Keywords

Ponatinib; Muscle toxicity; BMP-7; Apoptosis; In vitro and in vivo study

Abstract

Tyrosine Kinase Inhibitors associated muscle complaints like cramps, pain, and weakness are a few of the concerns contributing to declined disease control and quality of life. In this study, we investigated whether Ponatinib, a 3rd generation TKI, induces muscle toxicity in both In Vitro and In Vivo models and expand BMP-7 as a possible treatment option for its attenuation. For the In vitro study, Sol-8, a mouse myogenic cell line was exposed to Ponatinib and BMP-7 for 24hrs each. For the In vivo study, C57BL/6J mice were injected and euthanized after 14 days. The soleus muscle was isolated and used for experimentation. Both the studies were conducted with 3 groups: Control, Ponatinib, and Ponatinib+BMP-7. Ponatinib-induced muscle toxicity via apoptosis was established by TUNEL Assay, pro-apoptotic markers- Caspase 3, BAX, and anti-apoptotic marker Bcl2 via Immunocytochemistry and Immunohistochemistry. For the In vivo study, further confirmations of the above-mentioned apoptotic markers were done by RT-PCR. Ponatinib-induced muscle myopathy and loss in muscle function were also determined along with the effect on apoptotic pathway proteins PTEN and AKT. A significant (p < 0.05) increase in apoptotic positive nuclei as well as positive cells for pro-apoptotic markers was observed in Ponatinib treatment groups both in vitro and in vivo along with loss of muscle function and adverse muscle remodeling. Whereas BMP-7 treatment significantly (p < 0.05) attenuated Ponatinib-induced apoptosis, restored muscle function, and improved muscle remodeling. The result of our study suggests that Ponatinib-induces apoptotic cell death in skeletal cells which was attenuated by BMP-7.

Notes

If this is your thesis or dissertation, and want to learn how to access it or for more information about readership statistics, contact us at STARS@ucf.edu

Graduation Date

2022

Semester

Summer

Advisor

Singla, Dinender

Degree

Master of Science (M.S.)

College

College of Medicine

Department

Burnett School of Biomed Sciences

Degree Program

Biotechnology

Identifier

CFE0009266; DP0026870

URL

https://purls.library.ucf.edu/go/DP0026870

Language

English

Release Date

8-15-2027

Length of Campus-only Access

5 years

Access Status

Masters Thesis (Campus-only Access)

Subjects

Protein-tyrosine kinase--Inhibitors; Bone morphogenetic proteins; Muscles--Diseases--Research; Muscles--Effect of drugs on; Apoptosis--Research

Download

Restricted to the UCF community until 8-15-2027; it will then be open access.

Share

COinS
 

Accessibility Statement

This item was created or digitized prior to April 24, 2027, or is a reproduction of legacy media created before that date. It is preserved in its original, unmodified state specifically for research, reference, or historical recordkeeping. In accordance with the ADA Title II Final Rule, the University Libraries provides accessible versions of archival materials upon request. To request an accommodation for this item, please submit an accessibility request form.