Bafetinib (INNO-406) reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters

Zhang, Yun-Kai; Zhang, Guan‐Nan; Wang, Yijun; Patel, Bhargav A.; Talele, Tanaji T.; Yang, Dong‐Hua; Chen, Zhe‐Sheng

doi:10.1038/srep25694

Cited by 52 publications

(46 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Propidium iodide (PI) and Annexin-V were purchased from BD biosciences (San Jose, CA). The chemicals for the ATPase assay were similar to those used in our previous study [19]. Fumitremorgin C (FTC) was a gift from Dr. Susan Bates (Columbia University, NY).…”

Section: Methodsmentioning

confidence: 99%

“…The modified MTT colorimetric assay was used to detect the sensitivity of cells to anticancer drugs in vitro as previously described [19, 22]. The cells were trypsinized and resuspended in a final concentration of 4 × 10 3 cells/well.…”

Section: Methodsmentioning

confidence: 99%

“…Human homology ABCB1 model based on refined mouse ABCB1 (PDB ID: 4M1M) was provided by S. Aller and the docking grid was refined within the transmembrane region as previously described [19, 30]. Our previous grid on human homology ABCG2 on centroid of Arg482 was used for docking on ABCG2 [31].…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, GO-Y030 and GO-Y078 may have a joint role as a dual inhibitor of both ABCB1 and ABCG2. Recently, dual inhibitors were developed by screening based on the ABCB1 and ABCG2 docking model (Zhang et al, 2016) and the substrate common to both ABCB1 and ABCG2 (Bohn et al, 2017). It is also feasible that GO-Y030 and GO-Y078 could be used as dual inhibitors for both ABCB1-and ABCG2-expressing cancer cells.…”

Section: Synthetic Curcumin Analogs Modulate the Function Of Abcg2mentioning

confidence: 99%

Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance–Linked ATP-Binding Cassette Transporter ABCG2

Murakami

Ohnuma

Fukuda

et al. 2017

Drug Metabolism and Disposition

View full text Add to dashboard Cite

Multidrug resistance (MDR) caused by the overexpression of ATPbinding cassette (ABC) transporters in cancer cells is a major obstacle in cancer chemotherapy. Previous studies have shown that curcumin, a natural product and a dietary constituent of turmeric, inhibits the function of MDR-related ABC transporters, including ABCB1, ABCC1, and especially ABCG2. However, the limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinical setting. In this study, we investigated the effects of 24 synthetic curcumin analogs with increased bioavailability on the transport function of ABCG2. The screening of the 24 synthetic analogs by means of flow cytometry revealed that four of the curcumin analogs (GO-Y030, GO-Y078, GO-Y168, and GO-Y172) significantly inhibited the efflux of the ABCG2 substrates, mitoxantrone and pheophorbide A, from ABCG2-overexpressing K562/breast cancer resistance protein (BCRP) cells. Biochemical analyses showed that GO-Y030, GO-Y078, and GO-Y172 stimulated the ATPase activity of ABCG2 at nanomolar concentrations and inhibited the photolabeling of ABCG2 with iodoarylazidoprazosin, suggesting that these analogs interact with the substrate-binding sites of ABCG2. In addition, when used in cytotoxicity assays, GO-Y030 and GO-Y078 were found to improve the sensitivity of the anticancer drug, SN-38, in K562/BCRP cells. Taken together, these results suggest that nontoxic synthetic curcumin analogs with increased bioavailability, especially GO-Y030 and GO-Y078, inhibit the function of ABCG2 by directly interacting at the substrate-binding site. These synthetic curcumin analogs could therefore be developed as potent modulators to overcome ABCG2-mediated MDR in cancer cells.

show abstract

“…It has been designed according to a chemical structure of imatinib for chronic myelogenous leukemia treatment (9). It has a dual action on BCR/Abl and Lyn kinases and has shown an effective role on hematopoietic and multidrug resistance cells (10). No previous data has shown its role in endometrial cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

Bafetinib inhibits ishikawa cells growth through modulating p16 expression

Althubiti

2017

IJBAS

View full text Add to dashboard Cite

Bafetinib is a tyrosine kinase inhibitor of Lyn-BCR/ABL that has been used experimentally for leukemia therapy. From our previous experimental work with bafetinib, it showed an anti-proliferative effect on Ishikawa cell line at concentration of 200nM. This observation was supported by colonogenic assay, the number of colonies formed by Ishikawa cells was 6 folds in the control comparing to bafetinib treated cells. Cells counting also support this finding, Ishikawa treated cells were unable to continue growing after 2 days of the drug addition comparing to the control cells that continued dividing. This underscores the role of bafetinib as anti-neoplastic agent on Ishikawa cells. To understand its mechanism of action, cyclin-dependent kinase inhibitors p16INK4a and p21 WAF1 that have major role in cell cycle arrest were measured. No difference was noticed in p21 levels between the treated and control cells; however, increasing in p16 expression was observed in treated Ishikawa cells. This underlines the role of bafetinib in inhibiting Ishikawa cells through modulating p16 expression. This suggests that bafetinib could be used as a therapy in case of endometrial cancer. But, further work should be conducted to examine the effect of bafetinib on other endometrial cancer cells and on mice before testing its effect on endometrial cancer patients.

show abstract

Bafetinib (INNO-406) reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters

Cited by 52 publications

References 40 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

Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance–Linked ATP-Binding Cassette Transporter ABCG2

Bafetinib inhibits ishikawa cells growth through modulating p16 expression

Contact Info

Product

Resources

About