Falcarindiol Stimulates Apoptotic and Autophagic Cell Death to Attenuate Cell Proliferation, Cell Division, and Metastasis through the PI3K/AKT/mTOR/p70S6K Pathway in Human Oral Squamous Cell Carcinomas.

Human oral squamous cell carcinomas (OSCCs) have high cancer mortality and a 5-year survival rate lower than that of most other carcinomas. New therapeutic strategies are required for the treatment and prevention against OSCCs. An approach to cancer therapy using plant-derived natural compounds has been actively in progress as a trend. Falcarindiol (FALC), or its isolated form Ostericum koreanum Kitagawa (O. koreanum), is present in many food and dietary plants, especially in carrots, and this compound has a variety of beneficial effects. However, biological activity of FALC has not been reported in OSCCs yet. This study aimed to demonstrate the antitumor effects of FALC against OSCCs, YD-10B cells. In this study, FALC was selected as a result of screening for compounds isolated from various natural products in YD-10B cells. FALC suppressed cell growth, and FALC-induced apoptotic cell death was mainly accompanied by the dephosphorylation of PI3K, AKT, mTOR, and p70S6K. The apoptotic cell death was also associated with autophagy as evidenced by the expression of Beclin-1, the conversion of LC3-II, and the formation of autophagosome. FALC-induced autophagy was accompanied by MAPKs including ERK1/2 and p38. Furthermore, FALC caused the antimetastatic effects by inhibiting the migration and invasion of YD-10B cells. Taken together, the findings suggest the potential value of FALC as a novel candidate for therapeutic strategy against OSCCs.

Anti-cancer effects of Hederoside C, a pentacyclic triterpene saponin, through the intrinsic apoptosis and STAT3 signaling pathways in osteosarcoma.

Natural compounds have emerged as an approach in cancer therapy. Pulsatilla koreana Nakai is used as a traditional medicinal plant that found throughout China and Korea. However, anti-cancer effects of Hederoside C (HedC) isolated from P. koreana has not been investigated in osteosarcoma. The present study aimed to demonstrate anti-cancer functions of HedC against human osteosarcoma cells. Herein, we found that HedC suppressed the proliferation of MG63 cells and U2OS cells in the dose- and time-dependent manner, and caused intrinsic apoptosis pathways as evidenced by morphological changes, TUNEL-positive cells, cleaved-PARP, and cleaved-caspase 9 and 3. HedC increased p53, Bax, and p21, whereas HedC reduced Bcl-2. HedC-mediated apoptosis was accompanied by decreases in the mitogen-activated protein kinases (MAPKs) and STAT3 phosphorylation. Wound healing and Boyden chamber assays also showed the anti-metastatic effects of HedC by suppressing migration and invasion. In addition, the anti-cancer effects of HedC were observed in in vivo xenograft mice model, and HedC treatment induced the decreased PCNA and p-STAT3 as well as the increased p53 and cleaved caspase-3. Taken together, our results provide evidence that HedC might be an attractive therapeutic strategy against osteosarcoma.

Effects of the amide alkaloid piperyline on apoptosis, autophagy, and differentiation of pre-osteoblasts.

BACKGROUND: Amide alkaloidsare typical constituents in plants of the Piperaceae family. Most of the pharmacological properties of Piper nigrum L. are attributed to the major amide alkaloid, piperine. Piperyline (PIPE) is a further amide alkaloid that has been isolated from P. nigrum. HYPOTHESIS/PURPOSE: This study was performed to examine the biological effects of PIPE on pre-osteoblasts and elucidate the underlying mechanisms. STUDY DESIGN: We investigated the effects of PIPE in MC3T3E-1 cells, which are widely used for studying osteoblast behavior in in vitro cell systems. METHODS: We evaluated cell viability based on the MTT assay, apoptosis by TUNEL staining, adhesion and migration by cell adhesion and migration assays, and osteoblast differentiation by alkaline phosphatase activity and staining. Western blot and immunocytochemical analyses were used to investigate cell signaling pathways. RESULTS: We found that at concentrations ranging from 1 to 30 µM, PIPE inhibited cell growth and induced apoptosis in pre-osteoblasts, which was accompanied by the upregulation of apoptotic proteins but downregulation of anti-apoptotic proteins. In contrast, PIPE had no appreciable effect on the autophagy pathway. Nevertheless, PIPE reduced cell adhesion and migration via the inactivation of non-receptor tyrosine kinase (Src)/focal adhesion kinase (FAK) and mitogen-activated protein kinases, and also promoted the downregulation of matrix metalloproteinase 2 and 9 levels. Furthermore, at concentrations of 10 and 30 µM, PIPE suppressed osteoblast differentiation, as indicated by reductions in alkaline phosphatase staining and activity. In addition, PIPE reduced the protein levels of phospho-Smad1/5/8 and runt-related transcription factor 2, and the mRNA levels of osteopontin, alkaline phosphatase, and osteocalcin. CONCLUSION: The findings of this study indicate that PIPE has biological effects associated with cell adhesion, migration, proliferation, and osteoblast differentiation, and suggest a potential role for this alkaloid in the treatment of bone diseases.