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

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.

A Multifunctional Therapeutic Strategy Using P7C3 as A Countermeasure Against Bone Loss and Fragility in An Ovariectomized Rat Model of Postmenopausal Osteoporosis

“…The safety of this dose is supported by unpublished data where a range of doses were investigated, and a similar result was also obtained in our previous study. [ 67 ] P7C3‐induced alterations within the cytoskeletal morphology of hBMSCs was assessed via phalloidin and DAPI staining (Figure 2B ). On days 3 and 5, hBMSCs treated with 10 µM of P7C3 showed a similar morphology and actin filament content compared to the control group, indicating that 10 µM of P7C3 did not modify hBMSC cytoskeletal morphology.…”

Sphingolipid-Induced Bone Regulation and Its Emerging Role in Dysfunction Due to Disease and Infection

“…To this end, an increase in bone marrow adiposity has been observed in most bone loss conditions, including aging [ 55 , 70 ], osteoarthritis [ 71 , 72 ], obesity [ 73 ], osteomyelitis [ 74 ], and various other pathological conditions [ 55 , 75 , 76 , 77 ]. Further, adipokines contribute to the progression of chronic inflammation [ 78 ], which is also a key cause of multiple pathological bone loss conditions [ 79 , 80 , 81 , 82 , 83 ]. Together, this is of high significance, as our aging population and obesity continue to rise globally.…”