Coleusin Factor, a Novel Anticancer Diterpenoid, Inhibits Osteosarcoma Growth by Inducing Bone Morphogenetic Protein-2–Dependent Differentiation

Abstract

Coleusin factor is a diterpenoid compound isolated from the root of a tropical plant, Coleus forskohlii. Although Coleusin factor has been reported to suppress proliferation of and induce apoptosis in several types of cancer cells, the effects of Coleusin factor on osteosarcoma and the underlying mechanism are still not fully understood. In this study, we show that Coleusin factor treatment potently inhibits the growth of osteosarcoma cells associated with G 1 cell-cycle arrest. Interestingly, apoptosis and cell death are not induced. Instead, Coleusin factor causes osteosarcoma cells to exhibit typical properties of differentiated osteoblasts, including a morphologic alteration resembling osteoblasts, the expression of osteoblast differentiation markers, elevated alkaline phosphatase activity, and increased cellular mineralization. Coleusin factor treatment significantly increases the expression of bone morphogenetic protein-2 (BMP-2), a crucial osteogenic regulator, and runt-related transcription factor 2 (RUNX2), one of the key transcription factors of the BMP pathway. When BMP-2 signaling is blocked, Coleusin factor fails to inhibit cell proliferation and to induce osteoblast differentiation. Thus, upregulation of BMP-2 autocrine is critical for Coleusin factor to induce osteoblast differentiation and exert its anticancer effects on osteosarcoma. Importantly, administration of Coleusin factor inhibits the growth of osteosarcoma xenografted in nude mice without systemic or immunologic toxicity. Osteosarcoma is a highly aggressive cancer marked by the loss of normal differentiation. Coleusin factor represents a new type of BMP-2 inducer that restores differentiation in osteosarcoma cells. It may provide a promising therapeutic strategy against osteosarcoma with minimal side effects. Mol Cancer Ther; 13(6);

Development of a Model System to Evaluate Local Recurrence in Osteosarcoma and Assessment of the Effects of Bone Morphogenetic Protein-2

“…Geng and colleagues have shown Coleusin factor to inhibit osteosarcoma proliferation via BMP-2 upregulation and subsequent osteoblastic differentiation. The authors further demonstrated reversal of this effect with the addition of noggin, a BMP-2 inhibitor (27). Other investigators have reported that rhBMP both mitigates tumor growth and increases tumor predilection for apoptosis (28,29).…”

Glaucocalyxin A inhibits the growth of liver cancer Focus and SMMC-7721 cells

“…The ent-kaurene diterpenoid ent-16β-17α-dihydroxykaurane triggered apoptosis of MCF-7 cells by a decrease in telomerase mRNA (24). Oridonin, ponicidin, xindongnin A and xindoninin have been demonstrated to be potent inhibitors of NF-κB transcription activity (25). To investigate the possible mechanism for the anti-proliferative ability of GLA, the present study examined the DNA content of liver cancer cells by FCM.…”

The effect of bone morphogenetic protein-2 on osteosarcoma metastasis

“…In addition, the researchers were able to reverse this effect with the addition of a BMP-2 inhibitor, noggin. [20] Other investigators have found that BMP reduces tumor growth and increases the tendency for osteosarcoma to undergo apoptosis. [21] These studies suggest that normal BMP-2 acts as an osteosarcoma inhibitor and may drive differentiation, apoptosis, or both.…”