An approach for understanding the inflammation and cancer relationship;

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An approach for understanding the inflammation and cancer relationship; Chronic and persistent inflammation contributes to cancer development and can predispose to carcinogenesis. Using Huang Bai (Cortex Phellodendri) and Huang Qin Radix Scutellariae) in cancer treatment
Chronic inflammation
Chronic and persistent inflammation contributes to cancer development and can predispose to carcinogenesis. Infection-driven inflammations are involved in the pathogenesis of approximately 15–20% of human tumours. However, even tumours that are not epidemiologically linked to pathogens are characterised by the presence of an inflammatory component in their microenvironment. Hallmarks of cancer-associated inflammation include the presence of infiltrating leukocytes, cytokines, chemokines, growth factors, lipid messengers, and matrix-degrading enzymes. Schematically, two interrelated pathways link inflammation and cancer: (1) genetic events leading to neoplastic transformation promote the construction of an inflammatory milieu; (2) tumour-infiltrating leukocytes, in particular macrophages, are prime regulators of cancer inflammation. Thus, an intrinsic pathway of inflammation (driven in tumour cells), as well as an extrinsic pathway (in tumour-infiltrating leukocytes) have been described and both contribute to tumour progression.
The link between inflammation and cancer proposed more than a century ago by Rudolf Virchow, who noticed the infiltration of leukocytes in malignant tissues, has recently found a number of genetic and molecular confirmations. Experimental, clinical and epidemiological studies have revealed that chronic inflammation contributes to cancer progression and even predisposes to different types of cancer. Cancer-associated inflammation includes: the presence of leukocyte infiltration; the expression of cytokines such as tumour necrosis factor (TNF) or interleukin (IL)-1; chemokines such as CCL2 and CXCL8; active tissue remodelling and neo-angiogenesis.
The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, ‘smouldering’ inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
Tumour-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. Many observations indicate that, in the tumour micro-environment, TAM have several protumoural functions, including expression of growth factors, matrix proteases, promotion of angiogenesis and suppression of adaptive immunity. In this review we will discuss the role of TAM in the inflammatory micro-environment of solid tumours and will try to identify potential target for future therapeutic approaches.Over the past several years, there has been a renaissance of research into connection between inflammation and cancer [1]. Inflammation is a physiological process crucial for the function of the innate immune system as it is a response to acute tissue damage, whether resulting from physical injury, ischemic injury, infection, exposure to toxins, or other types of trauma. It can play a role in tumor suppression by stimulating an antitumor immune response, but more often, under certain conditions, it appears to stimulate tumor development [2]. The intensity and nature of the inflammation could explain this apparent contradiction [1].
Inflammation may become chronic either because an inflammatory stimulus persists or because of dysregulation in the control mechanisms that normally turn the process off. Recently, it has been suggested that inflammation associated with cancer is similar to that seen with chronic inflammation, which includes the production of growth and angiogenic factors that stimulate tissue repair, factors that can also promote cancer-cell survival, implantation, and growth [3]. Thus immune response can promote anticancer effects or carcinogenesis and tumor growth [1]. Many cancers arise from sites of infection, chronic irritation, and inflammation (Fig. 1); thus, it is now clear that the tumor microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process altering not only the metabolic needs of the tissue, but also fostering DNA and protein damage, proliferation, survival, mutagenesis, migration and metastasis of malignant cells [4] and [5]. Indeed all tumors in the presence of stromal and infiltrating inflammatory cells are facilitated and helped to maintain these metastatic processes [6].
Leukocytes, lymphocytes and other inflammatory cells are activated in this process and attracted to the inflamed site. Inflammation contributes to initiation by inducing the release of a variety of pro-inflammatory cytokines and chemokines and inflammatory enzymes as cyclo-oxygenases that alert the vasculature to release inflammatory cells and factors into the tissue milieu, thereby causing oxidative damage, DNA mutations, and other changes in the microenvironment, making it more conducive to cell transformation, increased survival and proliferation [7]. We must not forget that many cytokines and chemokines are inducible by hypoxia which is a major physiological difference between tumor and normal tissue [8]. An important aspect of the tumor microenvironment is the cytokine mediated communication between the tumor and cells. Cytokines and chemokines have many activities that permit cell–cell communication locally at the tissue, with the outcome determined by cytokine concentration milieu and cell type [7]. Current thinking is that activated immune cells provide both anti- and protumorigenic signals, thus representing targets to be harnessed or attacked for therapeutic advantage depending upon environmental and/or cellular context.
Because the control of cytokine production is highly complex and multifactorial, the effects of cytokines are mediated through multiple regulatory networks. The intricate complexity of both cytokine networks clearly conceals the role that a single cytokine may play in the pathogenesis of the disease. It is therefore informative to investigate the immunopathogenesis of a disease process by analyzing multiple cytokines. Utilizing a broad-spectrum bead-based multiplex immunoassay, it is possible to effectively characterize the serum levels of cytokines that mediate humoral and cellular immunity and inflammation, to correlate these serum cytokine levels with disease activity, and to define the immunomodulatory effects of a therapy also after months of treatment. This can provide a better understanding of the role of cellular, humoral and chemotactic immunity at a critical time in some cancer diseases and also in the treatment course of an infection.

S. Costantini, F. Caponea, E. Guerrieroa and G. Castello. An approach for understanding the inflammation and cancer relationship. Immunology Letters. Volume 126, Issues 1-2, 22 September 2009, Pages 91-2. doi:10.1016/j.imlet.2009.08.006

Berberine, a isolate found in Chinese herbs, the primary sources are phellodendron and coptis (similar isoquinoline alkaloids, in these herbs, such as jateorrhizine, coptisine, palmatine, and columbamine, also have a yellowish color). Berberine has long been used as a dye; it is currently known as “natural yellow 18,” being one of about 35 yellow dyes from natural sources. Berberine is an anti-inflammatery and anti-tumourigenic (
Chronic inflammation

Phytochemicals show promise as potential chemopreventive or chemotherapeutic agents against various cancers. Here we report the chemotherapeutic effects of berberine, a phytochemical, on human prostate cancer cells. The treatment of human prostate cancer cells (PC-3) with berberine induced dose-dependent apoptosis but this effect of berberine was not seen in non-neoplastic human prostate epithelial cells (PWR-1E). Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins. This effect of berberine on prostate cancer cells was initiated by the generation of reactive oxygen species (ROS) irrespective of their androgen responsiveness, and the generation of ROS was through the increased induction of xanthine oxidase. Treatment of cells with allopurinol, an inhibitor of xanthine oxidase, inhibited berberine-induced oxidative stress in cancer cells. Berberine-induced apoptosis was blocked in the presence of antioxidant, N-acetylcysteine, through the prevention of disruption of mitochondrial membrane potential and subsequently release of cytochrome c and Smac/DIABLO. In conclusion, the present study reveals that the berberine-mediated cell death of human prostate cancer cells is regulated by reactive oxygen species, and therefore suggests that berberine may be considered for further studies as a promising therapeutic candidate for prostate cancer.
Meeran SM, Katiyar S, Katiyar SK. Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation. Toxicol Appl Pharmacol. 2008 May 15;229(1):33-43. Epub 2008 Jan 17.

Berberine, a naturally occurring isoquinoline alkaloid, has been shown to possess anti-inflammatory and antitumor properties in some in vitro systems. Here, we report that in vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10–100 ?mol/L) and time-dependent (24–72 hours) manner. Treatment of nonneoplastic human prostate epithelial cells (PWR-1E) with berberine under identical conditions did not significantly affect their viability. The berberine-induced inhibition of proliferation of DU145, PC-3, and LNCaP cells was associated with G1-phase arrest, which in DU145 cells was associated with inhibition of expression of cyclins D1, D2, and E and cyclin-dependent kinase (Cdk) 2, Cdk4, and Cdk6 proteins, increased expression of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27), and enhanced binding of Cdk inhibitors to Cdk. Berberine also significantly (P

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