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Epirubicin is an anthracycline and is widely used in tumor treatment, but has toxic and undesirable side effects on wide range of cells and hematopoietic stem cells (HSC). Osteoblasts play important roles in bone development and in supporting HSC differentiation and maturation. It remains unknown whether epirubicin-induced bone loss and hematological toxicity are associated with its effect on osteoblasts. In primary osteoblast cell cultures, epirubicin inhibited cell growth and decreased mineralization. Moreover, epirubicin arrested osteoblasts in the G2/M phase, and this arrest was followed by apoptosis in which both the extrinsic (death receptor-mediated) and intrinsic (mitochondrial-mediated) apoptotic pathways were evoked. The factors involved in the extrinsic apoptotic pathway were increased FasL and FADD as well as activated caspase-8. Those involved in the intrinsic apoptotic pathway were decreased Bcl-2; increased reactive oxygen species, Bax, cytochrome c; and activated caspase-9 and caspase-3. These results demonstrate that epirubicin induced osteoblast apoptosis through the extrinsic and intrinsic apoptotic pathways, leading to the destruction of osteoblasts and consequent lessening of their functions in maintaining bone density and supporting hematopoietic stem cell differentiation and maturation.

Osteoarthritis (OA) is a common chronic disease with increasing prevalence in societies with more aging populations, therefore, it is causing more concern. S-Equol, a kind of isoflavones, was reported to be bioavailable and beneficial to humans in many aspects, such as improving menopausal symptoms, osteoporosis and prevention of cardiovascular disease. This study investigated the effects of S-Equol on OA progress in which rat primary chondrocytes were treated with sodium nitroprusside (SNP) to mimic OA progress with or without the co-addition of S-Equol for the evaluation of S-Equol’s efficacy on OA. Results showed treatment of 0.8 mM SNP caused cell death, and increased oxidative stress (NO and H2O2), apoptosis, and proteoglycan loss. Furthermore, the expressions of MMPs of MMP-2, MMP-3, MMP-9, and MMP-13 and p53 were increased. The addition of 30 μM S-Equol could lessen those caused by SNP. Moreover, S-Equol activates the PI3K/Akt pathway, which is an upstream regulation of p53 and NO production and is associated with apoptosis and matrix degradation. As a pretreatment of phosphoinositide 3-kinases (PI3K) inhibitor, all S-Equol protective functions against SNP decrease or disappear. In conclusion, through PI3K/Akt activation, S-Equol can protect chondrocytes against SNP-induced matrix degradation and apoptosis, which are commonly found in OA, suggesting S-Equol is a potential for OA prevention.

Arsenic trioxide is used to treat a variety of leukaemia types and causes tumour cell death. However, it is not well known whether arsenic trioxide is toxic to bone osteoblast cells, the precursor cells from which leukaemia cells originate. The aim of this study was to examine the response of osteosarcoma cell line MG63 and primary cultured osteoblasts to arsenic trioxide treatment. After 24h of treatment, arsenic trioxide was more effective at inhibiting cell growth and increasing oxidative stress and DNA damage in MG63 cells than in osteoblasts. In addition, arsenic trioxide arrested cell cycle progression in the G2/M phase, and induced apoptosis in MG63 cells, but not in primary cultured osteoblasts. The results further showed that the expression of transcription factor Nrf2 and its downstream antioxidant effectors, including hemeoxygenase-1, glutathione, and superoxide dismutase, was increased in primary cultured osteoblasts. Additionally, expression of heat shock proteins was also increased. Experiments using inhibitors of antioxidant enzymes in the presence of arsenic trioxide-treated osteoblasts demonstrated that glutathione and superoxide dismutase were responsible for reducing oxidative stress, caspase-3 activity, and apoptosis and that heat shock proteins helped reduce caspase-3 activity. Unexpectedly, there was no apparent effect of the markedly increased hemeoxygenase-1, suggesting that other functions might exist for hemeoxygenase-1. These findings demonstrate that osteosarcoma cells are more sensitive to arsenic trioxide treatment than primary cultured osteoblasts and that primary cultured osteoblasts activate the Nrf2 signalling pathway in response to arsenic trioxide exposure to escape from oxidative damage and apoptosis.

Osteoarthritis (OA) is the most prevalent joint disease. Dietary intake of vitamin C relates to a reduction in cartilage loss and OA. This study examined the efficacy of vitamin C to prevent OA with the in vitro chondrosarcoma cell line (SW1353) and the in vivo monosodium iodoacetate (MIA)-induced OA rat. Results demonstrated that, in SW1353 cells, treatment with 5 μM MIA inhibited cell growth and increased oxidative stress, apoptosis, and proteoglycan loss. In addition, the expression levels of the pro-inflammatory cytokines IL-6, IL-17A, and TNF-α and matrix metalloproteinases (MMPs) MMP-1, MMP-3, and MMP-13 were increased. All of these MIA-induced changes could be prevented with treatment of 100 μM vitamin C. In an animal model, intra-articular injection of MIA-induced cartilage degradation resembled the pathological changes of OA, and treatment of vitamin C could lessen these changes. Unexpectedly, vitamin C’s effects did not strengthen with the increasing dosage, while the 100 mg/kg dosage was more efficient than the 200 or 300 mg/kg dosages. Vitamin C possessed multiple capacities for prevention of OA progress, including a decrease in apoptosis and in the expression of pro-inflammatory cytokines and MMPs in addition to the well-known antioxidation.

Tanshinone IIA is a widely used Chinese herbal medicine isolated from Danshen (Salvia miltiorrhiza). Recent studies indicate that tanshinone IIA may have anti-inflammatory and anti-oxidant properties, as well as cytotoxic activities against multiple human cancer cell lines. This study was performed to determine the anti-cancer activity of tanshinone IIA on human breast cancer cells in vitro and in vivo and to elucidate the underlying mechanism of this activity. Human breast cancer cell lines (estrogen receptor-positive and -negative) were treated with tanshinone IIA and tamoxifen. The inhibitory effects of tanshinone IIA and tamoxifen on breast cancer cell proliferation were examined using MTT assays, BrdU incorporation, immunohistochemistry and flow cytometry. Upon treatment with tanshinone IIA, breast cancer cell proliferation was significantly inhibited in a dose- and time-dependent manner (IC50 = 0.25 microg/ml) and apoptotic cell populations increased, while tamoxifen inhibited only ER-positive breast cancer cells prominently and had no effect on ER-negative cells. In addition, tamoxifen had significantly weaker inhibitory effect than tanshinone IIA on ER-positive breast cancer cells in vitro and in vivo. Furthermore, tanshinone IIA decreased the expression of P53 and bcl-2, but not of cerbB-2, in estrogen receptor-positive and negative xenografted nude mice. Our findings suggest that tanshinone IIA might have potential anti-cancer activity that is stronger than tamoxifen in both ER-positive and ER-negative breast cancers. This function could be attributed in part to its inhibition of proliferation and apoptosis induction in cancer cells via the downregulation of multiple genes involved in cell cycle regulation, cell proliferation, apoptosis and DNA synthesis.

To investigate the proliferation inhibition and apoptosis-associated genes expression of both human breast cancer cells with estrogen receptor (ER) positive and negative (MCF-7 and MDA-MB-231) which treated with tanshinone II A, and to elucidate its mechanism of activity.Human ER positive breast cancer cells (MCF-7) and ER negative cells (MDA-MB-231) were tested in vitro for cytotoxicity of tanshinone II A with MTT method. The effect of tanshinone II A on DNA synthesis and apoptosis of both human breast cancer cells were evaluated with Brdu incorporation and flow cytometry. Immunohistochemistry were applied to test the P53, CerBb-2 and Bcl-2 protein expression of both cells.After Tanshinone II A treatment, a dose- and time-dependent decreased proliferation in both MCF-7 and MDA-MB-231 cells were observed (P0.05) with a IC50 0.25 microg/mL. A decreased BrdU incorporation and an increased apoptosis in both cells were also observed (P0.05 and P0.01 respectively). Immunohistochemistry test demonstrated that tanshinone A upregulate P53 expression in both cells and also weakly upregulate the CerBb-2 expression in MCF-7 (P0.05), whereas no influence on CerBb-2 expression of MDA-MB-231 and on Bcl-2 expression of both cells were demonstrated (P0.05).This study suggested that tanshione II A could inhibit the proliferation, induce apoptosis of ER-positive breast cancer cell MCF-7 and ER-negative breast cancer cell in vitro. The mechanism may be associated with the inhibition of DNA synthesis, induction of apoptosis, but may not with the expression level of gene p53, cer Bb-2 and bcl-2.