Oncotarget

Research Papers:

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

Jaganmohan R. Jangamreddy _, Soumya Panigrahi, Kourosh Lotfi, Manisha Yadav, Subbareddy Maddika, Anil Kumar Tripathi, Sabyasachi Sanyal and Marek J. Łos

PDF  |  HTML  |  How to cite

Oncotarget. 2014; 5:7198-7211. https://doi.org/10.18632/oncotarget.2278

Metrics: PDF 1759 views  |   HTML 2723 views  |   ?  


Abstract

Jaganmohan R. Jangamreddy1,*, Soumya Panigrahi2,*, Kourosh Lotfi3, Manisha Yadav4, Subbareddy Maddika5, Anil Kumar Tripathi6, Sabyasachi Sanyal4, Marek J. Łos1,7

1 Dept. Clinical & Experimental Medicine, Integrative Regenerative Med. Center (IGEN), Linköping University, Sweden

2 Dept. Medicine/ Infectious Diseases, Case Western Reserve University, Cleveland, OH 44106, USA

3 Dept. of Medical and Health Sciences, Linköping University, Department of Hematology, County Council of Östergötland, Linköping, Sweden

4 Division of Biochemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Rd, Lucknow 226031, UP, India

5 Laboratory of Cell Death & Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India

6 Department of Clinical Hematology and Medical Oncology, King George's Medical University, Lucknow 226003, Uttar Pradesh, India

7 Department of Pathology, Pomeranian Medical University, Szczecin, Poland

# Authors contributed equally

Correspondence to:

Dr. Marek J. Łos, MD/PhD, email: [email protected]

Keywords: apoptin, BCR-ABL1, CML, imatinib, STAT5,

Received: June 24, 2014     Accepted: July 25, 2014     Published: August 4, 2014

Abbreviations: ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; CO-IP, Co-immunoprecipitation; Cy3, Cyanine3; DAPI, 4′,6-diamidino-2-phenylindole; FITC, Fluorescein isothiocyanate; HRP, horse radish peroxidase; MAPK, Mitogen activated protein kinase; MTT, 4,5-Dimethylthiazol-2,5-diphenyltetrazolium bromide; nr-TK, non-receptor tyrosine kinase; PI3K, Phosphoinositide inositol 3 kinase; PI, Propidium iodide; r-TK, receptor tyrosine kinase; SH2, Src homology 2 domain; SH3, Src homology 3 domain; STI, signal transduction inhibitor; TK, tyrosine kinase

Abstract

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 2278