Schematic drawing of signal transduction pathways of apoptotic signals and targets of some natural compounds with stimulating activity. Abbreviations: TNF = Tumor Necrosis Factor; FAS = Fragment Apoptosis Stimulant; TRAIL = Tumor-necrosis-factor Related Apoptosis Inducing Ligand; APAF-1 = Apoptosis Activator Factor-1; Bcl-2 = B-cell lymphoma 2; Bax = Bcl-2-associated X protein; Bak = Bcl-2 homologous antagonist killer; SMAC = Second Mitocondrial Activator of Caspase; IAPs = Inhibiting Apoptosis Proteins; FADD = Fas-Associated protein with Death Domains; cFLIP = cellular caspase 8 (FLICE)-Inhibitory Protein; FLICE (also called caspase 8) = Fas-associated protein with death domain-Like IL- 1β -Converting Enzyme-inhibitory protein; BID = BH3 (Bcl-2 Homology-3)- Interacting Domain death agonist; tBID = Truncated BID. 

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... cell lines. The extracts exerted cytotoxic effects against various cell lines at relatively low doses (between 12 and 47 μg/ ml). The activity of the detoxification enzymes glutathione-S-transferase and quinone reductase is increased in the liver and stomach of animals fed with diets containing rosemary extract (Singletary and Rokusek, 1997). ( ... omissis ... ). The most active component of basil is ursolic acid, a triterpenoid, also derived from rosemary, whose antitumoral activity has recently been investigated (Sultana, 2011). Ursolic acid acts as an antitumor-promoting agent, inhibiting inflammation produced by tumor promoters and suppressing the expression of c-jun and c-fos oncogenes (Liu, 1995). ( ... omissis ... ). ( ... omissis ... ) The components of Aloe vera , in particular emodin, may well inhibit tumor growth, reduce tumor mass and inhibit metastasis (Akev et al. 2007; He et al., 2008). Some recent studies suggest an antiproliferative effect on cancer cells in vitro (El-Shemy et al., 2010) but evidence from clinical trials is currently lacking. ( ... omissis ... ). ( ... omissis ... ). Extensive studies suggest that capsaicin is also a cancer-suppressing agent through its antioxidant and anti- inflammatory activities , by blocking several signal transduction pathways, including Nf-kB and AP-1 (Surh et al., 1998; Surh 2002; Bai et al., 2011). In the context of chronic pancreatitis, capsaicin demonstrates strong activities against inflammation and proliferation and can inhibit progression of murine Pancreatic Intraepithelial Neoplasia (mPanIN) lesions and carcinogenesis, by blocking phospho-ERK and Hedgehog/GLI pathway activation. ( ... omissis ... ). ( ... omissis ... ) The effect of β -carotene supplementation on cancer incidence has been investigated in several randomized controlled trials. β -carotene has been proven to have anti-carcinogenic activity in several tissues, although high doses of β -carotene as dietary supplements failed to exhibit chemopreventive activity in clinical trials (Druesne-Pecollo et al., 2010). ( ... omissis ... ). ( ... omissis ... ). The use of juice, peel and oil has been shown to possess anticancer activities, including interference with tumor cell proliferation, cell cycle, invasion and angiogenesis (Adhami et al., 2009). These may be associated with plant based anti-inflammatory effects. Only a few well controlled clinical trials have been completed, despite the impressive amount of preclinical work indicating cancer preventive or therapeutic efficacy with limited toxicity (Lansky and Newman, 2007). ( ... omissis ... ). Radix curcumae , commonly known as turmeric, is a Chinese medicinal herb commonly used as food flavouring worldwide, to which a role is attributed in the treatment of malignancy and several other diseases such as liver cirrhosis, chronic renal disease, chronic obstructive lung disease, diabetes (Bengmark et al., 2009). ( ... omissis ... ). Cancer is a complex disease initiated by genetic mutations and carried out by continuous cell deregulation at many levels. Unrestrained cell proliferation and defective apoptosis are hallmarks of oncogenic transformation. Oncogenes and tumor suppressor genes are implied in cancer transformation and food components are a source of important molecules with biological activities acting on neoplastic progression. Since genetic and epigenetic abnormalities have been shown to be both causative and contributing factors in cancer initiation and/or progression, natural compounds that are regulators of the epigenome constitute an excellent approach in cancer prevention and potentially in anti-cancer therapy. Several nutrients have been shown to affect DNA methylation, target histone modification and regulate oncogenic and tumour suppressor micro-RNAs (Stefanska et al., 2012). Oncogenes are genes that promote cell cycle and cell proliferation and allow escaping from apoptosis, acting in a dominant fashion as a single alteration in one copy, inducing neoplastic growth. Figure 1 describes some molecular targets of natural compounds derived from foods and herbs on the signal transduction pathways and oncogenes that are involved in cell proliferation as is in turn stimulated by epidermal growth factor (EGF). Tumor suppressor genes are genes that negatively regulate cell cycle and cell proliferation, promoting apoptosis and differentiation. Tumor suppressor genes are involved in repairing DNA damage and both copies need to be inactivated, in order to promote cancer development, as Knudson's “two - hits” theory says. Conversely, agents that enhance the activity of defective oncogenes and/or stimulate apoptosis may slow down cell cancer growth. Apoptosis is controlled by two diverse pathways, the intrinsic or mitochondrial-mediated pathway and the extrinsic or death receptor-mediated pathway. A long list of dietary constituents is known to induce apoptosis of cancer cells without affecting normal cells (Khan et al., 2008). Figure 2 illustrates the major activation pathways, molecular steps and control systems of cell apoptosis, with indications of the demonstrated targets of several compounds described in this review. During the past several decades, there has been growing interest in natural products for the cure and prevention of cancer. The concept of disease prevention is becoming more and more attractive as healthcare costs continue to escalate. Strongest data, pointing to cancer chemoprevention by food components, is currently coming from epidemiological studies and from in vitro cell cultures, whereas the clinical evidence from intervention trials remains scanty. A large number of epidemiological observations have established links between diet and disease prevention, a number of biologically active compounds have been identified and a few plants used in folk and traditional medicine have been scientifically explored (Mukherjee et al., 2001). Recent studies have shown that conventional cancer therapies, such as chemotherapy, radiotherapy and surgery, could be administered in association with co-adjuvant therapies. Together, these can improve the prognosis and the quality of life for cancer patients. As a result, there is major interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow for decreased side effects and toxicity, without compromising therapeutic efficacy. Fruit, vegetables, herbs and spices comprise a plethora of opportunities for drug discovery. Unfortunately, at this time none of the completed trials have produced forceful evidence to justify the use of traditional antioxidant-related vitamins or minerals for cancer prevention. At the present time, acquired knowledge in the nutritional science shows that specific antioxidant activity is not the only mechanism of action for vitamins and minerals. Antioxidants and other components contained in foods act in synergy, with the consequence that the use of single substances at high doses could exert a paradoxical effect. The lack of success may be explained by a variety of factors that need to be considered for the next generation research. These factors include the following: a lack of good biological rationale for selecting specific agents of interest; a limited number of agents clinically tested; the use of pharmacological, rather than dietary doses and an insufficient duration of intervention and follow-up. These results are consistent with the hypothesis that the effects of antioxidant use may only be detectable at a subclinical (molecular) level, whereas a reduction in risk of clinically detectable disease requires prolonged exposures that may not be achievable in a traditional cancer prevention trial. Moreover, it is necessary to highlight that it is not possible to directly deduce a safe clinical effectiveness from in vitro models alone, since cell lines are not necessarily representative of complex tissue and organic systems that one would want to treat in human cancer (Goodman et al., 2011). There is also the problem of the biphasic effects , a phenomenon also called “hormesis” ( Calabrese, 2008) and consequently the selection of an appropriate dosage becomes a critical issue. For example, although genistein has many potentially therapeutic actions, its biphasic activity (cytotoxic at higher concentrations and vitalizing at low concentrations) requires caution in determining the therapeutic dose (Ravindranath et al., 2004). Similarly, resveratrol induces hormesis-like biphasic dose responses in a wide range of human tumor cell lines affecting breast, prostate, colon, lung, uterine and leukemia (Calabrese et al., 2010): this compound at low doses acts as an anti-apoptotic agent while at higher doses it acts as a pro-apoptotic compound, inducing . apoptosis in cancer cells, by exerting a death signal (Mukherjee et al., 2010). Quercetin is a powerful dietary polyphenol that can exert hormetic dose-responses on cells, depending on its concentration and on the agonist receptors used (Vargas and Burd, 2010; Chirumbolo et al., 2010). Another example of these complexities is given by folic acid or folate (the form naturally occurring in the body). Some investigations have proposed that diets high in folate may be related to a lower risk of colorectal cancer (Sanjoaquin et al., 2005). However, folate is important for cells and tissues that rapidly divide; many cancer cells have a high requirement for folic acid and overexpress the folic acid receptor and drugs that interfere with folate receptors or metabolism are used to treat cancer. Likewise, it has been suggested excess folate may promote tumor initiation (Kim, 2004). In addition, folic acid could even be contraindicated in patients affected by cancer or precancerous conditions. So, the benefits of folic acid against cancer may depend on dosage, type of dietary source or supplementation and individual conditions. It is reassuring that in a ...