Are ABCB1 (P-glycoprotein) polymorphisms clinically relevant in ovarian cancer? – Finally an Answer!

Konecny, Gottfried E.

doi:10.1016/j.ygyno.2013.09.001

Cited by 3 publications

(3 citation statements)

References 18 publications

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“…Paclitaxel and platinum combination chemotherapy has remained the global first-line chemotherapy regimen for patients with ovarian cancer for the past 20 years [ 38 ]. However, ∼80% of ovarian cancer cases are diagnosed at an advanced stage and these patients are intrinsically resistant to chemotherapy mainly due to ABCB1-mediated MDR [ 6 , 7 , 38 ]. Therefore, it is of vital medical significance to overcome or reverse ABCB1-mediated MDR in patients with ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

“…ABCB1-mediated MDR remains a major obstacle to successful chemotherapy in the clinic [ 1 – 5 ]. ABCB1 is highly expressed in human ovarian cancer and its overexpression is correlated inversely with a benign response to chemotherapy and good clinical prognosis [ 6 , 7 ]. For this reason, tremendous efforts have been made to discover or synthesize ABCB1 inhibitors to reverse ABCB1-mediated MDR in the past decades [ 8 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Afatinib reverses multidrug resistance in ovarian cancer via dually inhibiting ATP binding cassette subfamily B member 1

et al. 2015

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ABCB1-mediated multidrug resistance (MDR) remains a major obstacle to successful chemotherapy in ovarian cancer. Herein, afatinib at nontoxic concentrations significantly reversed ABCB1-mediated MDR in ovarian cancer cells in vitro (p < 0.05). Combining paclitaxel and afatinib caused tumor regressions and tumor necrosis in A2780T xenografts in vivo. More interestingly, unlike reversible TKIs, afatinib had a distinctive dual-mode action. Afatinib not only inhibited the efflux function of ABCB1, but also attenuated its expression transcriptionally via down-regulation of PI3K/AKT and MAPK/p38-dependent activation of NF-κB. Furthermore, apart from a substrate binding domain, afatinib could also bind to an ATP binding domain of ABCB1 through forming hydrogen bonds with Gly533, Gly534, Lys536 and Ala560 sites. Importantly, mutations in these four binding sites of ABCB1 and the tyrosine kinase domain of EGFR were not correlated with the reversal activity of afatinib on MDR. Given that afatinib is a clinically approved drug, our results suggest combining afatinib with chemotherapeutic drugs in ovarian cancer. This study can facilitate the rediscovery of superior MDR reversal agents from molecular targeted drugs to provide a more effective and safer way of resensitizing MDR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Afatinib reverses multidrug resistance in ovarian cancer via dually inhibiting ATP binding cassette subfamily B member 1

et al. 2015

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“…ABCA1 is also involved in coronary heart disease (CHD), type 2 diabetes (T2D), thrombosis, age-related macular degeneration (AMD), glaucoma, viral infections, and neurological disorders, such as traumatic brain injury, Alzheimer's disease, and Parkinson's disease [214]. ABCB1 is also overexpressed in ovarian cancer [215], causing multidrug resistance, which is a significant difficulty encountered during chemotherapy [247].…”

Section: Health Implications Of Impaired Functioning Of Arsenic and A...mentioning

confidence: 99%

Multilevel Regulation of Membrane Proteins in Response to Metal and Metalloid Stress: A Lesson from Yeast

Zbieralski,

Staszewski,

Konczak

et al. 2024

IJMS

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In the face of flourishing industrialization and global trade, heavy metal and metalloid contamination of the environment is a growing concern throughout the world. The widespread presence of highly toxic compounds of arsenic, antimony, and cadmium in nature poses a particular threat to human health. Prolonged exposure to these toxins has been associated with severe human diseases, including cancer, diabetes, and neurodegenerative disorders. These toxins are known to induce analogous cellular stresses, such as DNA damage, disturbance of redox homeostasis, and proteotoxicity. To overcome these threats and improve or devise treatment methods, it is crucial to understand the mechanisms of cellular detoxification in metal and metalloid stress. Membrane proteins are key cellular components involved in the uptake, vacuolar/lysosomal sequestration, and efflux of these compounds; thus, deciphering the multilevel regulation of these proteins is of the utmost importance. In this review, we summarize data on the mechanisms of arsenic, antimony, and cadmium detoxification in the context of membrane proteome. We used yeast Saccharomyces cerevisiae as a eukaryotic model to elucidate the complex mechanisms of the production, regulation, and degradation of selected membrane transporters under metal(loid)-induced stress conditions. Additionally, we present data on orthologues membrane proteins involved in metal(loid)-associated diseases in humans.

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ABCA1 Is Coordinated with ABCB1 in the Arsenic-Resistance of Human Cells

Tong

Niu

Yuan

et al. 2018

Appl Biochem Biotechnol

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Arsenic is one of the most widespread global environmental toxicants associated with endemic poisoning. ATP-binding cassette (ABC) proteins are transmembrane channels that transport and dispose of lipids and metabolic products across the plasma membrane. The majority of ABC family members (including ABCB1 and ABCC1) are reported to play a role in the development of arsenic and drug resistance in mammals. Previously, we established a human arsenic-resistant ECV-304 (AsRE) cell line and identified ABCA1 as a novel arsenic resistance gene. In the current study, we further investigated the potential contribution of ABCA1, ABCB1, and ABCC1 to arsenic resistance through measurement of survival rates and arsenic accumulation in AsRE cells with RNA interference. The arsenic resistance capacity of ABCC1 was the strongest among the three genes, while those of ABCA1 and ABCB1 were similar. Double or triple gene knockdown of ABCA1, ABCB1, and ABCC1 via RNA interference led to a decrease significant in arsenic resistance when ABCA1/ABCB1 or ABCB1/ABCC1 were simultaneously silenced. Interestingly, no differences were evident between cells with ABCA1/ABCC1 and ABCC1 only knockdown. Our findings suggest that ABCA1 and ABCB1 proteins display similar arsenic resistance capabilities and possibly coordinate to promote arsenic resistance in AsRE cells.

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Are ABCB1 (P-glycoprotein) polymorphisms clinically relevant in ovarian cancer? – Finally an Answer!

Cited by 3 publications

References 18 publications

Afatinib reverses multidrug resistance in ovarian cancer via dually inhibiting ATP binding cassette subfamily B member 1

Afatinib reverses multidrug resistance in ovarian cancer via dually inhibiting ATP binding cassette subfamily B member 1

Multilevel Regulation of Membrane Proteins in Response to Metal and Metalloid Stress: A Lesson from Yeast

ABCA1 Is Coordinated with ABCB1 in the Arsenic-Resistance of Human Cells

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