Breast Cancer Resistance Protein (BCRP/ABCG2) Induces Cellular Resistance to HIV-1 Nucleoside Reverse Transcriptase Inhibitors

Abstract

Breast cancer resistance protein (BCRP/ABCG2) is a novel member of ATP-binding cassette transporters, which induce multidrug resistance in cancer cells. We found that a high level of BCRP expression in CD4 ϩ T cells conferred cellular resistance to human immunodeficiency virus type-1 (HIV-1) nucleoside reverse transcriptase inhibitors. The cell line MT-4/DOX 500 was established through the long-term culture of MT-4 cells in the presence of doxorubicin (DOX) and had reduced sensitivity to not only DOX but also zidovudine (AZT). MT-4/DOX 500 cells showed reduced intracellular accumulation and retention of DOX and increased ATP-dependent rhodamine 123 efflux. The cells were also resistant to several anticancer agents such as mitoxantrone, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, and 7-ethyl-10-hydroxycamptothecin. AZT was 7.5-fold less inhibitory to HIV-1 replication in MT-4/DOX 500 cells than in MT-4 cells. Furthermore, the anti-HIV-1 activity of lamivudine was severely impaired in MT-4/DOX 500 cells. In contrast, the antiviral activity of non-nucleoside reverse transcriptase inhibitors and protease inhibitors was not affected in the cells. MT-4/DOX 500 cells expressed glycosylated BCRP but not P-glycoprotein (ABCB1), multidrug resistance protein 1, 2, or 4 (ABCC1, -2, or -4), or lung resistance-related protein. In addition, the BCRP-specific inhibitor fumitremorgin C completely abolished the resistance of MT-4/DOX 500 cells to AZT as well as to DOX. An analysis for intracellular metabolism of AZT suggests that the resistance is attributed to the increase of ATP-dependent efflux of its metabolites, presumably AZT 5Ј-monophosphate, in MT-4/DOX 500 cells.

Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides

“…We have found that ABCG2 can cause resistance to several nucleobase and nucleoside analogues used in cancer chemotherapy in addition to its effect on the antiretroviral nucleosides zidovudine and lamivudine (17,18). Remarkably, ABCG2 transports not only the nucleoside monophosphate metabolite of cladribine-in analogy with other ABC transporters that can cause resistance to nucleobase and nucleoside analogues (6,11,12,14)-but also cladribine itself.…”

“…One other member of this large subfamily of organic anion transporters, ABCC11, is also able to mediate resistance to some nucleobase and nucleoside analogues (16). In addition, several groups recently reported that an ABC transporter from the G family, the ABCG2 (breast cancer resistance protein), is able to cause cellular resistance to various nucleoside analogues, such as the antiretroviral compounds zidovudine, lamivudine (17,18), and PMEA (19) and the antileukemic purine analogue H]2-chloro-2 ¶-deoxyadenosine (cladribine, 2-CdA; ref. 19).…”

“…In the work of Wang et al (17,18), resistance to zidovudine caused by ABCG2 was shown to be due to reduced drug accumulation in the cells, but the nature of the metabolite exported was not defined. As we have shown that ABCG2, like ABCC4 and ABCC5 (6, 24 -27), is able to transport cyclic GMP (28), this raised the possibility that ABCG2 is also able to export nucleotide analogues, like ABCC4 and ABCC5 do.…”

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…Simvastatin acid [61] 18 Sulfasalazine [64] 0.6 a Triamcinolone [57] Simvastatin acid [61] Topotecan [57,67,80,84] Ulifloxacin [79] Zidovudine [74] MCT1 L-Lactate [26,88] 4 400/6 000 g-Hydroxybutyrate [26] Nateglinide [89] 187 a D-Lactate [26] Pyruvate [26,88] 2 100/2 500 L-Lactate [26] …”

“…Chenodeoxycholate-3-sulfate [15] 131 Glycodeoxycholate [15] 2.0 Glycoursodeoxycholate [15] 4.1 Cholate [15,54] [15,54] 7.3/13 Deoxycholate [15,54] 5.2-13 Glycochenodeoxycholate [54] 2.0/2.9 Glychodeoxycholate [54] 2.4/5.4 Glycholate [54] 11/21 Taurochenodeoxycholate [15,54] 1.0-6.1 Taurocholate [15,54] 7.3-25 Taurodeoxycholate [15] 4.5-17 Taurourosdeoxycholate [15] 28 Ursodeoxycholate [15,54] 36 [60] Estrone [56] Bisantrene [67] Betamethasone [57] Riboflavin [68] Taurolithocholate sulfate [56] 37 a Cerivastatin [61] Cerivastain [61] 18 Uric acid [69] Vitamin K3 [ [70] Ciprofloxacin [71] Daunorubicin [56] 59 a Daunorubicin [67] Dexamethasone [57] Diclofenac [72] Diclofenac [72] 71-78 Dipyridamole [73] Digoxin [57] Doxorubicin [67,74] Dipyridamole [73] 6.4 a Enrofloxacin [75] Doxorubicin [56,76] Epirubicin [67] Fluvastatin [61] 5.4 Fluvastatin [61,62] Glibenclamide [77] 150 a Glibenclamide …”