Nilotinib (AMN107, Tasigna®) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters

Tiwari, Amit K.; Sodani, Kamlesh; Wang, Si-Rong; Kuang, Yehong; Ashby, Charles R.; Chen, Xiang; Chen, Zhe-Sheng

doi:10.1016/j.bcp.2009.04.002

Cited by 196 publications

(153 citation statements)

References 45 publications

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“…Nilotinib inhibited ABCB1-mediated Rhodamine-123 efflux in K562-Dox cells (Online Supplementary Figure S2A and B) which is consistent with previously published findings 18,19 and increases dasatinib IUR in K562-Dox cells. Figure S2C).…”

supporting

confidence: 91%

“…Similarly, dasatinib did not increase IUR of 1 mM and 2 mM Figure S2E-J). Together these data suggest that, unlike nilotinib, 18 therapeutically achievable concentrations of dasatinib does not block ABCB1-mediated efflux. Dhose et al suggested that dasatinib is an ABCB1 inhibitor, but only at a very high concentration (10 mM) which is not achievable at therapeutic dosing schedule and, therefore, probably not clinically relevant.…”

Section: Dasatinib Does Not Block Efflux Of Abcb1 Substratesmentioning

confidence: 82%

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Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells

et al. 2012

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supporting

confidence: 91%

Section: Dasatinib Does Not Block Efflux Of Abcb1 Substratesmentioning

confidence: 82%

Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells

et al. 2012

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“…ABCG2 has been reported to mediate MDR by effluxing numerous agents, including mitoxantrone (MX), topotecan, irinotecan, DOX, nilotinib, and imatinib (16,(18)(19)(20). Indeed, upregulated expression of ABCG2 is observed in a variety of cancer stem cells, leading to the speculation that ABCG2 provides cellular protection against cytotoxic agents for cancer stem cells, which are inherently present in the cancer cell populations (21,22).…”

Section: Introductionmentioning

confidence: 99%

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

Chen

et al. 2016

Molecular Cancer Therapeutics

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The overexpression of ATP-binding cassette (ABC) transporters has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. In our study, we investigated whether osimertinib (AZD9291), a third-generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation, could reverse MDR induced by ABCB1 and ABCG2 in vitro, in vivo, and ex vivo. Our results showed that osimertinib significantly increased the sensitivity of ABCB1-and ABCG2-overexpressing cells to their substrate chemotherapeutic agents in vitro and in the model of ABCB1-overexpressing KBv200 cell xenograft in nude mice. Mechanistically, osimertinib increased the intracellular accumulations of doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1-or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, osimertinib stimulated the ATPase activity of both ABCB1 and ABCG2 and competed with the [ 125 I] iodoarylazidoprazosin photolabeling bound to ABCB1 or ABCG2, but did not alter the localization and expression of ABCB1 or ABCG2 in mRNA and protein levels nor the phosphorylations of EGFR, AKT, and ERK. Importantly, osimertinib also enhanced the cytotoxicity of DOX and intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. Overall, these findings suggest osimertinib reverses ABCB1-and ABCG2-mediated MDR via inhibiting ABCB1 and ABCG2 from pumping out chemotherapeutic agents and provide possibility for cancer combinational therapy with osimertinib in the clinic.

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“…At the same time, both LEF and TER were reported to be high affinity substrates of efflux transporter breast cancer resistance protein (BCRP) [9] . Since there are multiple anti-rheumatic drugs are reported to be the substrates of BCRP [10][11][12] , and the change of BCRP function may lead to toxicity [13] , the potential drug-drug interaction risk mediated by BCRP or other transporters should be investigated. Therefore, we want to explore whether transporters are involved in the liver toxicity of LEF and TER.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

Wang

et al. 2016

Acta Pharmacol Sin

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Aim: Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. Methods: The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg • kg, ig) for 4 weeks, their blood samples were analyzed. Results: A nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC 50 value of leflunomide in rat hepatocytes from 409 to 216 μmol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 μmol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC 0-t ) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg • kg -1 • d -1 ) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg • kg, all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats. Conclusion: Hepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major metabolite teriflunomide suppresses the expression and function of NTCP, leading to potential cholestasis.

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Nilotinib (AMN107, Tasigna®) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters

Cited by 196 publications

References 45 publications

Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells

Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

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