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The extracellular matrix (ECM) creates a tissue microenvironment able to regulate cellular signaling. The loss of ECM plasticity is associated with several pathologies, especially those involving chronic inflammation, therefore, the ECM represents a potential therapeutic target for certain conditions. The present study investigated the effects of a natural multi-component compound formulation, Galium-Heel®, on the growth, morphology and ECM production of human dermal fibroblasts (HDF). The effects of the formulation on HDF growth and morphology were assessed by sulforhodamine B assay, trypan blue exclusion staining, FACS and ultrastructural analyses. The effect of the compound on reactive oxygen species production by HDF was performed by dichlorofluorescin diacetate assay. The expression of ECM components, matrix metalloproteinases (MMPs) and signaling molecules was analyzed by western blot analysis. The present results demonstrated that Galium-Heel® did not significantly affect HDF growth, survival, cell cycle or morphology indicating the biocompatibility of the formulation. The formulation demonstrated antioxidant activity. Galium-Heel® was able to modulate ECM by regulating collagens (type I and III) and MMPs-3 and −7 expression. In addition, the formulation was able to regulate molecules involved in TGF-β signalling, including mitogen activated kinase-like protein, GLI family zinc finger 2 and pro-survival proteins such as AKT. The present results demonstrating the effects of a natural multi-component compound on ECM composition, highlighted the possibility of pharmacologically modulating ECM molecules. The recovery and the maintenance of ECM homeostasis might be considered as a potential therapeutic goal to ameliorate pathological conditions. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma (MM) is a primary tumor arising from mesothelial cells. The survival of MM patients following traditional chemotherapy is poor, thus innovative treatments for MM are needed. (-)-gossypol (AT-101) is a BH3 mimetic compound which possesses anti-tumoral activity by targeting multiple signaling transduction pathways. Several clinical trials employing AT-101 have been performed and some of them are still ongoing. Accordingly, we investigated the in vitro effects of AT-101 on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis and autophagy of human (MM-B1, H-Meso-1, and MM-F1) and mouse (#40a) MM cell lines. In addition, we explored the in vivo anti-tumor activities of AT-101 in a mouse model, in which the transplantation of MM cells induces ascites in the peritoneal space. AT-101 inhibited in vitro MM cells survival in a dose- and time-dependent manner and triggered autophagy, but the process was then blocked and was coincident with apoptosis activation. To confirm the effect of AT-101 in inducing the apoptosis of MM cells, MM cells were simultaneously treated with AT-101 and with the caspase inhibitor, Z-VAD-FMK. Z-VAD-FMK was able to significantly reduce the number of cells in the subG1 phase compared to the treatment with AT-101 alone. This result corroborates the induction of cell death by apoptosis following treatment with AT-101. Indeed, Western blotting results showed that AT-101 increases Bax/Bcl-2 ratio, modulates p53 expression, activates caspase 9 and the cleavage of PARP-1. In addition, the treatment with AT-101 was able to: (a) decrease the ErbB2 protein expression; (b) increase the EGFR protein expression; (c) affect the phosphorylation of ERK1/2, p38 and AKT; (d) stimulate JNK1/2 and c-jun phosphorylation. Our in vivo results showed that the intraperitoneal administration of AT-101 increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM therapies by employing AT-101 as an anticancer agent in combination with standard therapies. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma (MM) is a tumor arising from mesothelium. MM patients’ survival is poor. The polyphenol 40,5,7,-trihydroxyflavone Apigenin (API) is a “multifunctional drug”. Several studies have demonstrated API anti-tumoral effects. However, little is known on the in vitro and in vivo anti-tumoral effects of API in MM. Thus, we analyzed the in vitro effects of API on cell proliferation, cell cycle regulation, prosurvival signaling pathways, apoptosis, and autophagy of human and mouse MM cells. We evaluated the in vivo anti-tumor activities of API in mice transplanted with MM #40a cells forming ascites. API inhibited in vitro MM cells survival, increased reactive oxygen species intracellular production and induced DNA damage. API activated apoptosis but not autophagy. API-induced apoptosis was sustained by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of both caspase 9 and caspase 8, cleavage of PARP-1, and increase of the percentage of cells in subG1 phase. API treatment affected the phosphorylation of ERK1/2, JNK and p38 MAPKs in a cell-type specific manner, inhibited AKT phosphorylation, decreased c-Jun expression and phosphorylation, and inhibited NF-kB nuclear translocation. Intraperitoneal administration of API increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of tumor growth. Our findings may have important implications for the design of MM treatment using API. [ABSTRACT FROM AUTHOR]

Racemic Gossypol [(±)-GOS], composed of both (−)-GOS and (+)-GOS, is a small BH3-mimetic polyphenol derived from cotton seeds. (±)-GOS has been employed and well tolerated by cancer patients. Head and neck carcinoma (HNC) represents one of the most fatal cancers worldwide, and a significant proportion of HNC expresses high levels of antiapoptotic Bcl-2 proteins. In this study, we demonstrate that (±)-GOS inhibits cell proliferation and induces apoptosis and autophagy of human pharynx, tongue, and salivary gland cancer cell lines and of mouse salivary gland cancer cells (SALTO). (±)-GOS was able to: (a) decrease the ErbB2 protein expression; (b) inhibit the phosphorylation of ERK1/2 and AKT; (c) stimulate p38 and JNK1/2 protein phosphorylation. (±)-GOS administration was safe in BALB/cmice and it reduced the growth of transplanted SALTO cellsin vivoand prolonged mice median survival. Our results suggest the potential role of (±)-GOS as an antitumor agent in HNC patients. [ABSTRACT FROM PUBLISHER]

Cardiovascular diseases are the main cause of mortality and morbidity in the world. Hypertension, ischemia/reperfusion, diabetes and anti-cancer drugs contribute to heart failure through oxidative and nitrosative stresses which cause cardiomyocytes nuclear and mitochondrial DNA damage, denaturation of intracellular proteins, lipid peroxidation and inflammation. Oxidative or nitrosative stress-mediated injury lead to cardiomyocytes apoptosis or necrosis. The reactive oxygen (ROS) and nitrogen species (RNS) concentration is dependent on their production and on the expression and activity of anti-oxidant enzymes. Polyphenols are a large group of natural compounds ubiquitously expressed in plants, and epidemiological studies have shown associations between a diet rich in polyphenols and the prevention of various ROS-mediated human diseases. Polyphenols reduce cardiomyocytes damage, necrosis, apoptosis, infarct size and improve cardiac function by decreasing oxidative stress-induced production of ROS or RNS. These effects are achieved by the ability of polyphenols to modulate the expression and activity of anti-oxidant enzymes and several signaling pathways involved in cells survival. This report reviews current knowledge on the potential anti-oxidative effects of polyphenols to control the cardiotoxicity induced by ROS and RNS stress. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) exhibit an important function in extracellular matrix degradation. MMPs modulate the activation of growth factors, cytokines and metastasis. At present, the effect of exercise on serum levels of MMP-2 and -9 remains unclear. The aim of the present study was to investigate the effect of various physical activities on the circulating levels of MMP-2 and -9 in breast cancer (BC) survivors and healthy subjects. A total of 66 female subjects were enrolled in the present study. The cohort included 46 BC survivors and 20 healthy subjects divided into 5 groups: Group A (17 BC survivors, participating in recreational dragon boat paddling), group B (14 BC survivors, participating in recreational physical activity), group C (15 sedentary BC survivors), group D (10 healthy subjects, participating in recreational physical activity) and group E (10 sedentary healthy subjects). ELISA assays revealed a significant increase in the level of circulating MMP-2 in group B compared with all other groups. Recreational physical activity increased the levels of MMP-9 in healthy subjects (group D vs. E), however, the differences were not statistically significant, while in the BC survivor groups the results were opposite, with exercise reducing MMP-9 levels (group B vs. C). Furthermore, a significant increase in MMP-2 was observed in group B lymph node metastasis-positive (N+) subjects compared with group A and C N+ subjects. Thus, the results of the present study indicate that various physical activities modulate the levels of circulating MMP-2 and -9 in BC survivors, and the same exercise program induces a different effect when undertaken by healthy subjects and BC survivors. These results may have important implications with regard to the selection of appropriate physical activities for BC survivors, leading to improvements to their survival and prevention of recurrence, as well as amelioration of physical function, quality of life and fatigue. [ABSTRACT FROM AUTHOR]

Ascorbic acid (A) has been demonstrated to exhibit anti-cancer activity in association with chemotherapeutic agents. Potassium (K) is a regulator of cellular proliferation. In the present study, the biological effects of A and K bicarbonate, alone or in combination (A+K), on breast cancer cell lines were evaluated. The survival of cancer cells was determined by sulforhodamine B cell proliferation assay, while analysis of the cell cycle distribution was conducted via fluorescence-activated cell sorting. In addition, the expression of signaling proteins was analyzed upon treatment. The results indicated that there was a heterogeneous response of the different cell lines to A and K, and the best effects were achieved by A+K and A treatment. The interaction between A+K indicated an additive or synergistic effect. In addition, A+K increased the percentage of cells in the sub-G1 phase of the cell cycle, and was the most effective treatment in activating the degradation of poly(adenosine diphosphate-ribose) polymerase-1. In the breast cancer cell line MCF-7, A+K induced the appearance of the 18 kDa isoform of B-cell lymphoma-2-associated X protein (Bax), which is a more potent inducer of apoptosis than the full-length Bax-p21. The effects of A and K on the phosphorylation of extracellular signal-regulated kinase (ERK)1 and ERK2 were heterogeneous. In addition, treatment with K, A and A+K inhibited the expression of nuclear factor-κB. Overall, the results of the present study indicated that K potentiated the anti-tumoral effects of A in breast cancer cells in vitro. [ABSTRACT FROM AUTHOR]

Malignant Mesothelioma (MM) is a tumor of the serous membranes linked to exposure to asbestos. A chronic inflammatory response orchestrated by mesothelial cells contributes to the development and progression of MM. The evidence that: (a) multiple signaling pathways are aberrantly activated in MM cells; (b) asbestos mediated-chronic inflammation has a key role in MM carcinogenesis; (c) the deregulation of the immune system might favor the development of MM; and (d) a drug might have a better efficacy when injected into a serous cavity thus bypassing biotransformation and reaching an effective dose has prompted investigations to evaluate the effects of polyphenols for the therapy and prevention of MM. Dietary polyphenols are able to inhibit cancer cell growth by targeting multiple signaling pathways, reducing inflammation, and modulating immune response. The ability of polyphenols to modulate the production of pro-inflammatory molecules by targeting signaling pathways or ROS might represent a key mechanism to prevent and/or to contrast the development of MM. In this review, we will report the current knowledge on the ability of polyphenols to modulate the immune system and production of mediators of inflammation, thus revealing an important tool in preventing and/or counteracting the growth of MM. [ABSTRACT FROM AUTHOR]

Background The antitumor activity induced by intratumoral vaccination with poxvirus expressing a tumor antigen was shown to be superior to that induced by subcutaneous vaccination. Salivary gland carcinomas overexpress ErbB2. Trastuzumab, a monoclonal antibody to ErbB2, was proposed for salivary gland tumors treatment. We explored the effectiveness of intratumoral vaccination with the recombinant vaccinia virus ErbB2/neu (rV-neuT) vaccine in hampering the growth of transplanted Neu-overexpressing BALB-neuT salivary gland cancer cells (SALTO) in BALB-neuT mice. Methods BALB-neuT male mice were subcutaneously injected with SALTO tumor cells and intratumorally vaccinated twice with different doses of either rV-neuT or V-wt (wild-type). Tumors were measured weekly. The presence of anti-ErbB2/Neu antibodies was assayed by ELISA, immunoprecipitation or indirect immunofluorescence. Biological activity of immune sera was investigated by analyzing antibody-dependent cellular cytotoxicity (ADCC), SALTO cells proliferation and apoptosis, ErbB2/Neu receptor down regulation and ERK1/2 phosphorylation. Anti-Neu T cell immunity was investigated by determining the release of IL-2 and IFN-gamma in T cells supernatant. Survival curves were determined using the Kaplan-Meier method and compared using the log-rank test. Differences in tumor volumes, number of apoptotic cells, titer of the serum, percentage of ADCC were evaluated through a two-tailed Student's t-test. Results rV-neuT intratumoral vaccination was able to inhibit the growth of SALTO cancer cells in a dose-dependent manner. The anti-Neu serum titer paralleled in vivo antitumor activity of rVneuT vaccinated mice. rV-neuT immune serum was able to mediate ADCC, inhibition of SALTO cells proliferation, down regulation of the ErbB2/Neu receptor, inhibition of ERK1/2 phosphorylation and induction of apoptosis, thus suggesting potential mechanisms of in vivo tumor growth interference. In addition, spleen T cells of rV-neuT vaccinated mice released IFN-gamma and IL-2 upon in vitro stimulation with several Neu-specific peptides located in the extracellular domain of Neu sequence. Conclusions rV-neuT intratumoral vaccination could be employed to induce an efficient antitumor response and reject transplanted salivary gland tumors. Our findings may have important implications for the design of cancer vaccine protocols for the treatment of salivary gland tumors and other accessible tumors using intratumoral injection of recombinant vaccinia virus. [ABSTRACT FROM AUTHOR]

The sharing of molecules function that affects both tumor growth and neoangiogenesis with cells of the immune system creates a mutual interplay that impairs the host's immune response against tumor progression. Increasing evidence shows that tumors are able to create an immunosuppressive microenvironment by recruiting specific immune cells. Moreover, molecules produced by tumor and inflammatory cells in the tumor microenvironment create an immunosuppressive milieu able to inhibit the development of an efficient immune response against cancer cells and thus fostering tumor growth and progression. In addition, the immunoediting could select cancer cells that are less immunogenic or more resistant to lysis. In this review, we summarize recent findings regarding the immunomodulatory effects and cancer progression of the angiogenic growth factor namely placental growth factor (PlGF) and address the biological complex effects of this cytokine. Different pathways of the innate and adaptive immune response in which, directly or indirectly, PlGF is involved in promoting tumor immune escape and metastasis will be described. PlGF is important for building up vascular structures and functions. Although PlGF effects on vascular and tumor growth have been widely summarized, its functions in modulating the immune intra-tumoral microenvironment have been less highlighted. In agreement with PlGF functions, different antitumor strategies can be envisioned. [ABSTRACT FROM AUTHOR]

Polyphenols are natural antioxidant compounds ubiquitously found in plants and, thus, ever present in human nutrition (tea, wine, chocolate, fruits and vegetables are typical examples of polyphenol-rich foods). Widespread evidence indicate that polyphenols exert strong antioxidant, anti-inflammatory, anti-microbial and anti-cancer activities, and thus, they are generally regarded to as all-purpose beneficial nutraceuticals or supplements whose use can only have a positive influence on the body. A closer look to the large body of results of years of investigations, however, present a more complex scenario where polyphenols exert different and, sometimes, paradoxical effects depending on dose, target system and cell type and the biological status of the target cell. Particularly, the immunomodulatory potential of polyphenols presents two opposite faces to researchers trying to evaluate their usability in future cancer therapies: on one hand, these compounds could be beneficial suppressors of peri-tumoral inflammation that fuels cancer growth. On the other hand, they might suppress immunotherapeutic approaches and give rise to immunosuppressive cell clones that, in turn, would aid tumor growth and dissemination. In this review, we summarize knowledge of the immunomodulatory effects of polyphenols with a particular focus on cancer microenvironment and immunotherapy, highlighting conceptual pitfalls and delicate cell-specific effects in order to aid the design of future therapies involving polyphenols as chemoadjuvants. [ABSTRACT FROM AUTHOR]

Electrochemical reduced water (ERW) has been proposed to have beneficial effects on human health due to its rich content of H2 and the presence of platinum nanoparticles with antioxidant effects. Many studies have demonstrated that ERW scavenging properties are able to reduce the damage caused by oxidative stress in different experimental models. Although few in vivo studies have been reported, it has been demonstrated that ERW may display anticancer effects by induction of tumor cells apoptosis and reduction of both angiogenesis and inflammation. In this study, we show that ERW treatment of MCF-7, MDA-MB-453, and mouse (TUBO) breast cancer cells inhibited cell survival in a time-dependent fashion. ERW decreased ErbB2/neu expression and impaired pERK1/ERK2 and AKT phosphorylation in breast cancer cells. In addition, ERW treatment induced apoptosis of breast cancer cell lines independently of the status of p53 and ER and PR receptors. Our in vivo results showed that ERW treatment of transgenic BALB-neuT mice delayed the development of mammary tumors compared to the control. In addition, ERW induced a significant prolongation of tumor-free survival and a reduction in tumor multiplicity. Overall, these results suggest a potential beneficial role of ERW in inhibiting cancer cells growth. [ABSTRACT FROM AUTHOR]