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

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

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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.


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