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Original Article | Open Access

A novel multifunctional radioprotective strategy using P7C3 as a countermeasure against ionizing radiation-induced bone loss

Fei Wei1, Zewen Kelvin Tuong2,3, Mahmoud Omer1, Christopher Ngo1, Jackson Asiatico4, Michael Kinzel4, Abinaya Sindu Pugazhendhi1, Annette R. Khaled5, Ranajay Ghosh4, Melanie Coathup1( )
Biionix Cluster, and Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, USA
Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK
Department of Mechanical and Aerospace Engineering, University of Central Florida, Orlando, FL, USA
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA
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Abstract

Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone. Presently, no effective countermeasure exists, and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity. The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy. Our studies revealed that P7C3 repressed ionizing radiation (IR)-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition in vitro. We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened, osteoporotic bone. However, the administration of P7C3 significantly inhibited osteoclastic activity, lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area, architecture, and mechanical strength. Our findings revealed significant enhancement of cellular macromolecule metabolic processes, myeloid cell differentiation, and the proteins LRP-4, TAGLN, ILK, and Tollip, with downregulation of GDF-3, SH2B1, and CD200. These proteins are key in favoring osteoblast over adipogenic progenitor differentiation, cell matrix interactions, and shape and motility, facilitating inflammatory resolution, and suppressing osteoclastogenesis, potentially via Wnt/β-catenin signaling. A concern was whether P7C3 afforded similar protection to cancer cells. Preliminarily, and remarkably, at the same protective P7C3 dose, a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro. Together, these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy, leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications. Our data uncover a new approach for the prevention of radiation-induced bone damage, and further work is needed to investigate its ability to selectively drive cancer cell death.

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Bone Research
Volume 11,
December 2023
Article number: 34
DOI: 10.1038/s41413-023-00273-w
Cite this article:
Wei F, Tuong ZK, Omer M, et al. A novel multifunctional radioprotective strategy using P7C3 as a countermeasure against ionizing radiation-induced bone loss. Bone Research, 2023, 11: 34. https://doi.org/10.1038/s41413-023-00273-w

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Received: 03 January 2023
Revised: 16 May 2023
Accepted: 28 May 2023
Published: 29 June 2023
© The Author(s) 2023

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