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Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. (Marek Los)ORCID iD: 0000-0001-6105-1213
Case Western Reserve University, Cleveland, OH, USA.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
CSIR-Central Drug Research Institute, Lucknow, India.
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2014 (English)In: OncoTarget, ISSN 1949-2553, Vol. 5, no 16, 7198-7211 p.Article in journal (Refereed) Published
Abstract [en]

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.
Keyword [en]
apoptin, BCR-ABL1, CML, imatinib, STAT5
National Category
Basic Medicine
URN: urn:nbn:se:liu:diva-111667ISI: 000347920100055PubMedID: 25216532OAI: diva2:758801
Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2015-02-16Bibliographically approved
In thesis
1. Cancer and cancer stem cell targeting agents: A focus on salinomycin and apoptin
Open this publication in new window or tab >>Cancer and cancer stem cell targeting agents: A focus on salinomycin and apoptin
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Current cancer treatments involving surgery, radiotherapy, and chemotherapy target the vast majority of cancer cells, but they are only partially effective in eliminating the disease. Failure to eliminate cancer with conventional treatments can lead to recurrence, which usually kills patient. This often occurs when cancer cells develop resistance to cancer drugs or when cancer-initiating cells (cancer stem cells), unaffected by existing treatment procedures, are present. Here, we studied two drugs, salinomycin and apoptin, that exhibit great potential in the future of cancer treatment not only for restricting malignancy, but also in preventing tumor recurrence. Salinomycin is an antibiotic that was used in poultry farming that is now used clinically to target cancer stem cells, and apoptin is a chicken anemia virus-derived protein that is capable of detecting and killing transformed cells. In this study, we delved into the molecular mechanism of salinomycin action leading to cancer cell death. We showed that salinomycin induces autophagy in both cancer and normal primary cells. We further demonstrated that salinomycin promotes mitochondrial fission, thus increasing mitochondrial mass and mitochondria-specific autophagy, mitophagy. Salinomycin-induced cell death was both necrotic and apoptotic as determined by increased release of HMGB1 and caspase-3, -8 and -9 activation. We also found that stress responses of normal and cancer cells to salinomycin differ and this difference is aggravated by starvation conditions. We proposed that a combinational treatment with glucose starvation, or glucose analogues such as 2DG or 2FDG, might enhance the effects of salinomycin on cancer cells while protecting normal cells. We previously reported that apoptin interacts with BCRABL1, a protein that is expressed in patients with chronic myeloid leukemia (CML). We located a minimal region on the apoptin protein that triggers inhibition of downstream BCR-ABL1 signaling effects. This deca-peptide region was tested on patient samples and was shown to effectively kill cancer cells derived from patients, similar to the drug Imatinib. We further show that the apoptin decapeptide is cytotoxic to Imatinib-resistant patient-derived cancer cells. Thus, we identified a novel therapeutic targeting agent that can not only overcome drug resistance, but it can also induce cancer cell death without affecting normal cells.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 53 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1436
National Category
Basic Medicine Cell and Molecular Biology
urn:nbn:se:liu:diva-113709 (URN)10.3384/diss.diva-113709 (DOI)978-91-7519-153-9 (print) (ISBN)
Public defence
2015-02-26, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2015-01-29 Created: 2015-01-29 Last updated: 2015-03-04Bibliographically approved

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