Anti-tumor Effects of Cyclolinopeptide on Giant-cell Tumor of the Bone

Abstract

Aim: This study aimed to evaluate the antitumor effects of cyclolinopeptide (CL), which suppresses receptor activator of nuclear factor-ĸB ligand (RANKL) signalling on giant-cell tumours of the bone (GCTB) cells. Materials and Methods: GCTB cell lines were established, and the inhibition of cell growth by CL was evaluated using the water-soluble tetrazolium salt-8 cell proliferation assay, cell cycle assay, and 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay. RANKL and runt-related transcription factor 2 (RUNX2) expression levels were evaluated using real-time polymerase chain reaction before and after CL administration. Results: The dose-dependent inhibition of GCTB cells was significantly pronounced in the CL-administered group compared to the non-CL-administered group (p<0.05). In the CL-administered group, the ratio of cells in the G 0 /G 1 phase was increased, but the ratio of EdU-positive cells was decreased (p<0.05). RANKL and RUNX2 levels were decreased in the CLadministered group (p<0.05). Conclusion: CL has antitumor effects on GCTB in vitro.The incidence of giant-cell tumor of the bone (GCTB), which is classified as an intermediate malignancy in the 2013 WHO classification of tumors (1), is 4%-5% of the total cases of bone tumors (2-5). Approximately 2% of GCTB cases result in lung metastasis, which is fatal in some instances (6, 7). Curettage along with adjuvant therapy is the most common treatment method used for this tumor; nonetheless, the local recurrence rate is high, at approximately 15%-50%. Although the en bloc resection of the tumor can reduce the recurrence rate, loss of function due to resection is a major issue. Furthermore, it is difficult to perform the radical resection of tumors in anatomically difficult locations, such as the spine or pelvis, because an appropriate surgical margin cannot be secured (1).GCTB is composed of two kinds of cells: osteoclast-like giant cells or its precursor expressing receptor activator of nuclear factor-ĸB (RANK) and receptor activator of nuclear factor-ĸB ligand (RANKL) (8). Mesenchymal stromal cells are thought to have proliferative abilities and are important for tumour growth (1).Giant cells are induced by RANKL produced by proliferating stromal cells and cause bone absorption (8, 9). Furthermore, stromal cells express osteoblast markers such as alkaline phosphatase and runt-related transcription factor 2 (RUNX2) (10).Flax (scientific name: Linum usitatissimum) is an annual grass of Linaceae that has originated in Central Asia and is cultivated all over the world. The dried mature seed is called linseed (flaxseed). Linseed oil, which is obtained by compressing or crushing seeds and extracting them with a solvent, is rich in unsaturated fatty acids, such as α-linolenic acid (a ω-3 fatty acid) (11-13). Linseed oil is sold as food or a supplement. Cyclolinopeptide A (CL-A), which is a cyclic peptide extracted from linseed, was first introduced in 1959 by Kaufmann et al. (14). Several studies have reported the cytoprotective and immunosuppressive...

The Anti-Cancer Effect of Linusorb B3 from Flaxseed Oil through the Promotion of Apoptosis, Inhibition of Actin Polymerization, and Suppression of Src Activity in Glioblastoma Cells

“…Furthermore, cytotoxicity of this compound was not found in non-malignant cells, peritoneal macrophages ( Figure 1H). Similarly, other natural bioactive orbitides such as surfactins and beauvericin displayed anti-cancer activity in giant-cell tumors of the bone (GCTB) cells, MCF-7 breast tumor cells, and CT-26 lymphoma [38][39][40], implying that cytotoxic activity of LOB3 might be due to structural feature of this compound. Taken together, these results suggest that LOB3 plays an anti-cancer role by inducing cytotoxicity and reducing the proliferation of cancer cells).…”

Effects of Modifications on the Immunosuppressive Properties of Cyclolinopeptide A and its Analogs in Animal Experimental Models

“…Such property could be of advantage in delaying progress of osteoporosis. In addition, CLA was shown to inhibit growth of bone giant cell tumor by arresting cells in G0/G1 phase of cell cycle [23]. Of interest, our data from an investigation on 13-week toxicity in rats (unpublished) revealed that CLA lowered serum cholesterol level, albeit only in females.…”

Effects of Modifications on the Immunosuppressive Properties of Cyclolinopeptide A and Its Analogs in Animal Experimental Models

“…The immunosuppressive actions of CLA and some of its analogs are presented in Table 1. cyclolinopeptide A suppression of: graft-versus-host reaction, allogeneic graft rejection, post-adjuvant polyarthritis, humoral and cellular immune response and reduction of hemolytic anemia in New Zealand Black mice [4] cyclolinopeptide A inhibition of human Plasmodium falciparum growth in culture [21] cyclolinopeptide A inhibition of osteoclast differentiation [22] cyclolinopeptide A inhibition of bone giant cell tumor growth [23] H…”

“…Such property could be of advantage in delaying progress of osteoporosis. In addition, CLA was shown to inhibit growth of bone giant cell tumor by arresting cells in G0/G1 phase of cell cycle [ 23 ]. Interestingly, our data from an investigation on 13-week toxicity in rats (unpublished) revealed that CLA lowered serum cholesterol level, albeit only in females.…”