The ABCB1 3435C > T polymorphism influences docetaxel transportation in ovarian cancer

Abstract

Objective To investigate the effect of the ATP-binding cassette transporter superfamily B member 1 gene ( ABCB1) 3435C > T single nucleotide polymorphism (SNP) on docetaxel transportation in ovarian cancer cells. Methods ES-2 and SKOV3 cells were transfected with an ABCB1 3435C > T recombinant plasmid, and mRNA expression was detected by real-time PCR. The MTT assay was used to detect the toxicity of docetaxel. High-performance liquid chromatography determined the drug concentration in different cell models to evaluate intracellular accumulation, and a transmembrane resistance experiment was used to assess permeability and evaluate the effect of P-gp activity on drug transportation. A tumor-bearing mouse model was established to evaluate the effect of ABCB1 3435C > T on docetaxel resistance. Results P-gp was overexpressed in cells transfected with the ABCB1 3435C > T plasmid, leading to a significant increase in drug resistance to docetaxel. ABCB1 3435C/wild-type transfection significantly promoted the transport of docetaxel mediated by P-gp compared with ABCB1 3435T/mutant transfection. Conclusion P-gp encoded by the ABCB1 variant allele appears to be more efficient at transporting docetaxel compared with the wild-type allele. The ABCB1 3435C > T SNP dramatically affected the efflux ability of P-gp against docetaxel, and may influence P-gp expression and activity.

Novel players in the development of chemoresistance in ovarian cancer: ovarian cancer stem cells, non-coding RNA and nuclear receptors

“…Sortilin-related receptor 1 (SORL1) silencing inhibits the endosomal antigen 1 pathway, delaying ABCB1 stabilization, sensitizing cisdiamminedichloroplatinum(II) (CDDP)-resistant ovarian cells [77][78][79] . ABCB1 is regulated by the Hedgehog pathway, with Gli2 directly targeting and positively modulating its expression [80] . ABCB1 Single Nucleotide Polymorphism (SNP), 3435C>T, enhances docetaxel efflux in OC [81] .…”

Personalized medicine of non-gene-specific chemotherapies for non-small cell lung cancer

“…When combined with other chemotherapies such as cisplatin, the response rate would substantially (from ∼30% to ∼70%) improve in NSCLC patients as compared to docetaxel treatment alone 106 . Much of docetaxel's functions also depend on resistance mechanisms such as expression levels of drug efflux pumps (ABCB1, ABCC10 which are surmountable by ibrutinib), kinesins, and tumor suppressor gene P27 107 , 108 , 109 , 110 , 111 . While overexpression of the ABCB1 gene and kinesins are known to be detrimental to docetaxel efficacy, the inverse is true for PTEN (mechanism through P27) 108 , 109 , 110 .…”

“…Much of docetaxel's functions also depend on resistance mechanisms such as expression levels of drug efflux pumps (ABCB1, ABCC10 which are surmountable by ibrutinib), kinesins, and tumor suppressor gene P27 107 , 108 , 109 , 110 , 111 . While overexpression of the ABCB1 gene and kinesins are known to be detrimental to docetaxel efficacy, the inverse is true for PTEN (mechanism through P27) 108 , 109 , 110 . However, since P27 gene expression fluctuations in both directions have been reported to correlate with resistance to several chemotherapies without obvious connections to each other, the existence of a true causative relationship is questionable.…”

Over kanserli hastalardaki ERCC1 ve ABCB1 gen polimorfizminin platin ve taksan tedavisine yanıt ile ilişkisi

“…ABCB1 (MDR1) geni C3435T tek nükleotit değişimi hücre içine giren taksan gibi etken moleküllerin dışarı atılımını hızlandırmakta ve bu durumda daha erken progrese olmasına yol açmaktadır [12]. Ancak yapılan bir çalışmada ABCB1 gen polimorfizmleri (G2677T / A ve C3435T), ne hastalıksız ne de genel sağkalım ile ilişkili bulunmamıştır [13]. ABCB1 in kemoterapi tedavisindeki prognostik yerini inceleyen bir araştırmada ABCB1 gen polimorfizmleri ile OS, PFS veya yanıt oranları arasında herhangi bir ilişki için kanıt bulunamadı [14].…”