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.
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Master of Science (M.S.)
College of Medicine
Burnett School of Biomed Sciences
Length of Campus-only Access
Masters Thesis (Campus-only Access)
Srivastava, Ayushi, "BMP-7 Ameliorates Ponatinib Induced Muscle Cell toxicity: An in vitro and in vivo Study" (2022). Electronic Theses and Dissertations, 2020-. 1295.
Restricted to the UCF community until 8-15-2027; it will then be open access.