Abstract
Doxorubicin (Dox)-induced cardiotoxicity, a limiting factor in the use of Dox to treat cancer, can be mitigated by the mitogenic factor FGF2 in vitro, via a heme oxygenase 1 (HO-1)-dependent pathway. HO-1 upregulation was reported to require protein kinase CK2 activity. We show that a mutant non-mitogenic FGF2 (S117A-FGF2), which does not activate CK2, is cardioprotective against acute cardiac ischemic injury. We now investigate the potential of S117A-FGF2 to protect cardiomyocytes against acute Dox injury and decrease Dox-induced upregulation of oxidized phospholipids. The roles of CK2 and HO-1 in cardiomyocyte protection are also addressed.Rat neonatal cardiomyocyte cultures were used as an established in vitro model of acute Dox toxicity. Pretreatment with S117A-FGF2 protected against Dox-induced: oxidative stress; upregulation of fragmented and non-fragmented oxidized phosphatidylcholine species, measured by LC/MS/MS; and cardiomyocyte injury and cell death measured by LDH release and a live-dead assay. CK2 inhibitors (TBB and Ellagic acid), did not affect protection by S117A-FGF2 but prevented protection by mitogenic FGF2. Furthermore, protection by S117A-FGF2, unlike that of FGF2, was not prevented by HO-1 inhibitors and S117A-FGF2 did not upregulate HO-1. Protection by S117A-FGF2 required the activity of FGF receptor 1 and ERK.We conclude that mitogenic and non-mitogenic FGF2 protect from acute Dox toxicity by common (FGFR1) and distinct, CK2/HO-1- dependent or CK2/HO-1-independent (respectively), pathways. Non-mitogenic FGF2 merits further consideration as a preventative treatment against Dox cardiotoxicity.
Highlights
Doxorubicin (Dox) is a chemotherapy drug that is widely used to treat many types of malignancies including breast cancer, lymphoma and acute lymphoblastic leukemia in patients of all ages; cardiotoxicity that can manifest acutely, sub-acutely, or late-onset has posed limitation to the use of Dox (Zamorano et al 2016)
We recently reported that primary cultures of neonatal rat cardiomyocytes, referred to as cardiomyocytes on, represent a good in vitro model to study multiple aspects of acute Dox-induced toxicity (Koleini et al 2017)
Using an MTT assay as an estimate of cell number, we found that S117A-Fibroblast growth factor 2 (FGF2) had no effect on proliferation, unlike FGF2 that elicited a small but statistically significant increase in cell number (Fig. S1)
Summary
Doxorubicin (Dox) is a chemotherapy drug that is widely used to treat many types of malignancies including breast cancer, lymphoma and acute lymphoblastic leukemia in patients of all ages; cardiotoxicity that can manifest acutely, sub-acutely, or late-onset has posed limitation to the use of Dox (Zamorano et al 2016). Dox cardiotoxicity is attributed to elevated oxidative stress, DNA and mitochondrial damage and deleterious changes in gene expression, culminating in the dysregulation of multiple signal transduction pathways leading to cardiac cell death (Koleini and Kardami 2017). We have recently published that FGF2 protects neonatal rat cardiomyocytes against acute Dox-induced damage and cell death by a mammalian target of rapamycin/nuclear factor (erythroid-derived 2)-like (Nrf2)/heme oxygenase−1 (HO-1)-dependent pathway in vitro (Koleini et al 2017). Previous studies have demonstrated that a mutated form of FGF2, carrying a serineto-alanine (S117A) substitution (S117A-FGF2) retains acute cardioprotective potential against cardiac ischemic injury but lacks mitogenic and angiogenic activity (Bailly et al 2000; Jiang et al 2002; Jiang et al 2004). It is postulated that if the S117A-FGF2 retains cardioprotective properties against Doxinduced cardiomyocyte oxidative stress and injury/death, it would merit further consideration as a prophylactic treatment against Dox
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
