Mapping of apoptin-interaction with BCR-ABL1, and development of apoptin-based targeted therapy

Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imatinib however, 26-37% of patients discontinue imatinib therapy due to a suboptimal response or intolerance. Here we investigated derivatives of apoptin, a chicken anemia viral protein with selective toxic...

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Bibliographic Details
Published in:Oncotarget 2014-08, Vol.5 (16), p.7198-7211
Main Authors: Jangamreddy, Jaganmohan R, Panigrahi, Soumya, Lotfi, Kourosh, Yadav, Manisha, Maddika, Subbareddy, Tripathi, Anil Kumar, Sanyal, Sabyasachi, Łos, Marek J
Format: Article
Language:English
Subjects:
Animals
apoptin
BCR-ABL1
Capsid Proteins - pharmacology
Cell Proliferation - drug effects
CML
Drug Resistance, Neoplasm
Fusion Proteins, bcr-abl - antagonists & inhibitors
Fusion Proteins, bcr-abl - metabolism
Humans
imatinib
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - blood
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology
Mice
Molecular Targeted Therapy
Peptide Fragments - pharmacology
Protein Kinase Inhibitors - pharmacology
Research Paper
STAT5
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Summary:Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imatinib however, 26-37% of patients discontinue imatinib therapy due to a suboptimal response or intolerance. Here we investigated derivatives of apoptin, a chicken anemia viral protein with selective toxicity towards cancer cells, which can be directed towards inhibiting multiple hyperactive kinases including BCR-ABL1. Our earlier studies revealed that a proline-rich segment of apoptin interacts with the SH3 domain of fusion protein BCR-ABL1 (p210) and acts as a negative regulator of BCR-ABL1 kinase and its downstream targets. In this study we show for the first time, the therapeutic potential of apoptin-derived decapeptide for the treatment of CML by establishing the minimal region of apoptin interaction domain with BCR-ABL1. We further show that the apoptin decapeptide is able to inhibit BCR-ABL1 down stream target c-Myc with a comparable efficacy to full-length apoptin and Imatinib. The synthetic apoptin is able to inhibit cell proliferation in murine (32Dp210), human cell line (K562), and ex vivo in both imatinib-resistant and imatinib sensitive CML patient samples. The apoptin based single or combination therapy may be an additional option in CML treatment and eventually be feasible as curative therapy.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.2278