Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-kappaB (NF-kappaB) and interleukin-6 (IL-6)-GP130-Janus kinase (JAK) pathways, and by opposing STAT1- and NF-kappaB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy.

/pdf/stats-in-cancer-inflammation-and-immunity-a-leading-role-for-qkgjepy6w9.pdf

STATs in cancer inflammation and immunity: a leading role for STAT3

■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

https://jeffreydachmd.com/wp-content/uploads/2015/01/Molecular-targets-of-dietary-agents-prevention-cancer-aggarwal-2006.pdf

Molecular targets of dietary agents for prevention and therapy of cancer

The normal development and maintenance of the prostate is dependent on androgen acting through the androgen receptor (AR). AR remains important in the development and progression of prostate cancer. AR expression is maintained throughout prostate cancer progression, and the majority of androgen-independent or hormone refractory prostate cancers express AR. Mutation of AR, especially mutations that result in a relaxation of AR ligand specificity, may contribute to the progression of prostate cancer and the failure of endocrine therapy by allowing AR transcriptional activation in response to antiandrogens or other endogenous hormones. Similarly, alterations in the relative expression of AR coregulators have been found to occur with prostate cancer progression and may contribute to differences in AR ligand specificity or transcriptional activity. Prostate cancer progression is also associated with increased growth factor production and an altered response to growth factors by prostate cancer cells. The kinase signal transduction cascades initiated by mitogenic growth factors modulate the transcriptional activity of AR and the interaction between AR and AR coactivators. The inhibition of AR activity through mechanisms in addition to androgen ablation, such as modulation of signal transduction pathways, may delay prostate cancer progression.

/pdf/androgen-receptor-in-prostate-cancer-34uq77b1pv.pdf

Androgen Receptor in Prostate Cancer

Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation in various skin diseases including, premature aging of the skin and melanoma and non-melanoma skin cancers. Chronic UV radiation exposure-induced skin diseases or skin disorders are caused by the excessive induction of inflammation, oxidative stress and DNA damage, etc. The use of chemopreventive agents, such as plant polyphenols, to inhibit these events in UV-exposed skin is gaining attention. Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of these harmful events in the UV-exposed skin. A wide variety of polyphenols or phytochemicals, most of which are dietary supplements, have been reported to possess substantial skin photoprotective effects. This review article summarizes the photoprotective effects of some selected polyphenols, such as green tea polyphenols, grape seed proanthocyanidins, resveratrol, silymarin and genistein, on UV-induced skin inflammation, oxidative stress and DNA damage, etc., with a focus on mechanisms underlying the photoprotective effects of these polyphenols. The laboratory studies conducted in animal models suggest that these polyphenols have the ability to protect the skin from the adverse effects of UV radiation, including the risk of skin cancers. It is suggested that polyphenols may favorably supplement sunscreens protection, and may be useful for skin diseases associated with solar UV radiation-induced inflammation, oxidative stress and DNA damage.

/pdf/skin-photoprotection-by-natural-polyphenols-anti-2uq3372u23.pdf

Skin photoprotection by natural polyphenols: anti-inflammatory, antioxidant and DNA repair mechanisms

Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells

Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells.

We have reported recently the anticancer effect of flavonoid antioxidant silymarin, the major part of milk thistle extract, against advanced human prostate carcinoma DU145 cells (X. Zi et al. , Cancer Res., 58: 1920–1929, 1998) and later identified that silibinin is the main active component in silymarin responsible for its effect in cell culture studies. On the basis of these observations, here we assessed in vivo growth inhibitory potential of silibinin against advanced human prostate cancer (PCA). Dietary feeding of silibinin at 0.05 and 0.1% doses (w/w) for 60 days, 24 h after s.c. DU145 tumor xenograft implantation in athymic male nude mice, significantly inhibited tumor volume by 35 and 58% ( P < 0.05), and wet weight of tumor by 29 and 40% ( P < 0.05), respectively. In a second experiment where mice were fed with these test diets for 3 weeks before tumor xenograft implantation and continued on these diets for a total of 63 days, tumor volume and wet weight of tumor were reduced by 53–64% ( P < 0.001–0.05) and 31–52% ( P < 0.05), respectively. In both studies, animals did not show weight loss or reduced food consumption. These in vivo anticancer effects of silibinin were associated with an increased accumulation (up to 5.8 fold; P < 0.05) of human insulin-like growth factor-binding protein-3 in mouse plasma. In additional studies assessing biological availability of silibinin in nude mice and its antiproliferative activity at such doses in DU145 cells in culture, silibinin levels in plasma and prostate were found to be in the range of 7–13 μg/ml and 3.7–4.6 μg/g, respectively. At these biologically achievable silibinin concentrations, increased IGFBP-3 level in DU145 cell culture medium and a strong DU145 cell growth inhibition were observed that were irreversible in the absence of silibinin in culture medium. These findings extend and translate our observations on in vitro anticancer effect of silibinin/silymarin to an in vivo preclinical PCA model, which may form the basis for a Phase I clinical trial in PCA patients.

https://cancerres.aacrjournals.org/content/canres/62/11/3063.full.pdf

Dietary Feeding of Silibinin Inhibits Advance Human Prostate Carcinoma Growth in Athymic Nude Mice and Increases Plasma Insulin-like Growth Factor-binding Protein-3 Levels

Dietary intake of many fruits and vegetables has been shown to be associated with reduced risk of cancer. We investigated the in vivo efficacy of grape seed extract (GSE, patented as Traconol) against prostate cancer (PCA) and associated molecular events. Athymic nude mice were implanted with hormone-refractory human prostate carcinoma DU145 cells and fed with 100 and 200 mg/kg/day (5 days/week) doses of GSE for 7 weeks. At the end of experiment, tumors were immunohistochemically analyzed for cell proliferation, apoptosis and angiogenesis. Our data show that GSE feeding strongly inhibited tumor growth that accounted for 59-73% (p < 0.001) inhibition in tumor volume and 37-47% (p < 0.05) decrease in tumor weight at the end of the experiment. It did not show any significant change in body weight gain profile and diet consumption. Immunohistochemical analysis of tumors showed that GSE decreases proliferation index by 51-66% (p < 0.001) and increases apoptotic index by 3-4-fold (p < 0.001). CD31 staining for endothelial cells, showed decrease in intratumoral microvasculature in GSE-fed group of mice. Control tumors showed 64.0 +/- 1.6 CD31 positive cells/400x field compared to 23.2 +/- 0.9 and 15.7 +/- 0.08 (p < 0.001) CD31 positive cells in 100 and 200 mg/kg doses of GSE-treated tumors, respectively. GSE strongly inhibited (47-70%, p < 0.05) vascular endothelial growth factor (VEGF) secretion in conditioned medium by DU145 cells. Recently, the circulating level of insulin-like growth factor binding protein (IGFBP)-3 is shown to inversely related with PCA risk, growth and prognosis. Consistent with this, we observed 6-7-fold (p < 0.001) increase in tumor-secreted levels of IGFBP-3 after GSE feeding. In other immunohistochemical studies, compared to controls, tumor xenografts from GSE-fed groups of mice showed a moderate decrease in VEGF but an increase in IGFBP-3 levels. These findings suggest that GSE possesses in vivo anticancer efficacy against hormone-refractory human PCA, which is associated with its antiproliferative, proapoptotic and antiangiogenic activities together with upregulation of IGFBP-3.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.11620

Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3.

The multistep nature of cancer development provides a rationale for cancer prevention. Activation of oncogenes, inactivation of tumor suppressor genes and modulation of mitogenic signal transduction pathways are critical in cancer progression and present attractive targets for cancer prevention/intervention. In this respect, cell cycle regulation and its modulation by various natural (plant-derived) and synthetic agents are gaining widespread attention in recent years. A number of phytochemicals inhibit cell cycle progression in cancer cells, yet their clinical applications are still in infancy. The present review is focused on the modulatory effects of phytochemicals on critical cell cycle molecules, and discusses how they inhibit proliferation and/or induce apoptotic death in cancer cells. Key Words:Cell cycle, Cyclins, Growth factors, Oncogenes

Phytochemicals as cell cycle modulators--a less toxic approach in halting human cancers.

Prostate cancer (PCA) is one of the most common invasive malignancies of men in the US, however, there have been limited successes so far in its therapy. Even most potent agents (e.g. TNFalpha) are ineffective in killing human PCA cells possibly due to constitutive activation of NF-kappaB that subsequently activates a large number of anti-apoptotic genes. In such a scenario, strong apoptotic agent TNFalpha, further induces NF-kappaB activation rather than inducing apoptosis. In several recent studies, we have demonstrated both cancer preventive and anti-cancer efficacy of silymarin and its constituent silibinin in a variety of experimental tumor models and cell culture systems. Here we examined whether silibinin is effective in inhibiting constitutive NF-kappaB activation in human PCA cells, which would help in overcoming TNFalpha-insensitivity. Our studies reveal that silibinin effectively inhibits constitutive activation of NF-kappaB in advanced human prostate carcinoma DU145 cells. Consistent with this, nuclear levels of p65 and p50 sub-units of NF-kappaB were also reduced. In the studies assessing molecular mechanism of this effect, silibinin treatment resulted in a significant increase in the level of IkappaBalpha with a concomitant decrease in phospho-IkappaBalpha. Kinase assays revealed that silibinin dose-dependently decreases IKKalpha kinase activity. The effect of silibinin on IKKalpha seemed to be direct as evidenced by the in vitro kinase assay, where immunoprecipitated IKKalpha was incubated with silibinin. This shows that silibinin does not necessarily need an upstream event to bring about its inhibitory effect on IKKalpha and downstream effectors. Additional studies showed that silibinin also inhibits TNFalpha-induced activation of NF-kappaB via IkappaBalpha pathway and subsequently sensitizes DU145 cells to TNFalpha-induced apoptosis. These results indicate that silibinin could be used to enhance the effectiveness of TNFalpha-based chemotherapy in advanced PCA.

Silibinin inhibits constitutive and TNFalpha-induced activation of NF-kappaB and sensitizes human prostate carcinoma DU145 cells to TNFalpha-induced apoptosis.

Sivanandhan Dhanalakshmi

Papers

Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells.

Dietary Feeding of Silibinin Inhibits Advance Human Prostate Carcinoma Growth in Athymic Nude Mice and Increases Plasma Insulin-like Growth Factor-binding Protein-3 Levels

Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3.

Phytochemicals as cell cycle modulators--a less toxic approach in halting human cancers.

Silibinin inhibits constitutive and TNFalpha-induced activation of NF-kappaB and sensitizes human prostate carcinoma DU145 cells to TNFalpha-induced apoptosis.