Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer

Chen, Haiyang; Shien, Kazuhiko; Suzawa, Ken; Tsukuda, Kazunori; Tomida, Shuta; Sato, Hiroki; Torigoe, Hidejiro; Watanabe, Masahide; Namba, Kei; Yamamoto, Hiromasa; Soh, Junichi; Asano, Hiroaki; Miyoshi, Shinichiro; Toyooka, Shinichi

doi:10.3892/ol.2017.6678

Cited by 20 publications

(13 citation statements)

References 47 publications

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“…We found that elacridar recovered the sensitivity to docetaxel, but not to afatinib in H2170‐ARS and H2170‐ARH cells. These findings were similar to those in our previous report using docetaxel‐resistant NSCLC cells with EGFR‐ mutations . In contrast, the other afatinib‐resistant cell lines, including Calu3‐ARH, H1781‐ARS and H1781‐ARH, which showed EMT or had acquired CSC‐like features, showed maintained sensitivity to docetaxel, because ABCB1 was not upregulated in these acquired resistance cell lines.…”

Section: Resultssupporting

confidence: 90%

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Therapeutic strategies for afatinib‐resistant lung cancer harboring HER2 alterations

et al. 2018

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Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non‐small‐cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan‐HER inhibitor afatinib could be a useful therapeutic agent as HER2‐targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib‐resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib‐resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial‐to‐mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)‐like features. The afatinib‐resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC‐like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.

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Section: Resultssupporting

confidence: 90%

“…These findings were similar to those in our previous report using docetaxel-resistant NSCLC cells with EGFR-mutations. 32 In contrast, the other afatinib-resistant cell lines, including…”

Section: Sensitivity Of the Afatinib-resistant Cells To Chemotherapmentioning

confidence: 99%

Therapeutic strategies for afatinib‐resistant lung cancer harboring HER2 alterations

et al. 2018

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“…YHO-13351 is a potent inhibitor of ABCG2, and its combination with irinotecan effectively targets CSC from cervical carcinoma preventing resistance and tumor relapse [88]. Elacridar is a third-generation competitive inhibitor of ABCB1 that reverses multidrug resistance of lung cancer, sensitizing cancer stem cells to docetaxel [89]. In breast cancer, ABCC1 and ABCC3 transporters are implicated in multidrug resistance and are increased after chemotherapy.…”

Section: Strategies To Target Cancer Stem Cellsmentioning

confidence: 99%

Cancer Stem Cells: Powerful Targets to Improve Current Anticancer Therapeutics

Bighetti‐Trevisan

Sousa

Castilho

et al. 2019

Stem Cells International

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A frequent observation in several malignancies is the development of resistance to therapy that results in frequent tumor relapse and metastasis. Much of the tumor resistance phenotype comes from its heterogeneity that halts the ability of therapeutic agents to eliminate all cancer cells effectively. Tumor heterogeneity is, in part, controlled by cancer stem cells (CSC). CSC may be considered the reservoir of cancer cells as they exhibit properties of self-renewal and plasticity and the capability of reestablishing a heterogeneous tumor cell population. The endowed resistance mechanisms of CSC are mainly attributed to several factors including cellular quiescence, accumulation of ABC transporters, disruption of apoptosis, epigenetic reprogramming, and metabolism. There is a current need to develop new therapeutic drugs capable of targeting CSC to overcome tumor resistance. Emerging in vitro and in vivo studies strongly support the potential benefits of combination therapies capable of targeting cancer stem cell-targeting agents. Clinical trials are still underway to address the pharmacokinetics, safety, and efficacy of combination treatment. This review will address the main characteristics, therapeutic implications, and perspectives of targeting CSC to improve current anticancer therapeutics.

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“…Thus, the detection of FABP4 is helpful for predicting the prognosis of patients with NSCLC [70]. ABCB1 reportedly plays an important role in overcoming ABCB1mediated docetaxel resistance in lung cancer [71].…”

Section: Discussionmentioning

confidence: 99%

A bioinformatics investigation into the pharmacological mechanisms of javanica oil emulsion injection in non-small cell lung cancer based on network pharmacology methodologies

Liu

Meng

et al. 2020

BMC Complement Med Ther

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Background: Javanica oil emulsion injection (JOEI) is an effective therapeutic option for patients with non-small cell lung cancer (NSCLC), but its mechanisms have not been fully elucidated. Methods: In this study, we utilized network pharmacology to systematically investigate the bioactive components and targets of JOEI, identify common targets in NSCLC, and understand and evaluate the underlying mechanism of JOEI in the treatment of NSCLC through expression level, correlation, enrichment, Cox, survival and molecular docking analyses. The results indicated that five compounds of JOEI interact with five pivotal targets (LDLR, FABP4, ABCB1, PTGS2, and SDC4) that might be strongly correlated with the JOEI-mediated treatment of NSCLC. Results: The expression level analysis demonstrated that NSCLC tissues exhibit low expression of FABP4, ABCB1, LDLR and PTGS2 and high SDC4 expression. According to the correlation analysis, a decrease in FABP4 expression was strongly correlated with decreases in LDLR and ABCB1, and a decrease in LDLR was strongly correlated with decreased PTGS2 and increased in SDC4 expression. Cox and survival analyses showed that the survival rate of the high-risk group was significantly lower than that of the low-risk group (p = 0.00388). In the survival analysis, the area under the curve (AUC) showed that the pivotal gene model exhibited the best predictive capacity over 4 years (AUC = 0.613). Moreover, the molecular docking analysis indicated that LDLR, FABP4, ABCB1, PTGS2 and SDC4 exhibit good binding activity with the corresponding compounds. Conclusion: In conclusion, this study predicted and verified that the mechanism of JOEI against NSCLC involves multiple targets and signaling pathways. Furthermore, this study provides candidate targets for the treatment of NSCLC, lays a good foundation for further experimental research and promotes the reasonable application of JOEI in clinical treatment.

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Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer

Cited by 20 publications

References 47 publications

Therapeutic strategies for afatinib‐resistant lung cancer harboring HER2 alterations

Therapeutic strategies for afatinib‐resistant lung cancer harboring HER2 alterations

Cancer Stem Cells: Powerful Targets to Improve Current Anticancer Therapeutics

A bioinformatics investigation into the pharmacological mechanisms of javanica oil emulsion injection in non-small cell lung cancer based on network pharmacology methodologies

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