Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy
2014 (English)In: OncoTarget, ISSN 1949-2553, Vol. 5, no 16, 7198-7211 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2014. Vol. 5, no 16, 7198-7211 p.
apoptin, BCR-ABL1, CML, imatinib, STAT5
IdentifiersURN: urn:nbn:se:liu:diva-111667ISI: 000347920100055PubMedID: 25216532OAI: oai:DiVA.org:liu-111667DiVA: diva2:758801