Lapatinib Antagonizes Multidrug Resistance-Associated Protein 1-Mediated Multidrug Resistance by Inhibiting Its Transport Function

Lin, Shao; Hu, Ya Peng; Wang, Fang; Huang, Zhen; Chen, Yi Fan; Wang, Xiao Kun; Li, Fu

doi:10.2119/molmed.2014.00059

Cited by 38 publications

(32 citation statements)

References 55 publications

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“…Furthermore, the authors showed that administration of 5 μM of ibrutinib did not alter MRP1 expression. Finally, combination experiments in nude mice xenografts with vincristine showed a synergistic effect on tumor growth, as this was already found for lapatinib …”

Section: Pharmacological and Experimental Drugs And Synthetic Analogssupporting

confidence: 69%

“…With respect to MRP1 inhibition, Ma et al. found similar results . Using the doxorubicin‐selected human epidermoid carcinoma cell line C‐A120, lapatinib (Figure ) reversed doxorubicin and vincristine resistance partially at 2.5 μM, in comparable magnitude to the used standard inhibitor MK571.…”

Section: Pharmacological and Experimental Drugs And Synthetic Analogsmentioning

confidence: 73%

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Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

Stefan

Wiese

2018

Medicinal Research Reviews

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Multidrug resistance-associated protein 1 (MRP1, ABCC1) is an ATP-binding cassette (ABC) transport protein. This efflux pump uses the energy of ATP hydrolysis to export structurally diverse antineoplastic agents in human cancers. The upregulation of MRP1 (either inherent or acquired) is one major reason for the occurrence of the phenomenon called multidrug resistance (MDR). MDR is characterized by a reduced outcome of chemotherapy due to the active intracellular clearance of cytostatic drugs below the necessary effect concentration. Much effort has been made to overcome MDR, which implied high-throughput screenings of already known pharmacological and natural compounds, modification of intrinsic substrates, as well as design and synthesis of new inhibitors. This review is meant not only to summarize the most recent results over the past 10 years, but also to highlight major achievements regarding reversal of MRP1-mediated MDR, from the time of its discovery until today. The focus lies on small-molecule compounds that feature either direct MRP1 inhibition/transport blockage, toxicity against MRP1-overexpressing cells, inhibition/modification of intracellular processes necessary for MRP1 function, or modification of MRP1-related metabolic and genomic mechanisms. Considering all aspects, this review might be useful to (re)consider possible strategies to overcome MRP1-mediated MDR. Furthermore, it may be the basis for developing new, even better, highly potent, less toxic, and selective (as well as broad-spectrum) MRP1 inhibitors that will enter clinical evaluations in different malignancies and finally conduce to overcome MDR in general.

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Section: Pharmacological and Experimental Drugs And Synthetic Analogssupporting

confidence: 69%

Section: Pharmacological and Experimental Drugs And Synthetic Analogsmentioning

confidence: 73%

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

Stefan

Wiese

2018

Medicinal Research Reviews

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“…Previous studies have reported that several TKIs, including lapatinib, erlotinib, apatinib and afatinib, were able to modulate the MDR phenotype mediated by ABC transporters and encouraged evaluations of the potential of these TKIs to circumvent the anticancer drug resistance in clinical trials. 18, 19, 20, 21, 22, 23 …”

Section: Introductionmentioning

confidence: 99%

Alectinib (CH5424802) antagonizes ABCB1- and ABCG2-mediated multidrug resistance in vitro, in vivo and ex vivo

Yang

Chen

et al. 2017

Exp Mol Med

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Alectinib, an inhibitor of anaplastic lymphoma kinase (ALK), was approved by the Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). Here we investigated the reversal effect of alectinib on multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters, which is the primary cause of chemotherapy failure. We provide the first evidence that alectinib increases the sensitivity of ABCB1- and ABCG2-overexpressing cells to chemotherapeutic agents in vitro and in vivo. Mechanistically, alectinib increased the intracellular accumulation of ABCB1/ABCG2 substrates such as doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, alectinib stimulated ATPase activity and competed with substrates of ABCB1 or ABCG2 and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling bound to ABCB1 or ABCG2 but neither altered the expression and localization of ABCB1 or ABCG2 nor the phosphorylation levels of AKT and ERK. Alectinib also enhanced the cytotoxicity of DOX and the intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. These findings suggest that alectinib combined with traditional chemotherapy may be beneficial to patients with ABCB1- or ABCG2-mediated MDR.

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“…Lapatinib, which is primarily a tyrosine kinase inhibitor with some effect on inhibiting ABCG2-mediated efflux, has been well-studied with its potential to reverse MDR. (16,32,46) Lapatinib is currently the only compound affecting ABCG2 activity that has been examined in phase II clinical trial for recurrent ovarian cancer. (16) However, the trial was canceled due to substantial adverse hematologic events and no observed benefit.…”

Section: Discussionmentioning

confidence: 99%

Novel ABCG2 Antagonists Reverse Topotecan-Mediated Chemotherapeutic Resistance in Ovarian Carcinoma Xenografts

Ricci

Lovato

Severns

et al. 2016

Molecular Cancer Therapeutics

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Chemotherapeutic resistance remains a challenge in the treatment of ovarian carcinoma, especially in recurrent disease. Despite the fact that most patients with newly diagnosed tumors attain complete remission following cytoreductive surgery and chemotherapy, ovarian carcinoma has a recurrence rate that exceeds 75%. The ATP Binding Cassette family G member 2 (ABCG2) efflux protein has been described as one mechanism that confers multiple drug resistance (MDR) to solid tumors and contributes to topotecan (TPT) resistance in ovarian carcinoma. In fact, one clinical trial demonstrated ABCG2 expression in all patients with primary or recurrent ovarian carcinoma. On the basis of our previous work, we hypothesized that three compounds (CID44640177, CID1434724, and CID46245505), which represent a new piperazine-substituted pyrazolo[1,5]pyrimidine substructure class of ABCG2-specific antagonists, would restore chemosensitivity to drug-resistant ovarian cancer in vitro and in vivo. In order to address the treatment difficulties associated with chemotherapeutic resistance in ovarian cancer, we combined each compound (CID44640177, CID1434724, and CID46245505) with TPT and administered the mixture to chemoresistant Igrov1/T8 ovarian cancer cells in vitro and Igrov1/T8 xenografts in CB-17 SCID mice. We found that only nanomolar concentrations of each ABCG2-inhibitor in combination with TPT were required to restore chemosensitivity to Igrov1/T8 cells in vitro. In vivo, substantial tumor reduction was achieved with each compound in 4 days, with CID1434724 causing the largest reduction in excess of 60%. No signs of secondary toxic effects were observed with the ABCG2 antagonists. These novel compounds should be viewed as promising drug candidates to reverse ABCG2-mediated chemoresistance.

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Lapatinib Antagonizes Multidrug Resistance-Associated Protein 1-Mediated Multidrug Resistance by Inhibiting Its Transport Function

Cited by 38 publications

References 55 publications

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

Alectinib (CH5424802) antagonizes ABCB1- and ABCG2-mediated multidrug resistance in vitro, in vivo and ex vivo

Novel ABCG2 Antagonists Reverse Topotecan-Mediated Chemotherapeutic Resistance in Ovarian Carcinoma Xenografts

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