A Novel MDR1 G1199T Variant Alters Drug Resistance and Efflux Transport Activity of P-Glycoprotein in Recombinant Hek Cells

Crouthamel, Matthew H.; Wu, Daniel; Yang, Ziping; Ho, Rodney J. Y.

doi:10.1002/jps.20743

Cited by 41 publications

(29 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…P-glycoprotein is not such an effective transporter of topotecan as ABCG2 (23,43,44), but how effective it is cannot be deduced from the literature. Relative resistance levels up to 20-fold have been reported (25), although most recent papers find much lower P-glycoprotein-mediated resistance or transport (45)(46)(47). Our results show that even a 53-fold upregulation of P-glycoprotein, which makes the tumor completely resistant to doxorubicin, does not result in clear-cut resistance to topotecan.…”

Section: Discussionmentioning

confidence: 40%

Sensitivity and Acquired Resistance of BRCA1;p53-Deficient Mouse Mammary Tumors to the Topoisomerase I Inhibitor Topotecan

et al. 2010

View full text Add to dashboard Cite

There is no tailored therapy yet for human basal-like mammary carcinomas. However, BRCA1 dysfunction is frequently present in these malignancies, compromising homology-directed DNA repair. This defect may serve as the tumor's Achilles heel and make the tumor hypersensitive to DNA breaks. We have evaluated this putative synthetic lethality in a genetically engineered mouse model for BRCA1-associated breast cancer, using the topoisomerase I (Top1) poison topotecan as monotherapy and in combination with poly(ADP-ribose) polymerase inhibition by olaparib. All 20 tumors tested were topotecan sensitive, but response heterogeneity was substantial. Although topotecan increased mouse survival, all tumors eventually acquired resistance. As mechanisms of in vivo resistance, we identified overexpression of Abcg2/Bcrp and markedly reduced protein levels of the drug target Top1 (without altered mRNA levels). Tumor-specific genetic ablation of Abcg2 significantly increased overall survival of topotecan-treated animals (P < 0.001), confirming the in vivo relevance of ABCG2 for topotecan resistance in a novel approach. Despite the lack of ABCG2, a putative tumor-initiating cell marker, none of the 11 Abcg2 −/− ;Brca1 −/− ;p53 −/− tumors were eradicated, not even by the combination topotecanolaparib. We find that olaparib substantially increases topotecan toxicity in this model, and we suggest that this might also happen in humans.

show abstract

Section: Discussionmentioning

confidence: 40%

Sensitivity and Acquired Resistance of BRCA1;p53-Deficient Mouse Mammary Tumors to the Topoisomerase I Inhibitor Topotecan

et al. 2010

View full text Add to dashboard Cite

show abstract

“…24 Our results also concur with in vitro data on this SNP showing that cells expressing the 1199A variant have increased resistance to other chemotherapeutic agents such as doxorubicin, vincristine and vinblastine. [34][35] The effect of C1236T and G2677T/A on survival remained significant in multivariate analysis and -together with age, NPM1 and FLT3 status -these SNPs seem to be important variables for therapeutic response in AML. Noteworthy is that the hazard ratios of these ABCB1 SNPs had higher values than NPM1 and FLT3 in this population.…”

Section: Discussionmentioning

confidence: 99%

Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype

et al. 2010

View full text Add to dashboard Cite

Over expression of the multi-drug transporter P-glycoprotein, encoded by the ABCB1 gene, is a clinically relevant problem in acute myeloid leukemia (AML). Polymorphisms in ABCB1 might contribute to cancer risk and therapeutic response. We therefore investigated the influence of polymorphisms G1199A, C1236T, G2677T/A and C3435T on cancer susceptibility, in vitro cytotoxicity and overall survival in 100 de novo AML patients with normal karyotype. Patients with 1236C/C or 2677G/G genotypes showed poorer survival than patients with other genotypes (P=0.03 and P=0.02, respectively). Both these genotypes were significant factors for survival in multivariate analysis, along with age, NPM1 and FLT3 mutation status. In vitro cytotoxicity studies demonstrated that leukemic cells from 1236T/T and 2677T/T patients were significantly more susceptible to mitoxantrone (P=0.02), and tended to be more susceptible to etoposide and daunorubicin (P=0.07-0.09), but not to cytarabine. No significant difference in allele frequencies were found between patients and healthy volunteers (n=400).

show abstract

“…The ABCB1 S400N variant has been shown to confer higher drug resistance to paclitaxel, but the stable cell line overexpressing this P-gp was selected for G418 resistance (Crouthamel et al, 2006). It is unknown what other background changes occur during cell line creation that could affect total cellular resistance.…”

Section: Substrate-dependent Activity Of P-gp Variants 439mentioning

confidence: 99%

Substrate-Dependent Effects of Human ABCB1 Coding Polymorphisms

Gow¹,

Hodges²,

Chinn³

et al. 2008

J Pharmacol Exp Ther

View full text Add to dashboard Cite

One of the many obstacles to effective drug treatment is the efflux transporter P-glycoprotein (P-gp), which can restrict the plasma and intracellular concentrations of numerous xenobiotics. Variable drug response to P-gp substrates suggests that genetic differences in ABCB1 may affect P-gp transport. The current study examined how ABCB1 variants alter the P-gpmediated transport of probe substrates in vitro. Nonsynonymous ABCB1 variants and haplotypes with an allele frequency Ն2% were transiently expressed in HEK293T cells, and the transport of calcein acetoxymethyl ester and 4,4-difluoro-4-bora3a,4a-diaza-s-indacene (BODIPY-FL)-paclitaxel was measured in the absence or presence of the P-gp inhibitor cyclosporin A. The A893S, A893T, and V1251I variants and the N21D/ 1236CϾT/A893S/3435CϾT haplotype altered intracellular accumulation compared with reference P-gp in a substratedependent manner. It is interesting that certain variants showed altered sensitivity to cyclosporin A inhibition that was also substrate-specific. These functional data demonstrate that nonsynonymous polymorphisms in ABCB1 may selectively alter P-gp transport and drug-drug interactions in a substrateand inhibitor-dependent manner.

show abstract

A Novel MDR1 G1199T Variant Alters Drug Resistance and Efflux Transport Activity of P-Glycoprotein in Recombinant Hek Cells

Cited by 41 publications

References 18 publications

Sensitivity and Acquired Resistance of BRCA1;p53-Deficient Mouse Mammary Tumors to the Topoisomerase I Inhibitor Topotecan

Sensitivity and Acquired Resistance of BRCA1;p53-Deficient Mouse Mammary Tumors to the Topoisomerase I Inhibitor Topotecan

Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype

Substrate-Dependent Effects of Human ABCB1 Coding Polymorphisms

Contact Info

Product

Resources

About