Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: an in vitro and in vivo study

Abstract

Osteosarcoma is the most common primary malignant tumor of bone, the long-term survival of which has stagnated in the past several decades. Celastrol, a triterpene from traditional Chinese medicine, has been proved to possess potent anti-tumor effect on various cancers. However, the effect of celastrol on human osteosarcoma and the underlying mechanisms remains to be elucidated. We reported here that celastrol could inhibit cell proliferation by causing G2/M phase arrest. Exposure to celastrol resulted in the activation of caspase-3, -8, and -9, indicating that celastrol induced apoptosis through both extrinsic and intrinsic pathways. Autophagy occurred in celastrol-treated cells as evidenced by formation of autophagosome and accumulation of LC3B-II. The celastrol-induced cell death was remarkably restored by the combination of autophagy and apoptosis inhibitors. Furthermore, inhibition of apoptosis enhanced autophagy while suppression of autophagy diminished apoptosis. Celastrol also induced JNK activation and ROS generation. The JNK inhibitor significantly attenuated celastrol-triggered apoptosis and autophagy while ROS scavenger could completely reverse them. The ROS scavenger also prevented G2/M phase arrest and phosphorylation of JNK. Importantly, we found that celastrol had the similar effects on primary osteosarcoma cells. Finally, in vivo, celastrol suppressed tumor growth in the mouse xenograft model. Taken together, our results revealed that celastrol caused G2/M phase arrest, induced apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells. Celastrol is therefore a promising candidate for development of antitumor drugs targeting osteosarcoma.

Andrographolide inhibits proliferation and induces cell cycle arrest and apoptosis in human melanoma cells

“…Many studies have highlighted that induction of cell cycle arrest especially G2/M cycle phase may be an effective anticancer therapy (9,26). Many anticancer agents inhibit tumor cell proliferation by causing G2/M cycle arrest, such as celastrol (27), ophiopogonin D (26). The G2 checkpoint regulats cell caryomitosis when DNA is destroyed, which provides repair opportunities for damaged cells (28,29).…”

Celastrol inhibits migration and invasion through blocking the NF-κB pathway in ovarian cancer cells

“…Cell growth was measured by MTT assay (24). Briefly, OVCAR-3 and SKOV-3 cells (5x10 3 cells/well) were cultured with serially diluted celastrol (0.125, 0.25, 0.5, 1 and 2 µM) in 96-well plates.…”

Fisetin, a dietary flavonoid induces apoptosis via modulating the MAPK and PI3K/Akt signalling pathways in human osteosarcoma (U-2 OS) cells

“…Studies have demonstrated anti-cancer effects of various phytochemicals (Lin et al, 2011;Li et al, 2014Li et al, , 2015Zhao et al, 2015). Recent research have reported anti-proliferative (Chen et al, 2002;Haddad et al, 2006) and anti-metastasic effects (Chou et al, 2013) of fisetin, a polyphenolic flavonoid present in many fruits such as strawberries and cucumbers (Kim et al, 2012).…”