Tanshinone IIA induces intrinsic apoptosis in osteosarcoma cells both in vivo and in vitro associated with mitochondrial dysfunction

Tanshinone IIA (Tan IIA), a phytochemical derived from the roots of Salvia miltiorrhiza, has been shown to inhibit growth and induce apoptosis in various cancer cells. The association of its inhibitory effect on the primary malignant bone tumor, osteosarcoma, with mitochondrial dysfunction remains unclear. This study aimed to investigate the anti-proliferative effects of Tan IIA on human osteosarcoma 143B cells both in vitro and in vivo. Administration of Tan IIA to NOD-SCID mice implanted with 143B cells led to significant inhibition of tumor development. The inhibition of proliferation, migration, and invasion was observed in 143B cells treated with Tan IIA. The tumor proliferation markers, Ki67 and PCNA, were suppressed and apoptosis by TUNEL assay was activated respectively. Apoptosis in the Tan IIA-treated 143B cells and xerograft mice was associated with the activation of caspase cascade via the modulation of Bcl-2 family. The CD31 was inhibited in Tan IIA-treated xenografts to indicate anti-neovasculization. Tan IIA administration resulted in a significant decrease in the mitochondrial fusion proteins, Mfn1/2 and Opa1, as well as an increase in the fission protein Drp1. We concluded that mitochondrial dysfunction associated with dynamic change was involved in apoptosis and anti-angiogenesis elicited by Tan IIA.