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Cantharidin (CTD), a sesquiterpenoid bioactive substance, has been reported to exhibit anticancer activity against various types of cancer cells. The aim of the present study was to investigate the apoptosis effects and the underlying mechanisms of CTD on osteosarcoma U-2 OS cells. Results showed that CTD induced cell morphologic changes, reduced total viable cells, induced DNA damage, and G2/M phase arrest. CTD increased the production of reactive oxygen species and Ca2+, and elevated the activities of caspase-3 and −9, but decreased the level of mitochondrial membrane potential. Furthermore, CTD increased the ROS- and ER stress-associated protein expressions and increased the levels of pro-apoptosis-associated proteins, but decreased that of anti-apoptosis-associated proteins. Based on these observations, we suggested that CTD decreased cell number through G2/M phase arrest and the induction of cell apoptosis in U-2 OS cells and CTD could be a potential candidate for osteosarcoma treatments. The possible signaling pathways for CTD induced apoptosis in U-2 OS human osteosarcoma cancer cells [ABSTRACT FROM AUTHOR]

Lupeol, one of the common components from the fruits and natural foods, has been reported to exert antitumor activities in many human cancer cell lines; however, its effects on osteosarcoma cell metastasis were not elucidated. In the present study, lupeol at 10–25 μM induced cell morphological changes and decreased total viable cell number in U-2 OS cells. Lupeol (5–15 μM) suppressed cell mobility, migration, and invasion by wound healing and transwell chamber assays, respectively. Lupeol inhibited the activities of MMP-2 and −9 in U-2 OS cells by gelatin zymography assay. Lupeol significantly decreased PI3K, pAKT, β-catenin, and increased GSK3β. Furthermore, lupeol decreased the expressions of Ras, p-Raf-1, p-p38, and β-catenin. Lupeol also decreased uPA, MMP-2, MMP-9, and N-cadherin but increased VE-cadherin in U-2 OS cells. Based on these observations, we suggest that lupeol can be used in anti-metastasis of human osteosarcoma cells in the future. The possible signaling pathways for lupeol suppressed cell migration and invasion in U-2 OS cells in vitro [ABSTRACT FROM AUTHOR]

Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. CCN6 is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, and Nov) family of matricellular proteins. However, the effects of CCN6 on human chondrosarcoma cells are largely unknown. In this study, we found that CCN6 increased the migration and the expression of intercellular adhesion molecule-1 (ICAM-1) in human chondrosarcoma cells. αvβ3 and αvβ5 integrin monoclonal antibody and mitogen-activated protein kinase (MEK) inhibitors (PD98059 and U0126) inhibited the CCN6-induced increase of the migration and ICAM-1 up-regulation of chondrosarcoma cells. CCN6 stimulation increased the phosphorylation of focal adhesion kinase (FAK), MEK, and extracellular signal-regulated kinase (ERK). In addition, activator protein-1 (AP-1) inhibitors suppressed the cell migration and ICAM-1 expression enhanced by CCN6. Moreover, CCN6 increased AP-1 luciferase activity and binding of c-Jun to the AP-1 element on the ICAM-1 promoter. Taken together, our results indicate that CCN6 enhances the migration of chondrosarcoma cells by increasing ICAM-1 expression through the αvβ3 and αvβ5 integrin receptor, FAK, MEK, ERK, c-Jun, and AP-1 signal transduction pathway. J. Cell. Physiol. 227: 223-232, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Hepatic oval cells (HOC) are considered to be the stem cells of the liver and have been linked to the development of hepatic malignancies. Studies have demonstrated that chronic hepatitis B virus (HBV) infection and dietary aflatoxin B1 (AFB1) exposure are among the most important risk factors for the development of hepatocellular carcinoma (HCC). However, little research has been done to evaluate the role of oval cells in these two environmental factors on hepatocarcinogenesis. In this study, partial transformation of rat HOC (LE/6) were accomplished by transfected HBV x gene (HBx), and then transfected cells were implanted both intra-hepatically and subcutaneously into nude mice treated with AFB1 in vivo. We found the oval cells produced tumors (4/24 of the animals) in liver following transfection with HBx gene and treatment with AFB1. These intrahepatic tumors included HCC cells (immunopositive for HepParl, ALB, CK8 and AFP) and mesenchymal cells (immunopositive for Vimentin and SMA). Whereas mesenchymal tumors were observed at the subcutaneous tissue with a similar rate in all controls treated with cell lines (10/24 in HBx-oval cells/AFB1 group, 8/20 in HBx-oval cells/non-AFB1 group, 10/20 in non-HBx/AFB1 group; 9/20 in non-HBx/non-AFB1 group). Conversely, none of the controls developed intrahepatic tumors. These results provide an evidence that oval cells have the capacity to generate HCC through the combined effects of the HBx and AFB1 in the liver microenvironment. [Copyright &y& Elsevier]

Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to distant organs. Leptin, an adipocyte-derived cytokine that is closely associated with obesity, has recently been shown to be involved in carcinogenesis and cancer progression. The aim of this study was to investigate whether leptin is associated with the motility of prostate cancer cells. We found that leptin increased the migration of human prostate cancer cells and expression of αvβ3 integrin on these cells. Leptin-mediated migration and increased integrin expression were attenuated by OBRl receptor antisense oligonucleotide (ODN). Activation of insulin receptor substrate (IRS-1), phosphatidylinositol 3-kinase (PI3K), Akt, and NF-κB pathways after leptin treatment was demonstrated. Furthermore, leptin-induced integrin expression and migration activity were inhibited by specific inhibitors; small interfering RNAs (siRNAs); and mutants of the IRS-1, PI3K, Akt, and NF-κB cascades. Therefore, this study shows that leptin stimulates the migration of human prostate cancer cells, one of the mechanisms underlying leptin-directed migration was transcriptional up-regulation of αvβ3 integrin expression through the OBR1/IRS-1/PI3K/Akt/NF-κB signal transduction pathway. J. Cell. Physiol. 226: 1274-1282, 2011. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Currently, surgical resection is one of only a few options for treating hepatocellular carcinoma (HCC). Unfortunately, postoperative tumor recurrence remains almost inevitable despite additional radiation or chemotherapy treatment following radical resection. Clinical observations and a growing body of experimental evidence have led to speculation that there is a population of persistent hepatic cancer stem cells (HCSCs), which are difficult to completely remove surgically. HCSCs are most often in a quiescent state and thought to reside in a specific microenvironment known as a niche that provides the cues necessary for HCSCs to maintain a balance of self-renewal and differentiation. Residual HCSCs following surgery may alter their fate by invading into the blood circulation. Furthermore, it remains to be determined if hepatectomy render the postoperative niche more favorable for the survival and growth of HCSCs, and therefore the recurrence of HCC. A better understanding of the mechanisms for HCSCs self-renewal, invasion and recurrence may provide new insights into curative strategies for treating HCC. [Copyright &y& Elsevier]

The effects of two‐drug combination, all‐trans retinoic acid (ATRA) and bisdemethoxycurcumin (BDMC), on apoptosis induction of liver cancer cells were investigated in human liver Hep 3B cells. Two‐drug combination caused a more effective decrease in cell viability and in induction of S phase arrest, DNA damage, and cell apoptosis than that of ATRA or BDMC only. Also, the two‐drug combination caused more cells to undergo significantly increased ROS productions when compared to that of ATRA or BDMC only. Results of Western blotting demonstrated that two‐drug combination increased expressions of Fas, pro‐apoptotic proteins, and active form of caspase‐3 and ‐9, but decreased that of anti‐apoptotic proteins and XIAP than that of ATRA or BDMC only in Hep 3B cells. In conclusion, ATRA combined with BDMC enhance cell apoptosis and associated protein expression in Hep 3B cells. Practical applications: Bisdemethoxycurcumin (BDMC) derived from natural plants, turmeric (Curcuma longa), which had been used for Asia food for thousands of years. All‐trans retinoid acid (ATRA) is currently used as a primary treatment for patients with acute promyelocytic leukemia. In previous study, ATRA and BDMC were reported to have anti‐inflammatory and anticancer effects. Our results showed that treatment of ATRA combined with BDMC showed more effectively apoptosis than that of ATRA or BDMC only in Hep 3B cells. The findings also provided possible pathways concerning the induction of liver cancer cell apoptosis. We conclude that ATRA combined with BDMC may be potent anticancer agents or adjuvants for liver cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Casticin, a polymethoxyflavone derived from natural plants, has biological activities including induction of cell apoptosis. In this study, we showed the beneficial effects of casticin on the inhibition of prostate cancer cell metastasis. Casticin reduced total viable cell number, thus, we selected low doses of casticin for following experiments. Casticin decreased cell mobility, suppressed cell migration and invasion, and reduced cell gelatinolytic activities of MMP‐2/‐9. Furthermore, casticin inhibited the protein levels of AKT, GSK3 αβ, Snail, and MMPs (MMP‐2, ‐9, ‐13, and ‐7) at 24 and 48 hr treatment. Casticin diminished the expressions of NF‐κB p65, GRB2, SOS‐1, MEK, p‐ERK1/2, and p‐JNK1/2 at 48 hr treatment only. However, casticin reduced the level of E‐cadherin at 24 hr treatment but elevated at 48 hr. The novel findings suggest that casticin may represent a new and promising therapeutic agent for the metastatic prostate cancer. Practical applications: Casticin derived from natural plants had been used for Chinese medicine in Chinese population for thousands of years. In the present study, casticin attenuated metastatic effects, including decreasing viable cell number, inhibiting the migration, invasion, and adhesion, and reducing matrix metalloproteinases activity on human prostate DU 145 cancer cells. In addition, the results also provided possible pathways involved in casticin anti‐metastasis mechanism. We conclude that casticin may be an aptitude anticancer agent or adjuvant for the metastatic prostate cancer in the future. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptor 1 (mGlu 1 receptor) is expressed in many cancer cell types as compared to normal counterparts underscoring its potential role in tumor behavior. The aim of present study was to test the role of mGlu 1 receptor in experimental non-small cell lung cancer (NSCLC). First, protein expression of mGlu 1 receptor was higher in human NSCLC cell lines, including both adenocarcinoma and squamous carcinoma subtypes, when compared to normal bronchial epithelial cells. Inhibition of mGlu 1 receptor by BAY36-7620 (an mGlu 1 receptor-specific inhibitor) inhibited tumor growth and prolonged survival of mice with tumors of A549 or H1299. Treatment with BAY36-7620 suppressed AKT phosphorylation in A549 tumors and pre-treatment with BAY36-7620 blocked the L-quisqualate (a potent mGlu 1 receptor agonist)-induced AKT phosphorylation in A549 cells. Treatment with BAY36-7620 reduced cellular proliferation of A549 cells. Treatment with BAY36-7620 enhanced cleaved PARP levels and reduced protein expression of bcl-2, HIF-1α, and VEGF. In contrast, treatment with L-quisqualate reduced cleaved PARP levels and enhanced protein expression of bcl-2, HIF-1α, VEGF, and IL-8, which was reversed by co-incubation with MK2206 (an AKT inhibitor). Pre-treatment with BAY36-7620 blocked the VEGF-induced AKT phosphorylation in HUVECs. Treatment of HUVECs with L-quisqualate resulted in enhancement of capillary tube formation, which was reversed by co-incubation with MK2206. Furthermore, mGlu 1 receptor knockdown suppressed tumor growth and prolonged survival of mice with tumors of A549 or H1299. Collectively, inhibition of mGlu 1 receptor suppressed tumor growth and angiogenesis in experimental NSCLC. [ABSTRACT FROM AUTHOR]

Abstract: This study investigated the diosmin effect on HA22T human hepatocellular carcinoma cells in vitro and in an in vivo mouse xenograft model. HA22T cells were treated with different concentrations of diosmin and analysed with Western blot analysis, TUNEL, JC-1 staining and siRNA transfection assays. Additionally, the HA22T-implanted xenograft nude mice model was applied to confirm the cellular effects. Diosmin induced apoptosis, up-regulated death receptor apoptotic pathway markers as well as mitochondrial proteins. Pro-survival Bcl-2 family proteins were inhibited and the pro-apoptotic ones were increased. Protein phosphatase 2A (PP2A) siRNA or okadaic acid reversed the diosmin effects, confirming the role of PP2A in diosmin-induced HA22T apoptosis. The HA22T-implanted nude mice model revealed that diosmin inhibited tumour cell proliferation and enhanced tumour cell apoptosis. All our experimental evidence indicates that diosmin significantly promotes HA22T apoptosis and reduces tumour sizes in xenograft nude mice via PP2A in a dose-dependent manner. [Copyright &y& Elsevier]

Epidermal growth factor receptor (EGFR), an aberrantly over-expressed or activated receptor-tyrosine kinase in many cancers, plays a pivotal role in cancer progression and has been an attractive target for cancer therapy. Gefitinib and erlotinib, two EGFR-tyrosine kinase inhibitors, have been approved for non-small cell lung cancer. However, durable clinical efficacy of these EGFR inhibitors is severely limited by the emergence of acquired resistance. For example, the expression of breast cancer-resistant protein (BCRP/ABCG2) has been shown to confer acquired resistance of wild-type EGFR (wtEGFR)-expressing cancer cells to gefitinib. However, the underlying molecular mechanisms still remain unclear. Here, we show that wtEGFR expression is elevated in the nucleus of acquired gefitinib-resistant cancer cells. Moreover, nuclear translocation of EGFR requires phosphorylation at Ser-229 by Akt. In the nucleus, EGFR then targets the proximal promoter of BCRP/ABCG2 and thereby enhances its gene transcription. The nuclear EGFR-mediated BCRP/ABCG2 expression may contribute at least in part to the acquired resistance of wtEGFR-expressing cancer cells to gefitinib. Our findings shed light on the role of nuclear EGFR in the sensitivity of wtEGFR-expressing cancer cells to EGFR tyrosine kinase inhibitors and also deciphered a putative molecular mechanism contributing to gefitinib resistance through BCRP/ABCG2 expression. [ABSTRACT FROM AUTHOR]

Abstract: Background: Oral cancer is a worldwide problem. It is a universal aggressive disease in the population of smoking and drinking. The oral cancer mortality has been ranked 5th place in Taiwan in male cancer patients. A number of protein markers for oral cancer are still not applicable in large populations. Proteomic technologies provide excellent tools for rapid screening of a large number of potential biomarkers in malignant cells. Method: Proteomics and real-time quantitative RT-PCR were used to analyze over-expressed proteins in 10 OSCC patients. Result: Forty-one proteins were identified as commonly over-expressed in OSCC tissues. In OSCC tissues, αB-crystallin, tropomyosin 2, myosin light chain 1, heat shock protein 27 (HSP27), stratifin, thioredoxin-dependent peroxide reductase, flavin reductase, vimentin, rho GDP-dissociation inhibitor 2 (rho GDI-2), glutathione S-transferase Pi (GST-pi) and superoxide dismutase [Mn] (MnSOD) were significantly over-expressed (an average of 7.2, 6.0, 5.7, 4.3, 3.6, 3.4, 3.0, 3.0, 2.6, 2.5, 2.1-fold, respectively). In real-time quantitative RT-PCR analysis, the gene expressions of αB-crystallin, HSP27 and MnSOD were also increased in the cancer tissues, consistent with proteomic results. Conclusion: The identified proteins in this experiment may be used in future studies of carcinogenesis or as diagnostic markers and therapeutic targets for OSCC. [Copyright &y& Elsevier]

Background: The fact that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces profound apoptosis in a wide range of tumor cell lines but lacks cytotoxicity to mosnormal cells raises hope that TRAIL might become a novel potential anticancer agent. Our previous studies shown that hepatoma cells are not sensitive to TRAIL treatment . Overexpression of survivin reduced sensitivity of hepatoma cells to TRAIL.The aim of this study is to investigate whether tumor cells escape TRAIL-killing through survivin experssion and how to reverse this resistance. Methods: Human hepatoma cell lines (HepG2, SMMC 7721), cholangiocarcinoma cell line QBC939, no-small-cell lung cancer cell line A549, colorectal adenocarcinoma cell lines (SW480 and HCT-15), and malignant hematopoietic cell line Jurkat, were treated with or without TRAIL protein and survivin antisense oligodeoxynucleotide (ODN) in culture. Survivin mRNA levels in treated cells were detected by semiquantitative RT-PCR. Synchronization of hepatoma cells was used to test the sensitivity of hepatoma cells to TRAIL. Apoptosis and cell cycle were examined by flow cytometry. Cell viability and proliferation assay were evaluated by MTT. In vivo effects of TRAIL plasmid and /or survivin antisense ODN on tumor growth were investigated in a nude mouse HCC model of HepG2 cell grafts in the liver. Results: Survivin mRNA levels varied in cell lines evaluated and negatively correlated to TRAIL-induced apoptosis (r=−0.856,p<0.05).HepG2 and SMMC-7721 in G1 or S phase are more sensitive to TRAIL than those in G2 phase. Treatment with survivin antisence ODN caused S arrest and significantly enhanced TRAIL-killing.Treatment with TRAIL protein caused G2/M arrest and resulted in an increase in survivin protein levels in HepG2 cells.Combined intratumoral injection of TRAIL plasmid and survivin antisense ODN significantly supressed the growth of tumor xenografts in nude mice as compared to TRAIL plamid alone (0.31±0.05 vs 2.35 ±0.38 cm3, P <0.01) during a 4-week of observation. Conclusions: The findings indicate that survivin may play a role in tumor cell resistance to TRAIL-induced apoptosis, at least in part, through cell cycle regulation. Manipulation of survivin expression may sensitizes HCC to TRAIL-induced apoptosis. This approach may offer a novel approach in molecular therapy against HCC for which no effective treatment is available for an advanced stage.Molecular Therapy (2006) 13, S364–S365; doi: 10.1016/j.ymthe.2006.08.1035 [ABSTRACT FROM AUTHOR]