ABCG2 Overexpression Contributes to Pevonedistat Resistance.

MLN4924 (pevonedistat) is a first-in-class NEDD8-activating enzyme (NAE) inhibitor in clinical trials for the treatment of solid tumors and hematologic malignancies. Despite the promising activity of MLN4924 observed in early trials, drug resistance has been noted in some patients. Identifying the underlying cause of treatment failure may help to better stratify patients that are most likely to benefit from this novel agent.

The Chemoprevention of Ovarian Cancer: the Need and the Options.

Purpose Of Review: Ovarian cancer (OvCa) is the most lethal of all gynecological cancers, with a 5-year survival around 46%, mainly due to limitations in early diagnosis and treatment. Consequently, the chemoprevention of OvCa emerges as an important option to control this dismal disease. Here, we discuss the role of risk assessment in the design of chemoprevention strategies for OvCa, describe candidate agents, and assess future directions in this field.

Correction: The Chemoprevention of Ovarian Cancer: the Need and the Options.

[This corrects the article DOI: 10.1007/s40495-018-0133-6.].

The BTK Inhibitor Ibrutinib (PCI-32765) Overcomes Paclitaxel Resistance in ABCB1- and ABCC10-Overexpressing Cells and Tumors.

Paclitaxel is one of the most widely used antineoplastic drugs in the clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP-binding cassette subfamily B member 1 (ABCB1/P-glycoprotein) and subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance.

2-Trifluoromethyl-2-Hydroxypropionamide Derivatives as Novel Reversal Agents of ABCG2 (BCRP)-Mediated Multidrug Resistance: Synthesis and Biological Evaluations.

It has been postulated that one of the biggest impediments to a successful chemotherapy is the phenomena of multidrug resistance (MDR) in cancer cells. One of the main mechanisms of MDR is overexpression of the ATP-binding cassette (ABC) transporters in cancer cells which alters absorption, distribution, metabolism, and excretion of various chemotherapeutic drugs. Efforts have been made to find effective inhibitors of ABC transporters.

PBA2, a novel inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia.

Chronic Myeloid Leukemia (CML) is largely caused by the Philadelphia (Ph) chromosome carrying the Break point Cluster Region-Abelson (BCR-ABL) oncogene. Imatinib is a BCR-ABL-targeted therapy and considered the standard of care in CML management. Resistance to imatinib therapy often develops because of mutations in the BCR-ABL kinase domain.

A-803467, a tetrodotoxin-resistant sodium channel blocker, modulates ABCG2-mediated MDR in vitro and in vivo.

ATP-binding cassette subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which has been implicated in the development of multidrug resistance (MDR) in cancer, apart from its physiological role to remove toxic substances out of the cells. The diverse range of substrates of ABCG2 includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been reported to be significantly increased in some solid tumors and hematologic malignancies, correlated to poor clinical outcomes.

Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents.

Overexpression of ATP-Binding Cassette transporters leads to multidrug resistance in cancer cells and results in the failure of chemotherapy. In this in-vitro study, we investigated whether or not (20S, 24R/S)-epoxy-12β, 25-dihydroxy-dommarane-3β-amine (ORA and OSA), a pair of semi-synthetic ocotillol analogue epimers, could inhibit the ABCB1 transporter. ORA (1 μM and 3 μM) significantly reversed the resistance to paclitaxel and vincristine in ABCB1-overexpressing SW620/Ad300 and HEK/ABCB1 cells, whereas OSA had no significant effects.

ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10 (ABCC10) are not primary resistance factors for cabazitaxel.

Introduction: ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10 (ABCC10) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells. Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette (ABC) transporters.

Methods: We determined the effects of cabazitaxel, a novel tubulin-binding taxane, and paclitaxel on paclitaxel-resistant, ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant, ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.

The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade.

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.

The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study.

Paclitaxel exhibits clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance.

Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance.

The phenomenon of multidrug resistance (MDR) has attenuated the efficacy of anticancer drugs and the possibility of successful cancer chemotherapy. ATP-binding cassette (ABC) transporters play an essential role in mediating MDR in cancer cells by increasing efflux of drugs from cancer cells, hence reducing the intracellular accumulation of chemotherapeutic drugs. Interestingly, small-molecule tyrosine kinase inhibitors (TKIs), such as AST1306, lapatinib, linsitinib, masitinib, motesanib, nilotinib, telatinib and WHI-P154, have been found to have the capability to overcome anticancer drug resistance by inhibiting ABC transporters in recent years.

Tyrosine kinase inhibitors as reversal agents for ABC transporter mediated drug resistance.

Tyrosine kinases (TKs) play an important role in pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Aberrant activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to interfere with the activity of deregulated kinases.

In vitro, in vivo and ex vivo characterization of ibrutinib: a potent inhibitor of the efflux function of the transporter MRP1.

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.

Icotinib antagonizes ABCG2-mediated multidrug resistance, but not the pemetrexed resistance mediated by thymidylate synthase and ABCG2.

ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC). We conducted this study to investigate whether Icotinib, a small-molecule inhibitor of EGFR tyrosine kinase, could interact with ABCG2 transporter in NSCLC. Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug efflux function of ABCG2.

ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2.

ARRY-334543 is a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters. Lung cancer cell line NCI-H460 and its ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for the reversal study.

WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells.

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.

PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR.

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.

AST1306, a potent EGFR inhibitor, antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance.

AST1306, an inhibitor of EGFR and ErbB2, is currently in phase I of clinical trials. We evaluated the effect of AST306 on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters. We found that AST1306 significantly sensitized the ABC subfamily G member 2 (ABCG2)-overexpressing cells to ABCG2 substrate chemotherapeutics.

Linsitinib (OSI-906) antagonizes ATP-binding cassette subfamily G member 2 and subfamily C member 10-mediated drug resistance.

In this study we investigated the effect of linsitinib on the reversal of multidrug resistance (MDR) mediated by the overexpression of the ATP-binding cassette (ABC) subfamily members ABCB1, ABCG2, ABCC1 and ABCC10. Our results indicate for the first time that linsitinib significantly potentiate the effect of anti-neoplastic drugs mitoxantrone (MX) and SN-38 in ABCG2-overexpressing cells; paclitaxel, docetaxel and vinblastine in ABCC10-overexpressing cells. Linsitinib moderately enhanced the cytotoxicity of vincristine in cell lines overexpressing ABCB1, whereas it did not alter the cytotoxicity of substrates of ABCC1.

Masitinib antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance.

In this in vitro study, we determined whether masitinib could reverse multidrug resistance (MDR) in cells overexpressing the ATP binding cassette subfamily G member 2 (ABCG2) transporter. Masitinib (1.25 and 2.

Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo.

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.

Masitinib antagonizes ATP-binding cassette subfamily C member 10-mediated paclitaxel resistance: a preclinical study.

Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance.

Tivozanib reverses multidrug resistance mediated by ABCB1 (P-glycoprotein) and ABCG2 (BCRP).

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.