Molecular Mechanism Underlying the Action of a Celastrol-Loaded Layered Double Hydroxide-Coated Magnesium Alloy in Osteosarcoma Inhibition and Bone Regeneration

Abstract

Osteosarcoma (OS) is a malignant bone tumor that threatens human health. Surgical removal of the tumor and followed by implantation with a graft is the golden standard for its clinical treatment. However, avoiding recurrence by enhancing the antitumor properties of the implants and improving osteogenesis around the implants remain a challenge. Here, we developed a layered double hydroxide (LDH)-coated magnesium (Mg) alloy and loaded it with celastrol. The celastrol-loaded Mg alloy exhibited enhanced corrosion resistance and sustained release of celastrol. In vitro cell culture suggested that the modified Mg alloy loaded with an appropriate amount of celastrol significantly inhibited the proliferation and migration of bone tumor cells while having little influence on normal cells. A mechanistic study revealed that the celastrol-loaded Mg alloy upregulated reactive oxygen species (ROS) generation in bone tumor cells, resulting in mitochondrial dysfunction due to reduced membrane potential, thereby inducing bone tumor cell apoptosis. Furthermore, it was found that celastrol-induced autophagy in tumor cells inhibited cell apoptosis in the initial 6 h. After ≥12 h of culture, inhibition of the PI3K-Akt-mTOR signaling pathway was noted, resulting in excessive autophagy in tumor cells, finally causing cell apoptosis. The celatsrol-loaded Mg alloy also exhibited effective antitumor properties in a subcutaneous tumor model. In vitro tartrate-resistant acid phosphatase (TRAP) staining and gene expression results revealed that the modified Mg alloy reduced the viability of osteoclasts, inducing a potential pathway for the increased bone regeneration around the modified Mg alloy seen in vivo. Together, the results of our study show that the celatsrol-loaded Mg alloy might be a promising implant for treating OS.

Current approaches in tissue engineering-based nanotherapeutics for osteosarcoma treatment

“…The tumor cell apoptosis and inhibition of the PI3K-Akt-mTOR signaling pathway resulted in excessive autophagy in tumor cells. Also, the study revealed the osteoinductive properties in in vivo and in vitro models [131]. The phosphonatemodified methacrylamide chitosan and polyacrylamide hydrogel with magnesium oxide NPs and 2-Aminoethyl methacrylate grafted polydopamine suppressed tumor recurrence in human OS cells (143B).…”

Mg alloys with antitumor and anticorrosion properties for orthopedic oncology: A review from mechanisms to application strategies

“…Moreover, the developed Mg alloy exhibited a strong inhibitory effect on cancer cells because of the sustained release of celastrol while exerting little negative effects on healthy cells. 160 Li et al prepared a bisphosphonate (BP)-loaded MAO layer on the Mg–Sr alloy pellet (denoted as BP-coated Mg) through immersing the MAO treated Mg alloy in the zoledronic acid (ZA) solution. The in vitro experiments verified that the prepared BP-coated Mg could promote the apoptosis and necrosis of OCs as well as prevent their invasion.…”