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

Jangamreddy JR, Panigrahi S, Lotfi K, Yadav M, Maddika S, Tripathi AK, Sanyal S, Łos MJ - Oncotarget (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Dept. Clinical & Experimental Medicine, Integrative Regenerative Med. Center (IGEN), Linköping University, Sweden. Authors contributed equally.

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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Related in: MedlinePlus

Downstream effects of Bcr-Abl inhibition by apoptin or its bioactive decapeptide(a) Western blot image showing inhibition of c-Myc phosphorylation by Tat-apoptin among K562 cell lines similar to that of Imatinib. (b) Bioactive apoptin decapeptide shows similar attenuation of phosphorylation of c-Myc by 36 h but not the scrambled peptide sequence. (c) Quantification of western blot data from figure 5b. N=3. *p<0.05.
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Figure 5: Downstream effects of Bcr-Abl inhibition by apoptin or its bioactive decapeptide(a) Western blot image showing inhibition of c-Myc phosphorylation by Tat-apoptin among K562 cell lines similar to that of Imatinib. (b) Bioactive apoptin decapeptide shows similar attenuation of phosphorylation of c-Myc by 36 h but not the scrambled peptide sequence. (c) Quantification of western blot data from figure 5b. N=3. *p<0.05.

Mentions: In our earlier work [19], we showed that apoptin interacts directly with BCR-ABL1 and inhibits the phosphorylation of its down stream targets. Here we tested the effects of Tat-Apoptin, and our apoptin-decapeptide on the expression levels of c-Myc and its active phosphorylated form that enhances cell proliferation among BCR-ABL1 expressing K562 cell lines. Western blot image in figure 5a shows that Tat-Apoptin and Imatinib treated cells showed hampered phosphorylation of c-Myc compared to control and Tat-GFP treated cells. Similarly we tested the efficacy of synthetic apoptin-decapeptide in inhibiting c-Myc phosphorylation among K562 cells. As shown in the figure 5b apoptin decapeptide treated cells showed inhibited phosphorylation of c-Myc by 36 h similar to Imatinib treated cells at the same time period compared to control treated and scrambled peptide treated cells at the respective time interval. A quantified data of Western blot is shown in figure 5c depicting similar results.


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

Jangamreddy JR, Panigrahi S, Lotfi K, Yadav M, Maddika S, Tripathi AK, Sanyal S, Łos MJ - Oncotarget (2014)

Downstream effects of Bcr-Abl inhibition by apoptin or its bioactive decapeptide(a) Western blot image showing inhibition of c-Myc phosphorylation by Tat-apoptin among K562 cell lines similar to that of Imatinib. (b) Bioactive apoptin decapeptide shows similar attenuation of phosphorylation of c-Myc by 36 h but not the scrambled peptide sequence. (c) Quantification of western blot data from figure 5b. N=3. *p<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196195&req=5

Figure 5: Downstream effects of Bcr-Abl inhibition by apoptin or its bioactive decapeptide(a) Western blot image showing inhibition of c-Myc phosphorylation by Tat-apoptin among K562 cell lines similar to that of Imatinib. (b) Bioactive apoptin decapeptide shows similar attenuation of phosphorylation of c-Myc by 36 h but not the scrambled peptide sequence. (c) Quantification of western blot data from figure 5b. N=3. *p<0.05.
Mentions: In our earlier work [19], we showed that apoptin interacts directly with BCR-ABL1 and inhibits the phosphorylation of its down stream targets. Here we tested the effects of Tat-Apoptin, and our apoptin-decapeptide on the expression levels of c-Myc and its active phosphorylated form that enhances cell proliferation among BCR-ABL1 expressing K562 cell lines. Western blot image in figure 5a shows that Tat-Apoptin and Imatinib treated cells showed hampered phosphorylation of c-Myc compared to control and Tat-GFP treated cells. Similarly we tested the efficacy of synthetic apoptin-decapeptide in inhibiting c-Myc phosphorylation among K562 cells. As shown in the figure 5b apoptin decapeptide treated cells showed inhibited phosphorylation of c-Myc by 36 h similar to Imatinib treated cells at the same time period compared to control treated and scrambled peptide treated cells at the respective time interval. A quantified data of Western blot is shown in figure 5c depicting similar results.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Dept. Clinical & Experimental Medicine, Integrative Regenerative Med. Center (IGEN), Linköping University, Sweden. Authors contributed equally.

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.

Show MeSH
Related in: MedlinePlus