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Updated: Aug 22, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Apoptotic effect of PP2 a Src tyrosine kinase inhibitor, in murine B cell leukemia
Michael Lee1, Ji-Young Kim, Woo Suk Koh
1Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, P.O. Box 123, Yusong, Daejeon 305-600, Republic of Korea. mikelee@kitox.re.kr
Abstract:
Src is a non-receptor protein tyrosine kinase that transduces signals regulating cell growth and differentiation. We report here that activation of signaling pathway after blockade of tyrosine phosphorylation by PP2 (4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), a potent and selective inhibitor of the Src-family tyrosine kinase, can lead to cell death in murine B cell leukemia, 70Z/3. Death from PP2 occurred by apoptosis as indicated by the induction of caspase activation and annexin V/propidium iodide staining. Interestingly, PP2 was found to be able to enhance the DNA binding activity of nuclear factor kappaB (NF-kappaB) before induction of apoptosis without accompanying by increased phosphorylation of inhibitor of NF-kappaB-alpha (IkappaB-alpha). Additionally, immunoblotting analysis with PP2-treated cell extract demonstrated that, compared to other protein kinase C (PKC) isotypes, the translocation of novel PKC isotypes from the cytosol to membrane fraction was sustained for a longer time. These data suggest that the inhibition of Src-mediated tyrosine phosphorylation by PP2 may tilt the balance between each PKC isotypes, which in turn, activate NF-kappaB transcription factor, leading to apoptosis.
Insights
PP2, a Src-family tyrosine kinase inhibitor, induces apoptosis in murine B cell leukemia by activating nuclear factor kappaB (NF-kappaB). This inhibition of Src-mediated phosphorylation influences protein kinase C (PKC) isotypes, leading to programmed cell death.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Src is a non-receptor tyrosine kinase crucial for cell growth and differentiation signaling.
- Dysregulation of Src signaling is implicated in various cancers, including leukemia.
Purpose of the Study:
- To investigate the effects of PP2, a Src-family tyrosine kinase inhibitor, on murine B cell leukemia (70Z/3).
- To elucidate the molecular mechanisms underlying PP2-induced cell death.
Main Methods:
- Treatment of 70Z/3 cells with PP2.
- Assessment of apoptosis using caspase activation and Annexin V/propidium iodide staining.
- Analysis of nuclear factor kappaB (NF-kappaB) DNA binding activity and IkappaB-alpha phosphorylation.
- Immunoblotting to evaluate protein kinase C (PKC) isotype translocation.
Main Results:
- PP2 induced apoptosis in 70Z/3 cells.
- PP2 enhanced NF-kappaB DNA binding activity without increasing IkappaB-alpha phosphorylation.
- PP2 treatment led to sustained translocation of novel PKC isotypes from the cytosol to the membrane.
Conclusions:
- Inhibition of Src-mediated tyrosine phosphorylation by PP2 can trigger apoptosis in B cell leukemia.
- The mechanism involves altered PKC isotype balance and subsequent NF-kappaB activation.
- PP2 represents a potential therapeutic strategy for targeting Src-dependent leukemias.
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