lignans and Bone-Neoplasms

Metastasis is the major cause of cancer related death and targeting the process of metastasis has been proposed as a strategy to combat cancer. Therefore, to develop candidate drugs that target the process of metastasis is very important. In the preliminary studies, we found that schisandrin B (Sch B), a naturally-occurring dibenzocyclooctadiene lignan with very low toxicity, could suppress cancer metastasis.. BALB/c mice were inoculated subcutaneously or injected via tail vein with murine breast cancer 4T1 cells. Mice were divided into Sch B-treated and control groups. The primary tumor growth, local invasion, lung and bone metastasis, and survival time were monitored. Tumor biopsies were examined immuno- and histo-pathologically. The inhibitory activity of Sch B on TGF-β induced epithelial-mesenchymal transition (EMT) of 4T1 and primary human breast cancer cells was assayed.. Sch B significantly suppressed the spontaneous lung and bone metastasis of 4T1 cells inoculated s.c. without significant effect on primary tumor growth and significantly extended the survival time of these mice. Sch B did not inhibit lung metastasis of 4T1 cells that were injected via tail vein. Delayed start of treatment with Sch B in mice with pre-existing tumors did not reduce lung metastasis. These results suggested that Sch B acted at the step of local invasion. Histopathological evidences demonstrated that the primary tumors in Sch B group were significantly less locally invasive than control tumors. In vitro assays demonstrated that Sch B could inhibit TGF-β induced EMT of 4T1 cells and of primary human breast cancer cells.. Sch B significantly suppresses the lung and bone metastasis of 4T1 cells via inhibiting EMT, suggesting its potential application in targeting the process of cancer metastasis.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Cyclooctanes; Epithelial-Mesenchymal Transition; Female; Humans; Lignans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasm Transplantation; Polycyclic Compounds; Transplantation, Heterologous; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Bone Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclooctanes; Disease Models, Animal; Humans; Lignans; Lung Neoplasms; Mice; Osteosarcoma; Phosphatidylinositol 3-Kinases; Polycyclic Compounds; Proto-Oncogene Proteins c-akt; Wnt Signaling Pathway

Osteosarcoma is an aggressive primary malignant bone tumor that occurs in childhood. Although the diagnostic and treatment options have been improved, osteosarcoma confers poor prognosis. Magnolol, an active component of Magnoliae officinalis cortex, has been widely applied in herb medicine and has been shown to have multiple pharmacological activities. However, whether magnolol possesses anti-osteosarcoma capacity remains unknown.. We examined magnolol is cytotoxicity, and whether it regulates apoptosis and oncogene expression using MTT, flow cytometry and Western blotting assays in osteosarcoma cells.. Magnolol exerted toxicity towards U-2 OS cells by inducing intrinsic/extrinsic apoptosis pathways. Additionally, treatment of U-2 OS cells with magnolol inhibited MAPK1 mitogen-activated protein kinase 1 (ERK)/Nuclear factor kappa B (NF-B) signaling involved in tumor progression and reduced the expression of anti-apoptotic and metastasis-associated genes.. Magnolol may induce apoptosis and inactivate ERK/NF-B signal transduction in osteosarcoma cells.

Topics: Apoptosis; Biphenyl Compounds; Bone Neoplasms; Cell Line, Tumor; Extracellular Signal-Regulated MAP Kinases; Humans; Lignans; NF-kappa B; Osteosarcoma; Signal Transduction

Honokiol is the main active constituent of Magnolia officinalis. With effective and long‑term pharmacological functions of being antibacterial, anti‑oxidative, anti‑inflammatory, antitumor, anti‑spasmic, anti‑anxiety and anti‑viral, Honokiol is clinically used in the treatment of acute enteritis and chronic gastritis. The aim of the present study was to observe the possible anti‑effects of honokiol on autophagy and apoptosis of osteosarcoma, and to investigate the role of the PI3K/Akt/mTOR signaling pathway in its anticancer effects. MTT assay was used to evaluate cell proliferation and Annexin V‑fluorescein isothiocyanate/propidium iodide staining flow cytometry was used to analyze the apoptotic rate. The authors identified that honokiol could inhibit cell proliferation and induce the apoptotic rate of osteosarcoma cells. The expression level of Bcl‑2‑like protein 4, caspase‑3 and p53 protein expression were induced and cyclin D1 protein expression was suppressed in osteosarcoma cells by honokiol. Autophagy‑associated LC3II protein expression level was promoted, and PI3K, p‑Akt and p‑mTOR protein expression level was suppressed in osteosarcoma cells by honokiol. The present study demonstrated, to the best of the authors' knowledge, for the first time that honokiol induces autophagy and apoptosis of osteosarcoma cells through the PI3K/Akt/mTOR signaling pathway.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Bone Neoplasms; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Humans; Lignans; Osteosarcoma; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

Honokiol (HNK) is a small biphenolic compound, which exerts antineoplastic effects in various types of cancer. However, the mechanism underlying the antitumor effects of HNK in osteosarcoma (OS) cells is not yet fully understood. Emerging evidence has indicated that microRNAs (miRNAs/miRs) serve key roles in numerous pathological processes, including cancer. It has previously been reported that Chinese medicinal herbs harbor anticancer properties via modulating miRNA expression. Therefore, the present study aimed to determine whether HNK could suppress OS cell growth by regulating miRNA expression. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis were used to evaluate the cell proliferation and apoptosis in human OS cells after treatment with HNK, respectively. The results demonstrated that HNK inhibits proliferation and induces apoptosis of human OS cells in a dose‑dependent manner. Furthermore, HNK‑induced apoptosis was characterized by upregulation of proapoptotic proteins, including cleaved‑caspase‑3, cleaved‑poly (ADP‑ribose) polymerase and B‑cell lymphoma 2 (Bcl‑2)‑associated X protein, and downregulation of the anti‑apoptotic protein Bcl‑2. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) verified that HNK was able to induce aberrant expression of miRNAs in human OS cells, and miR‑21 was one of the miRNAs that was most significantly downregulated. To further investigate miR‑21 function, the present study validated that HNK reduces miR‑21 levels in a dose‑dependent manner. In addition, restoration of miR‑21 expression abrogated the suppressive effects of HNK on OS cells. Luciferase assay and western blot analysis identified that miR‑21 inhibits the expression of phosphatase and tensin homolog (PTEN) by directly targeting its 3'-UTR. Notably, HNK was able to suppress the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT) signaling pathway; however, it was reactivated by miR‑21 overexpression. Taken together, these data indicated that HNK may inhibit proliferation and induce apoptosis of human OS cells by modulating the miR‑21/PTEN/PI3K/AKT signaling pathway. Therefore, miR‑21 may be considered a potential therapeutic target for the treatment of osteosarcoma with HNK.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Lignans; MicroRNAs; Osteosarcoma; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction

Manassantin A has been well-established as an inhibitor of HIF-1. In the present study, a new manasantin A derivative, X609, with decreased stereochemical complexity, rendering it amenable to a simplified synthesis scheme, was synthesized and was found to increase HIF-1 inhibitory activity. X609 exhibited antiproliferative activity in a broad spectrum of tumor cell lines, via HIF-1-dependent mechanisms. X609 may induce apoptosis in MG-63 cells through activation of the mitochondrial pathway. Oral administration of X609 significantly inhibited the growth of human osteosarcomas implanted into nude mice. In light of the results of the present study, it may be possible to develop X609 for use as a novel antitumor agent, which targets human osteosarcoma.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Bone Neoplasms; Caspases; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lignans; Mice; Mice, Nude; Mitochondria; Osteosarcoma; Paclitaxel; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Metastasizing osteosarcoma has a mean 5-year survival rate of only 20% to 30%. Therefore, novel chemotherapeutics for more effective treatment of this disease are required.. The antineoplastic activity of honokiol, which was demonstrated previously in numerous malignancies, was studied in vivo in C3H mice subcutaneously injected with syngeneic β-galactosidase bacterial gene (lacZ)-expressing LM8 osteosarcoma (LM8-lacZ) cells. In vitro cytotoxic effects of honokiol were investigated in 8 human and 2 murine osteosarcoma cell lines with different in vivo metastatic potential.. Seven days after subcutaneous flank injection of LM8-lacZ cells, daily intraperitoneal treatment of mice with 150 mg/kg honokiol reduced the number of micrometastases in the lung by 41% and reduced the number of macrometastases in the lung and liver by 69% and 80%, respectively, compared with control. Primary tumor growth was not inhibited. In osteosarcoma cell lines, honokiol inhibited the metabolic activity with a half-maximal concentration (IC(50) ) between 8.0 μg/mL and 16 μg/mL. Cyclosporin A partially reversed the inhibition of metabolic activity in LM8-lacZ cells. Cell proliferation and wound healing migration of LM8-lacZ cells were inhibited by honokiol with an IC(50) between 5.0 μg/mL and 10 μg/mL. Higher concentrations caused rapid cell death, which was distinct from necrosis, apoptosis, or autophagy but was associated with swelling of the endoplasmic reticulum, cytoplasmic vacuolation, and morphologically altered mitochondria.. Honokiol exhibited prominent antimetastatic activity in experimental osteosarcoma and caused rapid cell death in vitro that was unrelated to necrosis, apoptosis, or autophagy. The authors concluded that honokiol has considerable potential for the treatment of metastasizing osteosarcoma.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Bone Neoplasms; Cell Death; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Humans; Lignans; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Inbred C3H; Osteosarcoma

Chondrosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. In the present study, we investigated the anti-cancer effect of a honokiol, an active component isolated and purified from the Magnolia officinalis in human chondrosarcoma cells. Honokiol-induced cell apoptosis in human chondrosarcoma cell lines (including: JJ012 and SW1353) but not primary chondrocytes. Honokiol also induces upregulation of Bax and Bak, downregulation of Bcl-XL and dysfunction of mitochondria in chondrosarcoma cells. Honokiol triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol-calcium levels. We also found that honokiol increased the expression and activities of glucose-regulated protein 78 (GRP78) and calpain. Transfection of cells with GRP78 or calpain siRNA reduced honokiol-mediated cell apoptosis in JJ012 cells. Importantly, animal studies have revealed a dramatic 53% reduction in tumor volume after 21days of treatment. This study demonstrates that honokiol may be a novel anti-cancer agent targeting chondrosarcoma cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Bone Neoplasms; Calcium; Calpain; Cell Line, Tumor; Chondrosarcoma; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Heat-Shock Proteins; Humans; Lignans; Male; Mice; Mice, Inbred BALB C; Mitochondria; Xenograft Model Antitumor Assays

Honokiol, a soluble nontoxic natural product derived from Magnolia spp., has been shown to induce apoptosis in malignant cells. The effect of honokiol and the combined therapy with docetaxel on prostate cancer (PCa) growth and bone metastasis was investigated in experimental models.. The in vitro proapoptotic effects of honokiol on human androgen-dependent and -independent PCa, bone marrow, bone marrow-derived endothelial, and prostate stroma cells were investigated. Honokiol-induced activation of caspases was evaluated by Western blot and FACS analysis. To confirm the cytotoxicity of honokiol, mice bone was inoculated in vivo with androgen-independent PCa, C4-2 cells and the effects of honokiol and/or docetaxel on PCa growth in bone were evaluated. Daily honokiol (100 mg/kg) and/or weekly docetaxel (5 mg/kg) were injected intraperitoneally for 6 weeks. PCa growth in mouse bone was evaluated by radiography, serum prostate-specific antigen (PSA) and tissue immunohistochemistry.. Honokiol induced apoptosis in all cell lines tested. In PCa cells honokiol induced apoptosis via the activation of caspases 3, 8, and 9 and the cleavage of poly-adenosine diphosphate ribose polymerase in a dose- and time-dependent manner. Honokiol was shown to inhibit the growth and depress serum PSA in mice harboring C4-2 xenografts in the skeleton and the combination with docetaxel showed additive effects that inhibited further growth without evidence of systemic toxicity. Immunohistochemical staining confirmed honokiol exhibited growth-inhibitory, apoptotic, and antiangiogenic effects on PCa xenografts.. The combination of honokiol and low-dose docetaxel may be used to improve patient outcome in androgen-independent prostate cancer with bone metastasis.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biphenyl Compounds; Blotting, Western; Bone Marrow Cells; Bone Neoplasms; Caspases; Cell Proliferation; Docetaxel; Drugs, Chinese Herbal; Flow Cytometry; Humans; Immunoenzyme Techniques; Lignans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Prostate-Specific Antigen; Prostatic Neoplasms; Radiography; Taxoids; Tumor Cells, Cultured