Reversal of ABCB1-related multidrug resistance by ERK5-IN-1
Abstract 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 a...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-03-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | http://link.springer.com/article/10.1186/s13046-020-1537-9 |
| _version_ | 1818334739882311680 |
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| author | Fang Wang Delan Li ZongHeng Zheng Kenneth Kin Wah To Zhen Chen Mengjun Zhong Xiaodong Su Likun Chen Liwu Fu |
| author_facet | Fang Wang Delan Li ZongHeng Zheng Kenneth Kin Wah To Zhen Chen Mengjun Zhong Xiaodong Su Likun Chen Liwu Fu |
| author_sort | Fang Wang |
| collection | DOAJ |
| description | Abstract 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 KBv200-inoculated 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 [125I]-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 [125I]-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. |
| first_indexed | 2024-12-13T14:12:20Z |
| format | Article |
| id | doaj.art-8fe0afdff1194bf4b229cd08a234a85d |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-13T14:12:20Z |
| publishDate | 2020-03-01 |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-8fe0afdff1194bf4b229cd08a234a85d2022-12-21T23:42:25ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662020-03-0139111310.1186/s13046-020-1537-9Reversal of ABCB1-related multidrug resistance by ERK5-IN-1Fang Wang0Delan Li1ZongHeng Zheng2Kenneth Kin Wah To3Zhen Chen4Mengjun Zhong5Xiaodong Su6Likun Chen7Liwu Fu8State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Gastrointestinal surgery, The Third Affiliated Hospital of Sun Yat-sen UniversitySchool of Pharmacy, the Chinese University of Hong KongState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterAbstract 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 KBv200-inoculated 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 [125I]-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 [125I]-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.http://link.springer.com/article/10.1186/s13046-020-1537-9ERK5-IN-1Multi-drug resistanceATP-binding cassette transporterABCB1 |
| spellingShingle | Fang Wang Delan Li ZongHeng Zheng Kenneth Kin Wah To Zhen Chen Mengjun Zhong Xiaodong Su Likun Chen Liwu Fu Reversal of ABCB1-related multidrug resistance by ERK5-IN-1 Journal of Experimental & Clinical Cancer Research ERK5-IN-1 Multi-drug resistance ATP-binding cassette transporter ABCB1 |
| title | Reversal of ABCB1-related multidrug resistance by ERK5-IN-1 |
| title_full | Reversal of ABCB1-related multidrug resistance by ERK5-IN-1 |
| title_fullStr | Reversal of ABCB1-related multidrug resistance by ERK5-IN-1 |
| title_full_unstemmed | Reversal of ABCB1-related multidrug resistance by ERK5-IN-1 |
| title_short | Reversal of ABCB1-related multidrug resistance by ERK5-IN-1 |
| title_sort | reversal of abcb1 related multidrug resistance by erk5 in 1 |
| topic | ERK5-IN-1 Multi-drug resistance ATP-binding cassette transporter ABCB1 |
| url | http://link.springer.com/article/10.1186/s13046-020-1537-9 |
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