Osimertinib (AZD9291) Attenuates the Function of Multidrug Resistance-Linked ATP-Binding Cassette Transporter ABCB1 in Vitro

Hsiao, Sung Han; Yu, Lijie; Huang, Yang; Hsieh, Chi-Hsun; Wu, Chung Pu

doi:10.1021/acs.molpharmaceut.6b00249

Cited by 46 publications

(59 citation statements)

References 55 publications

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“…Lastly, investigation of cell death revealed that voruciclib, at non-toxic concentration of 5 µM, potentiated paclitaxel or mitoxantrone-mediated apoptosis in drug resistant SW620/AD300 or NCI-H460/MX20 cells. Our findings were similar to Hsiao et al that osimertinib, at non-toxic concentration, induces colchicine-mediated apoptosis in drug resistant KB-V-1 cells [44], suggesting the apoptotic effect of voruciclib in combination with substrate chemotherapeutic drugs.…”

Section: Discussionsupporting

confidence: 91%

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Gupta

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. Methods: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter. The effects on expression and intracellular localization of ABCB1 and ABCG2 proteins were determined by Western blotting and immunofluorescence, respectively. Vanadate-sensitive ATPase assay was done to determine the effect of voruciclib on the ATPase activity of ABCB1 and ABCG2. Flow cytometric analysis was done to determine the effect of voruciclib on apoptosis of ABCB1 and ABCG2-overexpressing cells and docking analysis was done to determine the interaction of voruciclib with ABCB1 and ACBG2 protein. Results: Voruciclib significantly potentiated the effect of paclitaxel and doxorubicin in ABCB1-overexpressing cells, as well as mitoxantrone and SN-38 in ABCG2-overexpressing cells. Voruciclib moderately sensitized ABCC10- overexpressing cells to paclitaxel, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, voruciclib increased the intracellular accumulation and decreased the efflux of substrate anti-cancer drugs from ABCB1- or ABCG2-overexpressing cells. However, voruciclib did not alter the expression or the sub-cellular localization of ABCB1 or ABCG2. Voruciclib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Lastly, voruciclib exhibited a drug-induced apoptotic effect in ABCB1- or ABCG2- overexpressing cells. Conclusion: Voruciclib is currently a phase I clinical trial drug. Our findings strongly support its potential use in combination with conventional anti-cancer drugs for cancer chemotherapy.

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Section: Discussionsupporting

confidence: 91%

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Gupta

Zhang

et al. 2018

Cell Physiol Biochem

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“…The percentage of apoptotic cells induced by the indicated regimens was determined using the annexin V–FITC and propidium iodide (PI) staining method, as described previously [25]. Cells were treated with tyrphostin RG14620, topotecan or a combination of topotecan and tyrphostin RG14620 as indicated for 48 h. Cells were harvested, centrifuged and resuspended in FACS buffer containing 1.25 μg/mL annexin V–FITC (PharMingen) and 0.1 mg/mL PI and incubated for 15 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…(A) Drug-sensitive human colon S1 cancer cells (top panels) and ABCG2-overexpressing drug-resistant variant S1-M1-80 cancer cells (lower panels) were treated with either DMSO ( control ), 5 μM tyrphostin RG14620 (+ RG14620 ), 5 μM topotecan (+ topotecan ) or a combination of 5 μM topotecan and 5 μM of tyrphostin RG14620 ( topotecan + RG14620 ) for 48 h. Cells were isolated and analyzed by flow cytometry as described previously [25]. Representative dot plots and the mean values of three independent experiments are shown.…”

Section: Figmentioning

confidence: 99%

Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines

Hsiao

Murakami

et al. 2017

Cancer Letters

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The multidrug resistance (MDR) phenotype associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1, ABCC1 and ABCG2 is a major obstacle in cancer chemotherapy. Numerous epidermal growth factor receptor (EGFR) inhibitors have previously been shown capable of reversing MDR in ABCG2-overexpressing cancer cells. However, most of them are not transporter-specific due to the substantial overlapping substrate specificity among the transporters. In this study, we investigated the interaction between ABCG2 and tyrphostin RG14620, an EGFR inhibitor of the tyrphostin family, in multidrug-resistant cancer cell lines. We found that at nontoxic concentrations, tyrphostin RG14620 enhances drug-induced apoptosis and restores chemosensitivity to ABCG2-overexpressing multidrug-resistant cancer cells. More importantly, tyrphostin RG14620 is selective to ABCG2 relative to ABCB1 and ABCC1. Our findings were further supported by biochemical assays demonstrating that tyrphostin RG14620 stimulates ATP hydrolysis and inhibits photoaffinity labeling of ABCG2 with IAAP, and by a docking analysis of tyrphostin RG14620 in the drug-binding pocket of this transporter. Taken together, our findings indicate that tyrphostin RG14620 is a potent and selective modulator of ABCG2 that may be useful to overcome chemoresistance in patients with drug-resistant tumors.

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“…Preclinical results demonstrated that the combination of chemotherapy and EGFR TKIs might have a synergistic effect on NSCLC cell growth in vitro . Several reports manifested that EGFR TKIs such as erlotinib, and more recently osimertinib can have an important function as an ATP‐binding cassette transporter inhibitors . Examining the expression of ABCB1 (P‐glycoprotein) and ABCG2 (breast cancer resistant protein, BCRP) could serve to predict the synergism of EGFR TKIs with chemotherapeutic agents by reversing multidrug resistance (MDR) .…”

Section: Introductionmentioning

confidence: 99%

“…13,14 Several reports manifested that EGFR TKIs such as erlotinib, and more recently osimertinib can have an important function as an ATP-binding cassette transporter inhibitors. 15 Examining the expression of ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistant protein, BCRP) could serve to predict the synergism of EGFR TKIs with chemotherapeutic agents by reversing multidrug resistance (MDR). [16][17][18][19] Therefore, there is convincing evidence that EGFR TKIs can inhibit the MDR efflux of several chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial

et al. 2017

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To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head-to-head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first-line therapy, in terms of efficacy and safety. A total of 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin or gefitinib alone. The progression-free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3-19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2-6.3) or gefitinib (11.9 months, 95% CI, 9.1-14.6) group. The (hazard ratios) HRs of PFS for the combination group vs. chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09-0.29, p < 0.001) and 0.48 (95% CI, 0.29-0.78, p = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group and the gefitinib group was 82.5%, 32.5% and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, p = 0.016) or gefitinib (HR = 0.36, p = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations.

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Osimertinib (AZD9291) Attenuates the Function of Multidrug Resistance-Linked ATP-Binding Cassette Transporter ABCB1 in Vitro

Cited by 46 publications

References 55 publications

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines

Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial

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