Dacomitinib potentiates the efficacy of conventional chemotherapeutic agents via inhibiting the drug efflux function of ABCG2 in vitro and in vivo

Guo, Xiaoran; To, Kenneth K.W.; Chen, Zhen; Wang, Xiaokun; Zhang, Jianye; Luo, Min; Wang, Fang; Yan, Shirong; Fu, Liwu

doi:10.1186/s13046-018-0690-x

Cited by 25 publications

(19 citation statements)

References 36 publications

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“…The brief mechanism of that phenomenons is mainly based on the following three aspects: First MRPs as ATP-binding protein, plays an excretory function and protection of tissues and cells, mediated efflux exogenous toxins, which acts as a carrier molecule is an energy-dependent efflux pump outward, chemotherapy drugs can discharge cells, the drug concentration inside the cell targets to reduce 31 . Secondly, MRPs antineoplastic protein may enable it away from the site of action in the redistribution of the cell, resulting in a total concentration of intracellular drug has not yet decreased, but the drug cannot be combined with the target site, causing indirect resistance 32 . Third, MRPs protein may also affect pH in tumor cells and cell membrane permeability, and other functions are leading to drug resistance 33 .…”

Section: Discussionmentioning

confidence: 99%

Metformin reverses the drug resistance of cisplatin in irradiated CNE-1 human nasopharyngeal carcinoma cells through PECAM-1 mediated MRPs down-regulation

Sun¹,

Chen²,

Zhou³

et al. 2020

Int. J. Med. Sci.

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Objective: To explore a way to reverse the drug resistance for irradiated CNE-1 human nasopharyngeal carcinoma cells and try to develop a new high efficacy with low toxicity therapeutic approach. Methods: 300 Gy irradiated the CNE-1 human nasopharyngeal carcinoma cells, and then treated with single-agent cisplatin or metformin, or combination of both drugs. MTT assay and FCM were applied to detect cell viability and apoptosis. Western blot and RT-PCR were used to characterize the protein and mRNA expression after various drug administrations. Results: The results presented single-agent metformin was capable of arresting the tumor growth and inducing apoptosis in irradiated CNE-1 cells and also demonstrated a synergy effect with cisplatin. Furthermore, metformin down-regulates the PECAM-1 expression, which could regulate Multi-drug Resistance-associate Proteins (MRPs) expression leading to cisplatin resistance of irradiated CNE-1 cells. A pan-MRP inhibitor, probenecid, can resecure cisplatin resistance leading by radiation. Conclusions: Metformin, due to its independent effects on PECAM-1, had a unique anti-proliferative effect on irradiated CNE-1 cells. It would be a new therapeutic option to conquer cisplatin resistance for advanced NPC patients after radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Metformin reverses the drug resistance of cisplatin in irradiated CNE-1 human nasopharyngeal carcinoma cells through PECAM-1 mediated MRPs down-regulation

Sun¹,

Chen²,

Zhou³

et al. 2020

Int. J. Med. Sci.

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“…MTT assay was used to assess the cytotoxicity of ERK5-IN-1 and chemotherapeutic agents, individually or in combination as described previously [36]. Bliss method was used to calculate the half maximal (50%) inhibitory concentration (IC 50 ) values.…”

Section: Cell Cytotoxicity Assaymentioning

confidence: 99%

Reversal of ABCB1-related multidrug resistance by ERK5-IN-1

Wang

Zheng

et al. 2020

J Exp Clin Cancer Res

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Background: Inhibition of ABC transporters is considered the most effective way to circumvent multidrug resistance (MDR). In the present study, we evaluated the MDR modulatory potential of ERK5-IN-1, a potent extracelluar signal regulated kinase 5 (ERK5) inhibitor. Methods: The cytotoxicity and MDR reversal effect of ERK5-IN-1 were assessed by MTT assay. The KBv200inoculated nude mice xenograft model was used for the in vivo study. Doxorubicin efflux and accumulation were measured by flow cytometry. The modulation of ABCB1 activity was measured by colorimetric ATPase assay and [ 125 I]-iodoarylazidoprazosin (IAAP) photolabeling assay. Effect of ERK5-IN-1 on expression of ABCB1 and its downstream markers was measured by PCR and/or Western blot. Cell surface expression and subcellular localization of ABCB1 were tested by flow cytometry and immunofluorescence. Results: Our results showed that ERK5-IN-1 significantly increased the sensitivity of vincristine, paclitaxel and doxorubicin in KBv200, MCF7/adr and HEK293/ABCB1 cells, respectively. This effect was not found in respective drug sensitive parental cell lines. Moreover, in vivo combination studies showed that ERK5-IN-1 effectively enhanced the antitumor activity of paclitaxel in KBv200 xenografts without causing addition toxicity. Mechanistically, ERK5-IN-1 increased intracellular accumulation of doxorubicin dose dependently by directly inhibiting the efflux function of ABCB1. ERK5-IN-1 stimulated the ABCB1 ATPase activity and inhibited the incorporation of [ 125 I]iodoarylazidoprazosin (IAAP) into ABCB1 in a concentration-dependent manner. In addition, ERK5-IN-1 treatment neither altered the expression level of ABCB1 nor blocked the phosphorylation of downstream Akt or Erk1/2. No significant reversal effect was observed on ABCG2-, ABCC1-, MRP7-and LRP-mediated drug resistance. Conclusions: Collectively, these results indicated that ERK5-IN-1 efficiently reversed ABCB1-mediated MDR by competitively inhibiting the ABCB1 drug efflux function. The use of ERK5-IN-1 to restore sensitivity to chemotherapy or to prevent resistance could be a potential treatment strategy for cancer patients.

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“…The effect of CM on ABCG2 activity was assessed by measuring intracellular doxorubicin(DOX) accumulation that is a conventional substrate chemotherapeutic agent of ABCG2 [24]. CNE2 and CNE2/DPP(5×10 5 per well) cells were seeded into six-well plates respectively and treated by 4uM doxorubicin with or without various concentrations of CM for 1h.…”

Section: Drug Accumulation Assaymentioning

confidence: 99%

“…Then, the cells were collected and washed twice with ice-cold PBS and nally resuspended in 100μL of ice-cold PBS for DOX-associated MFI measured by ow cytometry. Fumitremorgin C (FTC, a speci c inhibitor of ABCG2 that can block the pumping out of doxorubicin in overexpressing ABCG2 cells [24]) was used as the positive control.…”

Section: Drug Accumulation Assaymentioning

confidence: 99%

Cardamonin Enhances Cisplatin Chemosensitivity of Nasopharyngeal Cancer Cells via Attenuating c-Myc-Mediated β-Catenin/ABCG2 Signaling

Qiao¹,

Li²,

Wu³

et al. 2020

Preprint

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Purpose: Resistance to chemotherapeutic drugs in nasopharyngeal carcinoma(NPC) remains a major obstacle of clinical therapy. To address the issue, screening for natural low-toxicity products as chemosensitizers has become a promising strategy for cancer therapy. In this study, we investigated chemosensitizing effects of cardamonin (CM), a plant-derived chalcone, on cisplatin (DPP)-resistant NPC cells, and explored the molecular mechanism for its antitumor activity. Methods: The chemotherapeutic efficacy of cardamonin, cisplatin and their combination in cisplatin-resistant NPC cells were analyzed using MTT assay, apoptosis assay, and cell cycle analysis. Real-time PCR, western blotting, and cell transfection analysis were performed to assess the synergistic inhibitory action of cardamonin supplemented with cisplatin on Wnt/β-catenin/ABCG2 signaling. The effect of cardamonin on ABCG2 drug efflux function was analyzed by doxorubicin accumulation assay. A CNE2/DPP nude mouse model was used to determine the combinatorial effects of cardamonin on tumor growth in vivo. Results: Cardamonin increased cisplatin-induced cytotoxicity, accompanied by induction of apoptosis and cell cycle arrest in DPP-resistant NPC cells. Moreover, cardamonin could synergized with cisplatin to downregulate β-catenin, c-Myc, and ABCG2. Specifically, cardamonin inhibited Wnt/β-catenin/ABCG2 signaling through c-Myc-mediated transcription inactivation, thereby suppressing the expression of ABCG2 in cisplatin-resistant NPC cells. These findings were confirmed in vivo, wherein cardamonin treatment with cisplatin resulted in reduced tumor growth in a CNE2/DPP xenograft animal model. Conclusions: Taken together, our data firstly demonstrated that cardamonin increased chemosensitivity of nasopharyngeal cancer cells to cisplatin through inactivation of Wnt/β-catenin/ABCG2 signaling, more specifically by inhibition of β-catenin/ABCG2 signaling through c-Myc-mediated transcriptional inactivation, thereby downregulation of ABCG2 and reversal of cisplatin resistance. Thus, in addition to its chemotherapeutic potential, cardamonin may serve as a useful chemosensitizer to conventional chemotherapeutic drugs in the treatment of nasopharyngeal carcinoma.

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Dacomitinib potentiates the efficacy of conventional chemotherapeutic agents via inhibiting the drug efflux function of ABCG2 in vitro and in vivo

Cited by 25 publications

References 36 publications

Metformin reverses the drug resistance of cisplatin in irradiated CNE-1 human nasopharyngeal carcinoma cells through PECAM-1 mediated MRPs down-regulation

Metformin reverses the drug resistance of cisplatin in irradiated CNE-1 human nasopharyngeal carcinoma cells through PECAM-1 mediated MRPs down-regulation

Reversal of ABCB1-related multidrug resistance by ERK5-IN-1

Cardamonin Enhances Cisplatin Chemosensitivity of Nasopharyngeal Cancer Cells via Attenuating c-Myc-Mediated β-Catenin/ABCG2 Signaling

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