title: Mapping of apoptin-interaction with BCR-ABL1, and development of apoptin-based targeted therapy.
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.
authors.affiliation: Dept. Clinical & Experimental Medicine, Integrative Regenerative Med. Center (IGEN), Linköping University, Sweden. Authors contributed equally.
authors.forename: Jaganmohan R
authors.initials: JR
authors.lastname: Jangamreddy
authors.affiliation: Dept. Medicine/ Infectious Diseases, Case Western Reserve University, Cleveland, OH 44106, USA. Authors contributed equally.
authors.forename: Soumya
authors.initials: S
authors.lastname: Panigrahi
authors.affiliation: Dept. of Medical and Health Sciences, Linköping University, Department of Hematology, County Council of Östergötland, Linköping, Sweden.
authors.forename: Kourosh
authors.initials: K
authors.lastname: Lotfi
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Rd, Lucknow 226031, UP, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Yadav
authors.affiliation: Laboratory of Cell Death & Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.
authors.forename: Subbareddy
authors.initials: S
authors.lastname: Maddika
authors.affiliation: Department of Clinical Hematology and Medical Oncology, King George's Medical University, Lucknow 226003, Uttar Pradesh, India.
authors.forename: Anil Kumar
authors.initials: AK
authors.lastname: Tripathi
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Rd, Lucknow 226031, UP, India.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
authors.affiliation: Dept. Clinical & Experimental Medicine, Integrative Regenerative Med. Center (IGEN), Linköping University, Sweden. Department of Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Marek J
authors.initials: MJ
authors.lastname: Łos
mesh_terms: D000818:Animals; D036022:Capsid Proteins / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D010446:Peptide Fragments / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: C581634:BCR-ABL1 fusion protein, human; D036022:Capsid Proteins; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; C091717:VP3 protein, Chicken anemia virus; D016044:Fusion Proteins, bcr-abl