Abstract
Nilotinib is a selective BCR-ABL tyrosine kinase inhibitor related to imatinib that is more potent than imatinib. Nilotinib is widely used to treat chronic myelogenous leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). The present study identifies Mouse double minute 2 homolog (MDM2) as a target of nilotinib. In studying ALL cell lines, we found that the expression of MDM2 in both Philadelphia positive (Ph+) and Philadelphia negative (Ph-) ALL cells was remarkably inhibited by nilotinib, in a dose- and time-dependent manner. Further studies demonstrated that nilotinib inhibited MDM2 at the post-translational level by inducing MDM2 self-ubiquitination and degradation. Nilotinib-mediated MDM2 downregulation did not result in accumulation and activation of p53. Inhibition of MDM2 in nilotinib-treated ALL cells led to downregulation of the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP), a translational target of MDM2, resulting in activation of caspases. Inhibition of XIAP following nilotinib-mediated downregulation of MDM2 resulted in apoptosis of MDM2-expressing ALL; however, similar nilotinib treatment induced stronger apoptosis in Ph+/MDM2+ ALL than in Ph-/MDM2+ or Ph+/MDM2- ALL. The ALL cells that were Ph-/MDM2- were totally resistant to nilotinib. These results suggested that nilotinib can inhibit MDM2 and induce a p53-independent apoptosis pathway by downregulating XIAP; thus, nilotinib can treat not only Ph+, but also Ph- ALL patients whose cancer cells overexpress MDM2.
Highlights
The tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib and nilitinib were designed and developed for the treatment of chronic myelogenous leukemia (CML) and certain acute lymphoblastic leukemia (ALL), based on the knowledge that the protein kinase ABL is constitutively activated in patients with these disease
Nilotinib inhibits Mouse double minute 2 homolog (MDM2) expression in ALL To investigate whether nilotinib can inhibit MDM2, we tested a group of ALL cell lines that were known to express different levels of MDM2 (Fig. 1) and have various p53 status (EU-1, UOC-B1 and SUPB13: wild-type-p53; EU-6: mutant p53; EU-5 and EU-9: p53null) [28]
The use of second-generation TKIs such as nilotinib to treat imatinib-resistant Ph+ ALL significantly improved the clinical outcome, there still existed cases that failed to respond to nilotinib
Summary
The tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib and nilitinib were designed and developed for the treatment of chronic myelogenous leukemia (CML) and certain acute lymphoblastic leukemia (ALL), based on the knowledge that the protein kinase ABL is constitutively activated in patients with these disease. Inhibition of the BCR-ABL tyrosine kinase activity by imatinib, the first generation of specific BCR-ABL inhibitors, results in durable cytogenetic and molecular remissions in the majority of CML and Ph+ ALL; not all patients benefit from treatment, due to drug resistance and intolerance [8,9]. This led to the development of second-generation TKIs, such as nilotinib, which is more potent than imatinib and is currently approved for the treatment of newly diagnosed, imatinib-resistant or imatinibintolerant CML and Ph+ ALL [10]. It is reported that several cell survival and anti-apoptotic proteins such as BCL-X, survivin and histone deacetylases are downregulated by imatinib and nilotinib, which contribute to their cytotoxic and apoptotic activities [15,16,17]
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