lignans and Osteosarcoma

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

Osteosarcoma represents one of the most devastating cancers due to its high metastatic potency and fatality. Osteosarcoma is insensitive to traditional chemotherapy. Identification of a small molecule that blocks osteosarcoma progression has been a challenge in drug development. Phillygenin, a plant-derived tetrahydrofurofuran lignin, has shown to suppress cancer cell growth and inflammatory response. However, how phillygenin plays functional roles in osteosarcoma has remained unveiled. In this study, we showed that phillygenin inhibited osteosarcoma cell growth and motility in vitro. Further mechanistic studies indicated that phillygenin blocked STAT3 signaling pathway. Phillygenin led to significant downregulation of Janus kinase 2 and upregulation of Src homology region 2 domain-containing phosphatase 1. Gene products of STAT3 regulating cell survival and invasion were also inhibited by phillygenin. Therefore, our studies provided the first evidence that phillygenin repressed osteosarcoma progression by interfering STAT3 signaling pathway. Phillygenin is a potential candidate in osteosarcoma therapy.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Janus Kinase 2; Lignans; Neoplasm Metastasis; Osteosarcoma; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Signal Transduction; STAT3 Transcription Factor

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

Osteosarcoma is the most common primary malignant tumor of bone, the long-term survival of which has stagnated in the past several decades. In the present study, we investigated the anticancer effect of honokiol (HNK), an active component isolated and purified from the magnolia officinalis on human osteosarcoma cells. Our results showed that honokiol caused dose-dependent and time-dependent cell death in human osteosarcoma cells. The types of cell death induced by honokiol were primarily autophagy and apoptosis. Furthermore, honokiol induced G0/G1 phase arrest, elevated the levels of glucose-regulated protein (GRP)-78, an endoplasmic reticular stress (ERS)-associated protein, and increased the production of intracellular reactive oxygen species (ROS). In contrast, reducing production of intracellular ROS using N-acetylcysteine, a scavenger of ROS, concurrently suppressed honokiol-induced cellular apoptosis, autophagy, and cell cycle arrest. Consequently, honokiol stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2. Furthermore, pretreatment of osteosarcoma cells with PD98059, an inhibitor of ERK1/2, inhibited honokiol-induced apoptosis and autophagy. Finally, honokiol suppressed tumor growth in the mouse xenograft model. Taken together, our results revealed that honokiol caused G0/G1 phase arrest, induced apoptosis, and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells. Honokiol is therefore a promising candidate for development of antitumor drugs targeting osteosarcoma.

Topics: Animals; Apoptosis; Autophagy; Autophagy-Related Protein 7; Biphenyl Compounds; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Endoplasmic Reticulum Stress; Enzyme Activation; Fibroblasts; Humans; Lignans; MAP Kinase Signaling System; Mice, Inbred BALB C; Mice, Nude; Osteosarcoma; Reactive Oxygen Species; Xenograft Model Antitumor Assays

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