Improving cachectic symptoms and immune strength of tumour-bearing mice in chemotherapy by a combination of Scutellaria baicalensis and Qing-Shu-Yi-Qi-Tang.

8th Monday, 2011  |   Herb or Compound  |  no comments

Wang H, Chan YL, Li TL, Wu CJ. Eur J Cancer. 2011 Jul 20. [Epub ahead of print] Figure 1: Scutellaria baicalensis or Chinese skullcap BACKGROUND: Cancer cachexia is characterised by the loss of body mass and directly compromises immune response and the quality of life of cancer patients. In the present study, we set out to investigate the role of Chinese herbs as anticancer medicines and/or chemotherapeutic adjuvants to increase therapeutic efficacy and/or ameliorate given side-effects in animal model. METHODS: Twelve kinds of herbs were chosen from the ingredients of major Chinese herbal medicines, and their effects on the antioxidant activity were investigated. To obtain the anticancer effects of 5-fluorouracil (5-FU) when consumed with minimal side-effects, we investigated the combination effect of Scutellaria baicalensis and Qing-Shu-Yi-Qi-Tang that may enhance the anticancer activity of 5-FU on subcutaneous tumour growth in C57BL/6 mice challenged with Lewis lung carcinoma cells. RESULTS: Qing-Shu-Yi-Qi-Tang, a multiple-component herbal extract, was shown to have high anti-oxidation activity, while S. baicalensis (Chinese skullcap) was demonstrated to have high tumour-growth inhibition activity. Thus, S. baicalensis and Qing-Shu-Yi-Qi-Tang were evaluated for their combinaton effects on the cancer-induced cachectic murine upon receiving 5-FU chemotherapy. As a result, tumour masses and losses of carcass and/or gastrocnemius muscle were found to be significantly decreased. This combination otherwise increased both Th1/Th2 ratio and NK cytotoxicity. In the mice receiving with or without 5-FU, the serum levels of monocyte chemoattractant protein-1 (MCP-1) increased by all means but otherwise decreased when the herbal combination was administrated. Additionally, the expressions of nuclear factor-kappa B (NF-?B) and muscle RING finger protein-1 (MuRF-1) decreased in the gastrocnemius muscle when the herbal combination was applied. CONCLUSION: Our results revealed that the combination of S. baicalensis and Qing-Shu-Yi-Qi-Tang is able to ameliorate cachectic symptoms and positively stimulate anti-tumour immunity while undergoing chemotherapy in animal model. Qing Shu Yi Qi Tang (Clear summer-heat and augment Qi) Xi Yang Shen (radix panacis quinquefolii) Xi Gua Pi (pericarpium citrulli vulgaris) Lian Geng (ramulus nelumbinis nuciferae) Shi Hu (herba dendrobii) Mai Men Dong (tuber ophiopogonis japonici) Dan

Zhu Ye (herba lphatheri gracilis) Zhi Mu (radix anemarrhenae asphodeloidis) Huang Lian (rhizoma coptidis) Gan Cao (radix glycyrrhizae uralensis) Geng Mi (non-glutinous rice)

Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin–Yang interplay between inflammation and cancer

2nd Tuesday, 2011  |   Inflammation  |  no comments

Danese S and Mantovani A. Oncogene 29, 3313-3323 (10 June 2010) | doi:10.1038/onc.2010.109
Colon cancer represents a paradigm for the connection between inflammation and cancer in terms of epidemiology and mechanistic studies in preclinical models. Key components of cancer promoting inflammation include master transcription factors (for example, nuclear factor ?B, STAT3), proinflammatory cytokines (for example, tumor necrosis factor, interleukin-6 (IL-6)), cyclooxygenase-2 and selected chemokines (for example, CCL2). Of no less importance are mediators that keep inflammation in check, including IL-10, transforming growth factor?, toll-like receptor and the IL-1 receptor inhibitor TIR8/SIGIRR, and the chemokine decoy and scavenger receptor D6. Dissection of molecular pathways involved in colitis-associated cancer may offer opportunities for innovative therapeutic strategies.

Tumor formation in humans is a multistage process involving a series of events and generally occurs over an extended period. During this process, accumulation of genetic and epigenetic alterations leads to the progressive transformation of a normal cell into a malignant cell. Cancer cells acquire several abilities that most healthy cells do not possess: they become resistant to growth inhibition, proliferate without dependence on growth factors, replicate without limit, evade apoptosis, and invade, metastasize, and support angiogenesis. It is now believed that 90–95% of all cancers are attributed to lifestyle, with the remaining 5–10% attributed to faulty genes

Metastasis: cancer cell’s escape from oxidative stress

1st Monday, 2011  |   Others  |  no comments

According to a “canonical” view, reactive oxygen species (ROS) positively contribute, in different ways, to carcinogenesis and to malignant progression of tumor cells: they drive genomic damage and genetic instability, transduce, as signaling intermediates, mitogenic and survival inputs by growth factor receptors and adhesion molecules, promote cell motility and shape the tumor microenvironment by inducing inflammation/repair and angiogenesis. Chemopreventive and tumor-inhibitory effects of endogenous, diet-derived or supplemented antioxidants largely support this notion.

Metastasis has been traditionally interpreted, in a darwinistic perspective, as a process whereby genetic instability in the primary tumor fuels cell heterogeneity, allowing few metastatic clones to eventually emerge and be positively selected to disseminate cancer at distance. It has also been suggested, based on genetic disparity between primary and metastatic tumors, that metastases may arise from cells leaving the primary tumor lesion at an early stage of its local progression, and thus develop in a parallel rather than sequential fashion with respect to the lesion of origin (Klein, 2009). Either way, it is becoming increasingly clear that only a minority of malignant cells undertakes the metastatic route, and, of those, an even smaller fraction succeeds in this task. Evidence also exists that these cells may share some properties with somatic or embryonic stem cells (Barnhart & Simon, 2007; Mani et al, 2008), which has led to the hypothesis that metastases are initiated by cell clones endowed of unique self-renewal and tumor propagating capacity, i.e., by cancer stem cells (CSC).

While molecular strategies employed by metastatic cells to leave the primary tumor, intravasate, disseminate at distance and grow into new colonies are being intensively and successfully investigated, less clear is what actually prompts some tumor cells to leave the primary tumor, or, in other words, what kind of environmental pressure operates on cells bound to a metastatic fate. We know, however, that a tumor can be a very hostile environment, due to shortage of oxygen and nutrients, inflammation and immune system attacks, and that both hypoxia and inflammation promote metastasis Bertout et al, 2008; Mantovani, 2009). Thus, metastasis may ultimately represent an escape strategy from cell death.

Fig. 1: ROS and/or RNS play important and multiple roles in each of the six hallmarks of cancers. Based on the model by Hanahan and Weinberg (2000), cellular and molecular mechanism for which a role for ROS/RNS has been demonstrated are indicated for each hallmark,
in the same color.
1. GROWTH EVEN IN THE ABSENCE OF NORMAL “GO” SIGNALS: Most normal cells wait for an external message before dividing. Conversely, cancer cells often counterfeit their individual proliferative messages.
2. GROWTH DESPITE “STOP” COMMANDS: As the tumor enlarges, it squeezes adjacent tissues and therefore receive messages that would normally stop cell division. Malignant cells ignore these commands.
3. ABILITY TO INVADE TISSUES AND SPREAD TO OTHER ORGANS: Cancers usually lead to death only after they overcome their confines to the particular organ in which they arose. Cancer cells need to escape the primary tumor, invade matrix of different organs,
find a suitable metastatic niche and then grow in this secondary site.
4. EFFECTIVE IMMORTALITY: Healthy cells can divide no more than 70 times, but malignant cells need more than 70 cycles to make tumors. Hence, tumors need to enforce the reproductive limit of cells.
5. ABILITY TO STIMULATE BLOOD VESSEL DE-NOVO ASSEMBLY: Tumors need oxygen and nutrients to survive and secrete factors recruiting new branches that run throughout the growing mass.
6. EVASION FROM ENDOGENOUS AUTODESTRUCT MECHANISMS: In healthy cells, several conditions (including genetic damage or lack of ECM adhesion) activates a suicide program, but tumor cells bypass these mechanisms, thereby surviving to death messages

Oxidative Damage
However, emerging lines of evidence indicates that tumor cells also need to defend themselves from oxidative damage in order to survive and successfully spread at distance. This “heresy” has recently received important impulse from studies on the role of antioxidant capacity in cancer stem cells self renewal and resistance to therapy; additionally, the transforming activity of some oncogenes has been unexpectedly linked to their capacity to maintain elevated intracellular levels of reduced glutathione (GSH), the principal redox buffer. These studies underline the importance of cellular antioxidant capacity in metastasis, as the result of a complex
cell program involving enhanced motility and a profound change in energy metabolism. The glycolytic switch (Warburg effect) observed in malignant tissues is triggered by mitochondrial oxidative damage and/or activation of redox sensitive transcription factors, and results in an increase of cell resistance to oxidants. On the other hand, cytoskeleton rearrangement underlying cell motile and tumor-aggressive behavior use ROS as intermediates and are therefore facilitated by oxidative stress. Along this line of speculation, we suggest that metastasis represents an integrated strategy for cancer cells to avoid oxidative damage and escape excess ROS in the primary tumor site, explaning why redox signaling pathways are often up-regulated in malignancy and metastasis.

Figure 2:
Antioxidant function of redox signaling and metastasis. Unfavorable environmental conditions that favor metastasis (inflammation, hypoxia, nutrient starvation, etc.) are associated with heavy oxidative stress.We speculate that redox cascades that lead to glycolytic switch, cell proliferation and motility/invasion and are activated in metastasis have originally evolved for the purpose of rescuing normal cells fromoxidative damage and allowing tissue repair (left side of the figure). Redox switches may have subsequently been incorporated into ligand (growth factors, ECM, semaphorins)-dependent cascaded that use NOXes, and other oxidases, as components of “normal” cell signaling (right side).
Oncogene-driven carcinogenesis hijacks these cascades, leading eventually to metastasis as the malignant counterpart of the original antioxidant response (right side). Metastasis may therefore be part of an integrated strategy whereby malignant cells escape oxidative damage at the primary tumour site.

Redox Signaling
Knowledge on the molecular mechanism and the biological contexts whereby oxidants (oxygen and nitrogen species) operate as signaling molecules has been expanding at an impressive rate over the last few years (Janssen-Heininger et al, 2008). “Redox signaling” has rapidly turned into a major area of “mainstream” cellular and molecular biology, with huge implications for human diseases. Yet, why cells use to regulate basic functions like proliferation/death, motility, and energy metabolism such dangerous compounds as nitrogen and oxygen species, is still far from clear, and it is reasonable to think that safer messenger molecules and molecular devices could serve the same scope.
One attractive possibility is that redox signaling has evolved for the main purpose of allowing cells to sense and avoiding oxidative stress and damage (Figure 2). At a single cell level, this idea is consistent with the observation that oxygen and nitrogen species play a central role in cell dynamic and in the triggering of antioxidant responses, two different and complementary strategies to reduce exposure to harmful oxidants. Yet cells die if stress is too massive, or if glucose in not available to maintain redox buffers. In a multicellular organism, redox signals gain two additional important functions related to tissue repair: regulation of cell.
Source:
Pani, G., Galeotti, T., & Chiarugi, P. Metastasis: cancer cell’s escape from oxidative stress. Cancer Metastasis Rev (2010) 29:351–378. DOI 10.1007/s10555-010-9225-4
References:
Barnhart, B. C., & Simon, M. C. (2007). Metastasis and stem cell pathways. Cancer and Metastasis Reviews, 26, 261–271.
Bertout, J. A., Patel, S. A.,& Simon, M. C. (2008). The impact of O2 availability on human cancer. Nature Reviews Cancer, 8, 967–975.
Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57–70.
Janssen-Heininger, Y. M., Mossman, B. T., Heintz, N. H., Forman, H. J., Kalyanaraman, B., Finkel, T., et al. (2008). Redox-based regulation of signal transduction: principles, pitfalls, and promises. Free Radical Biology and Medicine, 45, 1–17.
Klein, C. A. (2009). Parallel progression of primary tumours and metastases. Nature Reviews Cancer, 9, 302–312.
Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., et al. (2008). The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell, 133, 704–715.
Mantovani, A. (2009). Cancer: inflaming metastasis. Nature, 457, 36–37.

Microbial deprivation, inflammation and cancer

1st Monday, 2011  |   Inflammation  |  no comments

Sufficient exposure to a large variety of microbes is likely crucial for the development of a normally functioning immune system and for prevention of cancerous growths. The modern lifestyles may reduce this substantially, and, therefore, further studies to unravel the potential influence of microbial exposure on tumorigenesis are highly warranted and might pave a way for novel strategies for cancer prevention and therapy

Dysregulated immune function is involved in the pathogenesis of many common human diseases. Living in urban, microbe-poor environment may have a profound influence on the immune function and eventually also on carcinogenesis. Unfortunately, few studies have thus far addressed the role of exposure to the environmental microbiota on the risk of cancer. Which mechanisms are broken in individuals prone to develop chronic inflammation in response to exposure that does not cause harm in others? Recent work in immunology has revealed that Th17 cells, a third subset of Th cells, and inflammatory cytokines, particularly IL-23, are closely linked with tumour-associated inflammation. Albeit the precise role of Th17 cells in cancer is still unclear and a matter of debate, accumulating evidence shows that Th17 cells are enriched in a wide range of human tumours, and that these tumour-derived Th17 cells may promote angiogenesis, tumour growth and inflammation. Regulatory T cells, in turn, appear to have counter-regulatory effects on Th17 cells and can inhibit their function. Thus, the regulatory network, induced and strengthened by continuous exposure to environmental microbiota, may play an important role in tumour immunobiology in preventing the establishment of chronic inflammation in its early phases. In addition, the discovery of the Toll-like receptor (TLR) system has brought micro-organisms to new light; continuous signalling via these TLRs and other receptors that sense microbial components is necessary for epithelial cell integrity, tissue repair, and recovery from injury. In this communication, we summarise the epidemiological data of living in environments with diverse microbial exposures and the risk of cancer, and discuss the related immunological mechanisms, focusing on the links between environmental microbiota, the Th17/IL-23 axis and cancer-associated inflammation.

The link between cancer and inflammation was recognised by Virchow already in the 1860s (Balkwill & Mantovani, 2001). Epidemiological studies have further shown that chronic inflammation may predispose to some cancer (Vesterinen et al, 1993; Rubio et al, 2009) and in turn, that a regular use of non-steroidal anti-inflammatory drugs may reduce the risk of breast and colon cancer (Smyth et al, 2009; Wang et al, 2007). Inflammatory cells and mediators are present in the microenvironment of virtually all types of tumours in experimental settings and in humans from the early stages of development (Mantovani et al, 2008).
Carcinogenesis has been associated with chronic irritation, inflammation and tissue damage, and defective homeostatic mechanisms that govern tissue repair and stem cell renewal may be involved (Vakkila et al, 2004). Triggering factors include pathogens, irritants, toxic compounds and particles, and even components from changed tissues of the host (Medzhitov, 2008). The continuous state of repair and inflammation leads to the sustained presence of signalling molecules (cytokines, chemokines and non-cytokine mediators, such as Cox-2 and prostaglandins), angiogenesis and tissue remodelling. The states of repair and scarring continue as, due to defective homeostatic mechanisms, the cells are unable to return to quiescence that normally follows regeneration (Beachy et al, 2004). In this vicious circle, cancer-associated inflammation may further promote, rather than inhibit, tumour growth and progression (Mantovani, 2005).

Fig. 1 The involvement of environmental microbiota, receptors (TLRs, NLRs) on/in innate immune cells recognising microbial structures and the regulatory network in prevention of the Th17/IL-23-mediated chronic inflammation associated with carcinogenesis. Establishment of chronic inflammation can be prevented via at least two different mechanisms; via TLR/NLR triggering by microbial components which enhances epithelial cell homeostasis and tissue repair after injury (left arm), or via the regulatory network, primarily T reg cells and DCs secreting regulatory cytokines which prevent the production of pro-inflammatory cytokines and non-cytokine mediators by inflammatory cells (right arm). NLR, Nod nucleotide-binding oligomerisation domain-like receptor, TLR Toll-like receptor, DC dendritic cell, T reg regulatory T cell

Th1 immunity has traditionally been considered an important defence mechanism in immunosurveillance influencing tumour development and progression. T reg cells in turn have been viewed as deleterious promoting cancer progression. Novel data have added another level of complexity to this issue. Immune cells in human tumours have recently been found to produce high levels of IL-23, a cytokine linked with a new subset of Th cells, Th17 cells. Inflammation exerted by this Th17/IL-23 axis is associated with tumour progression, and suppressing this inflammation in early phases by T reg cells may hinder the progression (Figure). In advanced cancers, the presence of T reg cells could indicate the host’s attempt to limit the severe tumour-associated inflammation, and/or T reg cells may participate in the process by downregulating the antitumour activity of effector cells. In addition, both Th17 and T reg cells have shown considerable plasticity, albeit the relevance of this plasticity to tumorigenensis in humans is incompletely understood.
Epidemiological data suggest that exposure to environmental microbiota might be associated with protection against major cancers, but many other factors can also be involved. Experimental models using various microbial components lend some further support to this hypothesis. Continuous microbial exposure may be associated with
1. Activation of microbial receptors on/in immune and other cells, which may have direct antitumour effect and an indirect effect by endorsing innate immunity and homeostatic mechanisms,
2. Strengthening of the regulatory network, which in turn can prevent or dampen in early phases the development of Th17 cells and inflammatory mediators, such as Cox-2 and PGE2, central to cancer-promoting inflammation.

Source:
von Hertzen LC, Joensuu H & Haahtela T. Microbial deprivation, inflammation and cancer. Cancer and Metastasis Reviews. DOI: 10.1007/s10555-011-9284-1
References:
Balkwill, F., & Mantovani, A. (2001). Inflammation and cancer: Back to Virchow? Lancet, 357, 539–545.
Beachy, P. A., Karhadkar, S. S., & Berman, D. M. (2004). Tissue repair and stem cell renewal in carcino-genesis. Nature, 432, 324–331.
Mantovani, A. (2005). Cancer: Inflammation by remote control. Nature, 435, 752–753.
Mantovani, A., Allavena, P., Sica, A., & Balkwill, F. (2008). Cancer-related inflammation. Nature, 454, 436–444.
Medzhitov, R. (2008). Origin and physiological roles of inflammation. Nature, 454, 428–435.
Rubio, C. A., Kapraali, M., & Befrits, R. (2009). Further studies on the frequency of colorectal cancer in Crohn’s colitis: An 11-year survey in the Northwest Stockholm County. Anticancer Research, 29, 4291–4295.
Smyth, E. M., Grosser, T., Wang, M., Yu, Y., & FitzGerald, G. A. (2009). Prostanoids in health and disease. Journal of Lipid Research, 50, S423–S428.
Vakkila, J., & Lotze, M. T. (2004). Inflammation and necrosis promote tumour growth. Nature Reviews. Immunology, 4, 641–648.
Vesterinen, E., Pukkala, E., Timonen, T., & Aromaa, A. (1993). Cancer incidence among 78,000 asthmatic patients. International Journal of Epidemiology, 22, 976–982.
Wang, M. T., Honn, K. V., & Nie, D. (2007). Cyclooxygenases, prostanoids, and tumor progression. Cancer and Metastasis Reviews, 26, 525–534.

Tocotrienols: Inflammation and Cancer

29th Friday, 2011  |   Inflammation  |  no comments

Inflammation is an organism’s response to environmental assaults. It can be classified as acute inflammation that leads to therapeutic recovery or chronic inflammation, which may lead to the development of cancer and other ailments. Genetic changes that occur within cancer cells themselves are responsible for many aspects of cancer development but are dependent on ancillary processes for tumor promotion and progression. Inflammation has long been associated with the development of cancer. The distinct characteristics of cancer cells to proliferate, metastasize, evade apoptotic signals, and develop chemoresistance have been linked to the inflammatory response. Due to the involvement of multiple genes and various pathways, current drugs that target single genes have not been effective in providing a therapeutic cure. On the other hand, natural products target multiple genes and therefore have better success compared to drugs. Tocotrienols, the potent isoforms of vitamin E, are such a natural product. This review will discuss the relationship between cancer and inflammation with particular

focus on the roles played by NF-?B, STAT3, and COX-2.
NF-B and its gene products have been closely linked to cancer development and progression. As synthetic drugs have adverse effects, natural chemopreventive agents have thus been vastly investigated because of their availability and reduced toxicity. Tocotrienols were initially recognized for their role as an antioxidant. However, the emerging results on their anticancer, anti-angiogenic, antiproliferative, and immune enhancement activity broaden the horizon for the usage of tocotrienols in the field of cancer research. The currently available in vitro and in vivo studies have provided valuable information that proves tocotrienols’ potential beyond their antioxidant capacity. However, due to the close association between the proinflammatory cytokines and cancer, there is an urgent need to look into the molecularmechanisms on how tocotrienolsmay affect these inflammatory markers. The combination study of tocotrienols with low-dose celocoxib has indeed enhanced the therapeutic effect. This has provided evidence for the synergistic activity of tocotrienols with other drugs. Based on the promising results obtained from preclinical studies, more clinical trials and molecular analyses should be conducted to provide us with the essential information to utilize the anti-inflammatory effect of tocotrienols in the diagnosis, prognosis, and treatment of cancer patients.

Source:
Nesaretnam K & Meganathan P. Annals of the New York Academy of Sciences. Volume 1229, Nutrition and Physical Activity in Aging, Obesity, and Cancer pages 18–22, July 2011. DOI: 10.1111/j.1749-6632.2011.06088.x