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.
Highlights
The identification of breakpoint cluster region (BCR)-abl oncogene 1 (ABL1) as the single cause of chronic myeloid leukemia (CML), enabled novel therapeutic approaches aiming at the inhibition of the tyrosine kinase activity of BCR-ABL1 [1]
We showed that Tat-apoptin, a cellpenetrating conjugate of apoptin strongly binds to the Src homology 3 domain (SH3) domain of BCR-ABL1, modifies the phosphorylation and inhibit the activity of BCR-ABL1 followed with an attenuation of several of its downstream targets [19]
Using human CML cells K562 and BCR-ABL1p210 expressing murine cell line 32Dp210 as a model, which are highly responsive to apoptin, we further ventured into identifying the smallest fragment of apoptin that can inhibit BCR-ABL1 activity and mimic the anti-cancer activity of apoptin
Summary
The identification of BCR-ABL1 as the single cause of CML, enabled novel therapeutic approaches aiming at the inhibition of the tyrosine kinase activity of BCR-ABL1 [1]. The leukemogenic properties of BCR-ABL1 originate from the constitutive tyrosine kinase activity of the ABL1-encoded part of the protein in combination with a region in the BCR moiety that facilitates dimerization of BCR-ABL1. The activated GRB2/ GAB2/SOS complex in turn activates several downstream signaling cascades including the RAS/mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 5 (STAT5) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways [2, 3]. These pathways influence genetic transcription so that uncontrolled cell survival, proliferation, and anti-apoptotic pathways are promoted and the CML cell clone has been created
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