Anti-CD33 monoclonal antibodies enhance the cytotoxic effects of cytosine arabinoside and idarubicin on acute myeloid leukemia cells through similarities in their signaling pathways.
OBJECTIVE: Chemotherapy agents (CA) such as cytosine arabinoside (ara-C), idarubicin (IDA), and etoposide (VP-16) are widely used in the treatment of acute myeloid leukemia (AML) However, their effects on signaling pathways leading to cytotoxicity have only been described recently. Ligation of the leukemia-associated antigen CD33 by anti-CD33 monoclonal antibody (mAb) also results in signaling events that induce a downregulation of cell growth. We examined the possibility that anti-CD33 mAb and CA might cooperate in mediation of growth inhibition in primary AML samples and AML cell lines. MATERIALS AND METHODS: We investigated two AML cells lines and 14 primary AML samples for their proliferative response ((3)H-thymidine incorporation), colony formation, and biochemical (Western blot analysis) to anti-CD33 mAb treatment combined with chemotherapy agents. RESULTS: CD33 ligation induced a significant increase in ara-C- or IDA- but not VP-16-or Bryostatin-mediated inhibition of proliferation and colony formation. Ara-C and IDA induced SHP-1 and SHP-2 protein tyrosine phosphatase (PTPs) phosphorylation and Lyn/SHP-1 complex formation, while VP-16 and Bryostatin did not. CD33 ligation, however, mediated phosphorylation of these PTPs and Syk/SHP-1 complex formations. Combined treatment of AML cells by ara-C or IDA with anti-CD33 mAb resulted in higher levels of SHP-1 phosphorylation. Reduction in SHP-1 by short interfering RNA abrogated these effects. CONCLUSION: These data suggest that combined incubation of leukemia cells with anti-CD33 mAb and ara-C or IDA, but not VP-16 or Bryostatin, independently triggers similar events in the downstream signaling cascade, and therefore leads to additive antiproliferative effects and enhanced cytotoxicity.[1]References
- Anti-CD33 monoclonal antibodies enhance the cytotoxic effects of cytosine arabinoside and idarubicin on acute myeloid leukemia cells through similarities in their signaling pathways. Balaian, L., Ball, E.D. Exp. Hematol. (2005) [Pubmed]
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