Combination of Melatonin and Zoledronic Acid Suppressed the Giant Cell Tumor of Bone in vitro and in vivo

Abstract

Melatonin (Mlt) confers potential antitumor effects in various types of cancer. However, to the best of our knowledge, the role of Mlt in the giant cell tumor of bone (GCTB) remains unknown. Moreover, further research is required to assess whether Mlt can enhance the therapeutic effect of zoledronic acid (Zol), a commonly used anti-GCTB drug. In this research, we investigated the effects of Mlt, Zol, and the combination of these two drugs on GCTB cells’ characteristics, including cell proliferation, apoptosis, osteogenic differentiation, migration, and invasion. The cell counting kit-8 (CCK-8) assay, colony formation assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay (TUNEL), alkaline phosphatase (ALP) staining, alizarin red staining (ARS), scratch wound healing assay, and transwell experiment were performed, respectively. Our results showed that Mlt could effectively inhibit the proliferation, migration, and invasion of GCTB cells, as well as promote the apoptosis and osteogenic differentiation of tumor cells. Of note, a stronger antitumor effect was observed when Mlt was combined with Zol treatment. This therapeutic effect might be achieved by inhibiting the activation of both the Hippo and NF-κB pathways. In conclusion, our study suggests that Mlt can be a new treatment for GCTB, which could further enhance the antitumor effect of Zol.

Denosumab induction and Zoledronic acid maintenance therapy for recurrent unresectable giant cell tumour of the distal tibia: A case report with sustained tumour control after drug withdrawal

“…In difficult-to-treat GCTBs conservative approaches have been conceptualized on the basis of breaking the vicious cycle established at the TME level in GCTB [5] , [12] . BPs like ZA are, besides their osteoclast inhibitory effects, believed to impair tumour growth by targeting both cellular components, MNGCs, and mutated H3F3A G34W + cells [18] , [19] , [20] , [21] , [22] , [23] , while RANKL inhibitors suppress only the osteoclastogenesis with limited direct effects on tumour cells [3] , [22] , [24] .…”

“…In different in-vitro and animal studies, it was demonstrated that nitrogen-containing BPs did cause substantial apoptotic effect in GCTB stromal cells [25] , [26] , [29] . This effect can be enhanced by melatonin, which acts synergistically with ZA [23] . Using flow cytometry following fluorescent Annexin-V labeling, it was observed that statistically significant increase of tumour cell apoptosis in GCTB primary cultures started at 30 µM of ZA or PAM with maximal effects at 150 µM [29] .…”

“…In different in-vitro and animal studies, it was shown that ZA induced neoplastic stromal cell osteogenic differentiation, which was associated with transcriptional activation of RUNX2, osterix (Sp7 transcription factor) and osteocalcin genes [30] . Wang et al explored the effects of different melatonin and ZA concentrations on the mRNA and protein expression of osteogenesis markers (OPN, OCN, RUNX2 and ALP) in GCTB cells and found that different concentrations of either melatonin or ZA promoted the mRNA expression of osteogenesis markers, and the effect of a higher concentration was more obvious [23] .…”