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Research Article
biqing han
Second Affiliated Hospital of Harbin Medical University
Corresponding Author
ORCiD: https://orcid.org/0000-0003-4609-6207
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Purpose
Because of the dose-dependent increased risk of cardiovascular events we tried to lower the dose of ponatinib without reducing its efficacy in the treatment of BCR-ABL T315I-containing CML. Combination with hydroxychloroquine can enhance the efficiency of ponatinib and axitinib through autophagy inhibition in CML cell with T315I.
Methods
Cell viability, cell cycle, cellular senescence, formation of cell clones and apoptosis assay were taken to test the efficiency of medicine. Lentiviral vectors containing shRNA was used to block autophagy and to verify the mechanism of the medicine. Establish tumor models in nude mice, and verify the experimental results in vivo.
Results
ponatinib and axitinib killed 32Dp210-T315I cells as well as inducing autophagy, which promoted their survival under pressure from TKIs. By inhibiting autophagy, HCQ enhanced the killing effect of ponatinib and axitinib on 32Dp210-T315I cells. In vivo HCQ also enhanced the killing effect of axitinib on 32Dp210-T315I cells.
Conclusion
HCQ combined with ponatinib may be a new strategy for treating CML and ALL that harbor the T315I mutation. Thus, this combination may make it possible to reduce the dose of ponatinib and reduce its side effects without compromising efficacy.
Keywords
Autophagy, Ponatinib, Axitinib, CML with T315I mutation
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A new preprint design is coming!
We have improved readability, clarity, accessibility, and opportunities for engagement.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research Article
biqing han
Second Affiliated Hospital of Harbin Medical University
Corresponding Author
ORCiD: https://orcid.org/0000-0003-4609-6207
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 20 Apr, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Purpose
Because of the dose-dependent increased risk of cardiovascular events we tried to lower the dose of ponatinib without reducing its efficacy in the treatment of BCR-ABL T315I-containing CML. Combination with hydroxychloroquine can enhance the efficiency of ponatinib and axitinib through autophagy inhibition in CML cell with T315I.
Methods
Cell viability, cell cycle, cellular senescence, formation of cell clones and apoptosis assay were taken to test the efficiency of medicine. Lentiviral vectors containing shRNA was used to block autophagy and to verify the mechanism of the medicine. Establish tumor models in nude mice, and verify the experimental results in vivo.
Results
ponatinib and axitinib killed 32Dp210-T315I cells as well as inducing autophagy, which promoted their survival under pressure from TKIs. By inhibiting autophagy, HCQ enhanced the killing effect of ponatinib and axitinib on 32Dp210-T315I cells. In vivo HCQ also enhanced the killing effect of axitinib on 32Dp210-T315I cells.
Conclusion
HCQ combined with ponatinib may be a new strategy for treating CML and ALL that harbor the T315I mutation. Thus, this combination may make it possible to reduce the dose of ponatinib and reduce its side effects without compromising efficacy.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12
Loading...