Poziotinib Inhibits the Efflux Activity of the ABCB1 and ABCG2 Transporters and the Expression of the ABCG2 Transporter Protein in Multidrug Resistant Colon Cancer Cells

Wu, Zhuo‐Xun; Yang, Yuqi; Wang, Jingquan; Li, Jun; Sun, Zoey; Teng, Quincy; Ashby, Charles R.; Yang, Dong‐Hua

doi:10.3390/cancers12113249

Cited by 20 publications

(17 citation statements)

References 79 publications

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“…The reduction in paclitaxel-induced ATPase activity in vitro when lapatinib or poziotinib are present demonstrates physical interference with ABCB1 function. Our results are in agreement with others that have proposed a mechanism whereby TKIs, including lapatinib and poziotinib, physically bind to and inhibit ABCB1 rendering the transporter non-functional [ 27 , 33 ].…”

Section: Discussionsupporting

confidence: 93%

“…Others have previously reported synergistic antitumor activity using paclitaxel and lapatinib in combination for esophageal and ovarian cancer [ 31 , 32 ]. To our knowledge, this is the first report of anticancer synergy using poziotinib in combination with paclitaxel in ovarian cancer, although poziotinib-mediated inhibition of ABCB1 activity was recently reported in colon cancer cells [ 33 ]. Both poziotinib and lapatinib are TKIs that primarily target ErbB protein tyrosine kinases EGFR, ERBB2, and ERBB4 [ 34 – 36 ].…”

Section: Introductionmentioning

confidence: 99%

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Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer

et al. 2021

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Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We established in vitro paclitaxel-resistant ovarian cancer cell line and organoid models. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing. We manipulated candidate genes associated with paclitaxel resistance using siRNA or small molecule inhibitors, and then screened the cells for paclitaxel sensitivity using cell viability assays. We used the Bliss independence model to evaluate the anti-proliferative synergy for drug combinations. ABCB1 expression was upregulated in paclitaxel-resistant TOV-21G (q < 1x10-300), OVCAR3 (q = 7.4x10-156) and novel ovarian tumor organoid (p = 2.4x10-4) models. Previous reports have shown some tyrosine kinase inhibitors can inhibit ABCB1 function. We tested a panel of tyrosine kinase inhibitors for the ability to sensitize resistant ABCB1-overexpressing ovarian cancer cell lines to paclitaxel. We observed synergy when we combined poziotinib or lapatinib with paclitaxel in resistant TOV-21G and OVCAR3 cells. Silencing ABCB1 expression in paclitaxel-resistant TOV-21G and OVCAR3 cells reduced paclitaxel IC50 by 20.7 and 6.2-fold, respectively. Furthermore, we demonstrated direct inhibition of paclitaxel-induced ABCB1 transporter activity by both lapatinib and poziotinib. In conclusion, lapatinib and poziotinib combined with paclitaxel synergizes to inhibit the proliferation of ABCB1-overexpressing ovarian cancer cells in vitro. The addition of FDA-approved lapatinib to second-line paclitaxel therapy is a promising strategy for patients with recurrent ovarian cancer.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer

et al. 2021

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“…The varying expression levels of ABC transporter genes are responsible for drug resistance in many chronic diseases and cancer [19]. Up-regulation of many kind of ABC transporters, including ABCB1 and ABCG2 leads to diminished cellular drug efflux [20]. Compatible with this fact, in this current study, we found significantly changed expression levels of ABC genes in the CP group.…”

Section: Discussionsupporting

confidence: 61%

Melatonin has favorable preventive effects on experimental chronic pancreatitis rat model

Tanoğlu¹,

Tanoğlu²,

Meriçöz³

et al. 2021

Turk J Med Sci

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Background/Aim:Currently, there is not any specific treatment for chronic pancreatitis (CP). It was aimed to investigate the effects of melatonin administration on endoplasmic reticulum (ER) stress, oxidative stress, fibrosis, biochemical and histopathological parameters and Abcc2,Abcc5 and Abcg2 gene levels in an experimental rat CP model. Methods: Forty rats were randomized into five groups: Sham, CP, CP+25 mg/kg melatonin, CP+50 mg/kg melatonin, and CP+placebo. In all rats except the sham group, a model of chronic pancreatitis was accomplished with intraperitoneal caerulein administration. In treatment groups, melatonin was used as a therapeutic agent. Serum TGF-β, TNF-α, MDA and GPx levels were studied. Pancreatic tissues were evaluated histopathologically. The expression levels of αSma,IR1α,Perk,Abcc2,Abcc5 and Abcg2 genes were measured with the qRT-PCR.Results: Biochemical results of the melatonin groups exhibited favorable changes compared to the CP and placebo groups. αSma,IR1α,Perk expression levels were significantly lower in the melatonin groups. The expression levels of Abcc2, Abcc5 and Abcg2 were significantly higher in the CP group compared to the sham group and these gene levels were significantly lower in the melatonin groups compared to the CP group (p<0.01, p<0.05, p<0.05, respectively). Conclusion:In light of these favorable positive results, melatonin may be a useful preventive agent in the course of CP.

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“…Till now, tremendous efforts have been made to explore the mechanism of MDR, mostly by establishing ABC transporter-overexpressing cancer cell lines (9,29). By comparing parental and resistant cancer cell lines using molecular biology and cellular methods, researchers have identified numerous ABC transporter substrates (21,(30)(31)(32)(33)(34) as well as inhibitors (16,(35)(36)(37)(38)(39)(40). Computational strategies were also developed to boost the modulator discovery process especially multitarget modulators (41,42).…”

Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

Wang

Yang

et al. 2021

Front. Oncol.

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Ovarian cancer is one of the leading female malignancies which accounts for the highest mortality rate among gynecologic cancers. Surgical cytoreduction followed by chemotherapy is the mainstay of treatment. However, patients with recurrent ovarian cancer are likely to exhibit resistance to chemotherapy due to reduced sensitivity to chemotherapeutic drugs. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been extensively studied as multidrug resistance (MDR) mediators since they are responsible for the efflux of various anticancer drugs. Multidrug resistance protein 7 (MRP7, or ABCC10) was discovered in 2001 and revealed to transport chemotherapeutic drugs. Till now, only limited knowledge was obtained regarding its roles in ovarian cancer. In this study, we established an MRP7-overexpressing ovarian cancer cell line SKOV3/MRP7 via transfecting recombinant MRP7 plasmids. The SKOV3/MRP7 cell line was resistant to multiple anticancer drugs including paclitaxel, docetaxel, vincristine and vinorelbine with a maximum of 8-fold resistance. Biological function of MRP7 protein was further determined by efflux-accumulation assays. Additionally, MTT results showed that the drug resistance of the SKOV3/MRP7 cells was reversed by cepharanthine, a known inhibitor of MRP7. Moreover, we also found that the overexpression of MRP7 enhanced the migration and epithelial-mesenchymal transition (EMT) induction. In conclusion, we established an in vitro model of MDR in ovarian cancer and suggested MRP7 overexpression as the leading mechanism of chemoresistance in this cell line. Our results demonstrated the potential relationship between MRP7 and ovarian cancer MDR.

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Poziotinib Inhibits the Efflux Activity of the ABCB1 and ABCG2 Transporters and the Expression of the ABCG2 Transporter Protein in Multidrug Resistant Colon Cancer Cells

Cited by 20 publications

References 79 publications

Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer

Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer

Melatonin has favorable preventive effects on experimental chronic pancreatitis rat model

Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

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