have advanced to the clinic. We employed a range of intracellular fluorescence and radio-ligand accumulation and efflux assays, together with cytotoxicity and MDR reversal assays, as well as flow cytometry, fluorescence microscopy and radioimmunoprecipitation, to discover and evaluate new P-gp inhibitors from a unique library of southern Australian and Antarctic marine natural products. This study successfully characterized two rare bromoditerpenes, parguerenes I and II, sourced from a southern Australian collection of the red alga Laurencia filiformis, as P-gp inhibitors. We determined that the parguerenes were non-cytotoxic, dose-dependent inhibitors of P-gp mediated drug efflux, that modify the extracellular antibody binding epitope of P-gp in a manner that differs markedly from that of the known inhibitors verapamil and cyclosporine A. We confirmed that parguerenes were capable of reversing P-gp mediated vinblastine, doxorubicin and paclitaxel MDR, that inhibitory properties span both P-gp and multidrug resistant protein 1 (MRP1), but do not extend to breast cancer resistance protein (BCRP), and that parguerene II is superior (more potent) to verapamil. Our investigations validate the proposition that marine natural products can deliver new ABC transporter inhibitor scaffolds, with structure characteristics fundamentally different from existing inhibitor classes. [Copyright &y& Elsevier]

• Overexpression of ABCG2 transporter in cancer cells can decrease the cytotoxicity of GSK1070916. • The inclusion of ABCG2 inhibitor can enhance the anticancer effect of GSK107916 in ABCG2-overexpressing cancer cells. • Tumor ABCG2 expression level may be a predictor for clinical response to GSK1070916. The emergence of multidrug resistance (MDR) is one of the main factors that impair therapeutic outcome in cancer therapy. Among all the factors that contribute to MDR, overexpression of ABCG2 transporter has been described as a key factor. GSK1070916 is a potent Aurora kinase inhibitor with broad anticancer effects. The robust efficacy shown in preclinical studies allowed the drug progress to clinical investigation. However, the potential mechanisms of acquired resistance to GSK1070916 remain inconclusive. Since several Aurora kinase inhibitors were reported to be transported substrates of ABCG2, we aimed to identify the potential interaction of GSK1070916 with ABCG2. Our data showed that ABCG2-overexpressing cells demonstrated high resistance-fold to GSK1070916 compared to the parental cells. In addition, combination of GSK1070916 with an ABCG2 inhibitor was able to restore its sensitivity. The multicellular tumor spheroid assay supported this finding by demonstrating attenuated growth inhibition in ABCG2-overexpressing tumor spheroids. In addition, the ABCG2 ATPase assay and computational modeling suggested that GSK1070916 could bind to ABCG2 substrate-binding site. The HPLC assay provided another direct evidence that ABCG2-overexpressing cells showed attenuated intracellular accumulation of GSK1070916, and such phenomenon was abolished by Ko143, a known ABCG2 inhibitor. Furthermore, GSK1070916 was able to hinder the efflux activity of ABCG2, indicating possible drug-drug interactions with other ABCG2 substrate drugs. In summary, we revealed that overexpression of ABCG2 can cause GSK1070916 resistance in cancer cells. The combination of an ABCG2 inhibitor with GSK1070916 may be a rational strategy to overcome the drug resistance and should be considered for clinical investigation. [ABSTRACT FROM AUTHOR]

The enhancement of drug efflux caused by ATP-binding cassette (ABC) transporters (including ABCG2 and ABCB1) overexpression is an important factor for multidrug resistance (MDR) in cancers. After testing the reversal activities of 19 chalcone and bis-chalcone derivatives on MDR cancer cell lines, we found that non-basic chalcone CYB-2 exhibited the most potent reversal activities against both ABCG2- and ABCB1-mediated MDR. The mechanistic studies show that this compound can increase the accumulation of anticancer drugs in both ABCG2- and ABCB1-overexpressing cancer cell lines, resulting from the blocked efflux function of the MDR cancer cell lines. This inhibition is due to the barred ABCG2 and ABCB1 ATPase activities rather than altering the expression or localization of ABCG2 or ABCB1 transporters. The previous studies showed that non-basic chalcones were ABCG2-specific inhibitors; however, we found that non-basic chalcone CYB-2 can be developed as an ABCG2/ABCB1 dual inhibitor to overcome MDR in cancers that co-express both ABCG2 and ABCB1. Moreover, non-basic chalcone CYB-2 has synthetic tractability compared to other chalcone-based derivatives. [ABSTRACT FROM AUTHOR]