title: Nilotinib reverses ABCB1/P-glycoprotein-mediated multidrug resistance but increases cardiotoxicity of doxorubicin in a MDR xenograft model.
abstract: The BCR-Abl tyrosine kinase inhibitor (TKI), nilotinib, was developed to surmount resistance or intolerance to imatinib in patients with Philadelphia-positive chronic myelogenous leukemia. Recent studies have shown that nilotinib induces potent sensitization to anticancer agents by blocking the functions of ABCB1/P-glycoprotein (P-gp) in multidrug resistance (MDR). However, changes in P-gp expression or function affect the cardiac disposition and prolong the presence of both doxorubicin (DOX) and doxorubicinol (DOXol) in cardiac tissue, thus, enhancing the risk of cardiotoxicity. In this study, we used a MDR xenograft model to evaluate the antitumor activity, tissue distribution and cardiotoxicity of DOX when co-administered with nilotinib. This information will provide more insight into the pharmacological role of nilotinib in MDR reversal and the risk of DOX cardiotoxicity. Our results showed that nilotinib significantly enhanced DOX cytotoxicity and increased intracellular rhodamine 123 accumulation in MG63/DOX cells in vitro and strongly enhanced DOX inhibition of growth of P-gp-overexpressing MG63/DOX cell xenografts in nude mice. Additionally, nilotinib significantly increased DOX and DOXol accumulation in serum, heart, liver and tumor tissues. Importantly, nilotinib induced a disproportionate increase in DOXol in cardiac tissue. In the co-administration group, CBR1 and AKR1A1 protein levels were significantly increased in cardiac tissue, with more severe necrosis and vacuole formation. These results indicate that nilotinib reverses P-gp- mediated MDR by blocking the efflux function and potentiates DOX-induced cardiotoxicity. These findings represent a guide for the design of future clinical trials and studies of pharmacokinetic interactions and may be useful in guiding the use of nilotinib in combination therapy of cancer in clinical practice.
authors: Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China; College of Medical Science, Three Gorges University, 443002 Yichang, Hubei, China.
authors: Zhi-Yong
authors: ZY
authors: Zhou
authors: Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China.
authors: Li-Li
authors: LL
authors: Wan
authors: Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China.
authors: Quan-Jun
authors: QJ
authors: Yang
authors: Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China.
authors: Yong-Long
authors: YL
authors: Han
authors: Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China.
authors: Dan
authors: D
authors: Li
authors: Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China.
authors: Jin
authors: J
authors: Lu
authors: Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China. Electronic address: guopharm@126.com.
authors: Cheng
authors: C
authors: Guo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005786:Gene Expression Regulation / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011743:Pyrimidines; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; C555915:carbonyl reductase 1, mouse; D000449:Aldehyde Reductase; C498826:nilotinib
keywords: Cardiotoxicity; Doxorubicin; Multidrug resistance; P-glycoprotein