Objective The negative effects of incidental radiation on the heart and its vessels, particularly in the treatment of locally advanced non-small cell lung cancer, esophageal cancer, left-sided breast cancer, and lymphoma, are known. Late cardiac events induced by radiotherapy including coronary artery disease, ischemia, congestive heart failure, and myocardial infarction can manifest months to years after radiotherapy. We have previously demonstrated that soy isoflavones mitigate inflammatory responses induced in lungs by thoracic irradiation resulting in decreased vascular damage, inflammation, and fibrosis. In the current study, we investigate the use of soy isoflavones to protect cardiac vessels and myocardium from radiation injury. Methods Mice received a single dose of 10-Gy thoracic irradiation and daily oral treatment with soy isoflavones. At different time points, hearts were processed for histopathology studies to evaluate the effect of soy isoflavones on radiation-induced damage to cardiac vessels and myocardium. Results Radiation damage to arteries and myocardium was detected by 16 weeks after radiation. Soy isoflavones given in conjunction with thoracic irradiation were found to reduce damage to the artery walls and radiation-induced fibrosis in the myocardium. Conclusion Our histopathological findings suggest a radioprotective role of soy isoflavones to prevent cardiac injury. This approach could translate to the use of soy isoflavones as a safe complement to thoracic radiotherapy with the goal of improving the overall survival in patients whose cancer has been successfully controlled by the radiotherapy but who otherwise succumb to heart toxicity.
Malignant melanoma is characterized by mutations in a number of driver genes, most notably BRAF and NRAS. Recently, genomic analyses revealed that 4-9% of sun-exposed melanoma bear activating mutations in RAC1, which encodes a small GTPase that is known to play key roles in cell proliferation, survival, and migration. The RAC1 protein activates several effector pathways, including Group A p21-activated kinases (PAKs), phosphoinositol-3-kinases (PI3Ks), in particular the beta isoform, and the serum-response factor/myocardin-related transcription factor (SRF/MRTF). Having previously shown that inhibition of Group A PAKs impedes oncogenic signaling from RAC1 P29S , we here extend this analysis to examine the roles of PI3Ks and SRF/MITF in melanocytes and/or in a zebrafish model. We demonstrate that a selective Group A PAK inhibitor (Frax-1036) and certain PI3Ks inhibitors (BKM120, TGX221, GSK2636771) impede the growth of melanoma cells driven by mutant RAC1 but not mutant BRAF, however other PI3K inhibitors, including PI3Kα-selective inhibitors are less effective. Similar results were seen in vivo, using embryonic zebrafish development as a readout, but now including an SRF/MRTF inhibitor (CCG-203971). These results suggest that targeting Group A PAKs and/or SRF/MRTF represent promising approach to suppress RAC1 signaling in malignant melanoma.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.