Archive for the ‘curcumin’ Category

Pancreatic Cancer Killed Steve Jobs, the Truth About How You Can Prevent It

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Posted 15 Oct 2011 — by James Street
Category Alternative Therapies, CURCUMIN, curcumin, Pancreatic
Friday, October 14, 2011 04:16 PM

By: Sylvia Booth Hubbard

The death of Steve Jobs from pancreatic cancer last week added yet another name to the list of celebrities who have died as a result of that type of cancer, a stellar group which includes Patrick Swayze, Michael Landon, Luciano Pavarotti, and Jack Benny. Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and has the highest mortality rate of all cancers, killing 95 percent of its victims, according to the American Cancer Society.

“It’s a dismal, deadly disease,” surgical oncologist Dr. Robert Wascher tells Newsmax Health. “But like other forms of cancer, up to 65 percent can be prevented by relatively modest diet and lifestyle changes,” says Wascher, author of “A Cancer Prevention Guide for the Human Race.”

One simple preventative step to lower the risk of pancreatic cancer is to take the spice turmeric, which is a strong cancer fighter, says Wascher.

Pancreatic Cancer took Steve Jobs in the prime of his life.Steve Jobs lived for seven years after he announced he was suffering from pancreatic cancer. Most victims aren’t nearly so fortunate as Steve Jobs was and often live less than a year after their diagnosis. But Steve Jobs had a rare type of pancreatic cancer called neuroendocrine. “Only 5 to 8 percent of pancreatic cancers are this type, and its biology is different from the more common garden variety called adenocarcinoma that most people get,” says Wascher. “The form Jobs had is less aggressive and patients tend to live longer.”

One reason for the poor survival statistics is that pancreatic cancer usually causes no symptoms until it is advanced and has metastasized to other organs. The fortunate few who survive, including Supreme Court Justice Ruth Bader Ginsburg, are diagnosed early, when the disease is treatable by surgery — and usually as a result of a CT scan or MRI conducted for another reason.

Treatment options are few, says Wascher: “The only cure comes with very radical surgery. No one is cured by chemotherapy or radiation without surgery. If pancreatic tumors can’t be removed surgically, they tend to be quite resistant to chemotherapy and radiation therapy.

“Conventional medical and surgical procedures obviously do not cure pancreatic cancer for the vast majority of patients,” he says. “So, I think it’s reasonable to be a little more open-minded about complementary and alternative therapies when you have tried conventional therapies and have no other options. Both laboratory and clinical studies suggest there are some nutritional therapies that might have an effect on pancreatic cancer.”

Turmeric. Turmeric has a cancer-fighting component called curcumin. “Laboratory tests and some animal studies show it has potential activity against pancreatic cancer.” But, he warns, “What works in a laboratory environment doesn’t necessarily work in humans.” Wascher himself takes 1,000 mg of turmeric twice a day. “I don’t know for sure that it will help me, but I’m pretty sure it won’t hurt.” There is no established dosage, but most experts recommend taking between 500 mg and 2,000 mg daily.

A Phase II clinical trial at MD Anderson Center involved 25 patients with pancreatic cancer who were given 8 grams of turmeric a day for two months. Tumor growth stopped in two patients, one for eight months and another for two-and-a-half years. Another patient’s tumor temporarily regressed by 73 percent. Since the only two drugs approved by the FDA are effective in no more than 10 percent of patients, turmeric’s effectiveness was similar with no side effects.

In another study, turmeric reduced tumor growth in mice with pancreatic cancer by 43 percent. When combined with fish oil, tumor growth was reduced by 70 percent.

Since turmeric is poorly absorbed by the body, experts advise mixing it with olive oil or a combination of olive oil and black pepper to increase absorption.

Metformin. Metformin is a drug used to treat Type 2 diabetes. University of Texas MD Anderson Center researchers found that diabetics who took metformin had a 60 percent lower risk of developing pancreatic cancer compared to diabetics who didn’t use the drug. “In clinical studies, we’ve found that people who take metformin tend to survive longer,” Wascher says. “Based on that data, I tend to put patients who have pancreatic cancer on metformin even if they have very mild diabetes. It’s such a lethal disease that it’s worth the hope of even a small benefit.”

By far the best option is to avoid pancreatic cancer, and as in the prevention of other cancers, changes in diet and lifestyle offer you your best chances of living a long and healthy life. Steps to lower risk include:

Quit smoking. Approximately 27 percent of pancreatic cancers are linked with smoking. One study in Los Angeles County found that smoking a pack or more of cigarettes a day was associated with a fivefold to sixfold increase in the risk. Research at Jefferson Medical College of Thomas Jefferson University found that a protein in the body which makes cancer cells more likely to spread is much higher in the pancreas of smokers who have pancreatic cancer.

Lose weight. About 25 percent of pancreatic cancer is associated with obesity. Women who are severely obese have a 45 percent higher risk of developing pancreatic cancer, according to a study published in the American Journal of Epidemiology. And a study published in the Journal of the American Medical Association found that adults who were overweight as teens had a 60 percent higher risk of developing pancreatic cancer as adults.

Eat fresh vegetables and whole grains. A study published in the journal Cancer Epidemiology, Biomarkers & Prevention found that people who ate the most vegetables lowered their risk of pancreatic cancer by 55 percent when compared to those who ate the least. A study published in the American Journal of Epidemiology found that people with the highest fiber intake lowered their risk of pancreatic cancer up to 48 percent when compared with those with the lowest fiber intake.

Keep sugar levels in check. Studies have found that 1 percent of patients diagnosed with Type 2 diabetes after the age of 50 will be diagnosed with pancreatic cancer within three years.

Avoid sugary drinks. The Georgetown University Medical Center found that people who drank as few as two soft drinks a week doubled their risk of pancreatic cancer.

Shun processed meats and red meat. Research from the Cancer Research Center at the University of Hawaii found that people who ate the highest amount of processed meats increased their risk of pancreatic cancer by 67 percent. Diets high in red meats upped cancer risk by about 50 percent.

“When it comes to cancer prevention,” says Wascher, “the old adage about an ounce of prevention being worth a pound of cure should probably be revised to ‘An ounce of cancer prevention is worth a ton of cancer cure.’”

Epigenetic changes induced by curcumin and other natural compounds

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Posted 20 Sep 2011 — by James Street
Category CURCUMIN, curcumin, Docetaxel (deoxycytidine drug), Epigenetics, MicroRNA, Molecular, RNAi
Genes Nutr. 2011 May; 6(2): 93–108.
Published online 2011 April 24. doi:  10.1007/s12263-011-0222-1
PMCID: PMC3092901
Copyright © Springer-Verlag 2011
Simone Reuter,1 Subash C. Gupta,1 Byoungduck Park,1 Ajay Goel,2 and Bharat B. Aggarwalcorresponding author1
1Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
2Gastrointestinal Cancer Research Laboratory Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75246 USA
Bharat B. Aggarwal, Phone: +713-794-1817, Fax: +713-745-6339, Email: aggarwal@mdanderson.org.
corresponding authorCorresponding author.
Received February 1, 2011; Accepted April 5, 2011.
Epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression without any change in the DNA sequence, constitutes an important mechanism by which dietary components can selectively activate or inactivate gene expression. Curcumin (diferuloylmethane), a component of the golden spice Curcuma longa, commonly known as turmeric, has recently been determined to induce epigenetic changes. This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment.
Keywords: Curcumin, Epigenetics, Histone acetyltransferase, Histone deacetyltransferase, DNA methyltransferase, microRNA
Introduction
Epigenetics, heritable changes in gene expression that occur without a change in the DNA sequence, constitute an important mechanism by which dietary components can selectively activate or inactivate gene expression (Davis and Ross 2007). Epigenetic mechanisms include changes in DNA methylation, histone modifications, and altered microRNA (miRNA) expression (Yoo and Jones 2006; Winter et al. 2009).
Changes to the structure of chromatin influence gene expression by either inactivating genes, which occurs when the chromatin is closed (heterochromatin), or by activating genes when the chromatin is open (euchromatin) (Rodenhiser and Mann 2006). The nucleosome (Fig. 1a), which is the fundamental repeating unit of chromatin, is composed of DNA wrapped around a histone octamer, formed by four histone partners, an H3-H4 tetramer, and two H2A-H2B-dimers. Each successive nucleosomal core is separated by a DNA linker associated with a single molecule of histone H1. Chromatin modifications usually occur at the amino acids of the N-terminal tails of histones (Fig. 1b) and either facilitate or hinder the association of DNA repair proteins and transcription factors with chromatin. These core histones undergo a wide range of post-translational modifications, including acetylation, controlled by histone acetyltransferases (HATs), and associated with gene expression (Zhang and Dent 2005); deacetylation, controlled by histone deacetylases (HDACs), and associated with gene inactivation; and methylation, phosphorylation, ubiquitination, sumoylation, ADP-ribosylation, and possibly biotinylation (Davis and Ross 2007).
Fig. 1
Fig. 1

a The fundamental repeating unit of the chromatin is the nucleosome. A single nucleosomal core is composed of a DNA fragment wrapped around a histone octamer, formed by an H3-H4 tetramer and two H2A-H2B dimers. Each successive nucleosomal core is separated (more …)
In addition, epigenetic factors can also affect the expression of miRNAs (Croce 2009). Aberrant expression of miRNAs can arise through numerous mechanisms, including genomic abnormalities, transcriptional regulation, and processing of miRNAs (Winter et al. 2009). miRNAs are small, endogenous, single-stranded RNAs of 19–25 nucleotides in length that regulate gene expression, for example, by binding imperfectly to the 3′ untranslated region of target mRNAs, leading to translational repression, or by targeting mRNA cleavage because of the imperfect complementarity between miRNA and mRNA.
Recently, natural compounds, such as curcumin, epigallocatechin gallate (EGCG), and resveratrol, have been shown to alter epigenetic mechanisms, which may lead to increased sensitivity of cancer cells to conventional agents and thus inhibition of tumor growth (Li et al. 2010). Curcumin (diferuloylmethane), a yellow spice and the active component of the perennial herb Curcuma longa, commonly known as turmeric (Aggarwal and Sung 2009), is one of the most powerful and promising chemopreventive and anticancer agents, and epidemiological evidence demonstrates that people who incorporate high doses of this spice in their diets have a lower incidence of cancer (Wargovich 1997). Furthermore, epidemiological evidence exists indicating that there is a correlation between increased dietary intake of antioxidants and a lower incidence of morbidity and mortality (Devasagayam et al. 2004). For instance, a population-based case–control study in approximately 500 newly diagnosed gastric adenocarcinoma patients and approximately 1,100 control subjects in Sweden found that the total antioxidant potential of several plant-based dietary components was inversely associated with gastric cancer risk (Serafini et al. 2002).
Dietary and other environmental factors induce epigenetic alterations which may have important consequences for cancer development (Penn et al. 2009). Butyrate was the first food-derived substance shown to affect posttranslational modifications of histones through its action as an inhibitor of class 1 HDACs (Davie 2003; Kruh 1982; Vidali et al. 1978). More recently, a number of other dietary components have been identified which modulate the acetylation state of histones or affect the activities of HDACs and/or histone acetyl transferases [reviewed by Delage and Dashwood (2008)]. Proof of principle that dietary exposures may have lifelong consequences for epigenetic marks comes from recent studies of the adult offspring of women exposed to famine during pregnancy. Methylation of the imprinted gene insulin-like growth factor 2 was lower in adults (approximately 60 years of age) who were periconceptionally exposed to famine during the Dutch Hunger Winter of 1944–1945 (Heijmans et al. 2008). Interest in the effects of dietary compounds such as resveratrol which activate class III HDACs (sirtuins) is growing rapidly because of their demonstrable role in extending lifespan and in reducing, or delaying, age-related diseases including cancers (Baur 2010).
How curcumin exerts its powerful anticancer activities has been thoroughly investigated, and several mechanisms of action have been discovered. Although pharmacokinetic studies have shown that curcumin is present in much lower plasma concentration in humans than in vitro, numerous preclinical reports have demonstrated curcumin’s anticancer activity (Sharma et al. 2004; Cheng et al. 2001). One explanation for its activity in humans, even at lower concentrations, might be that curcumin exerts its biological activities through epigenetic modulation (Fig. 2).
Fig. 2
Fig. 2

Schematic representation of epigenetic factors modulated by curcumin
Effect of curcumin on histone acetylation/deacetylation
Histone modifications are among the most important epigenetic changes, because it can alter gene expression and modify cancer risk (Gibbons 2005). Abnormal activity of both HATs and HDACs has been linked to the pathogenesis of cancer. HDACs are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. Its action is opposite to that of HATs. HDAC enzymes do not bind to DNA directly but rather interact with DNA through multiprotein complexes that include corepressors and coactivators. At least 18 HDACs have been identified in humans, primarily occupying 4 classes based on homology with yeast deacetylases (Xu et al. 2007). HDAC inhibitors are being explored as cancer therapeutic compounds because of their ability to alter several cellular functions known to be deregulated in cancer cells (Davis and Ross 2007).
Recently, various studies have investigated the effect of curcumin on HDAC expression. Of these, Bora-Tatar et al. (2009) reported that among 33 carboxylic acid derivatives, curcumin was the most effective HDAC inhibitor, and that it was even more potent than valproic acid and sodium butyrate, which are well-known HDAC inhibitors. Another study revealed that HDAC 1, 3, and 8 protein levels were significantly decreased by curcumin, resulting in increased levels of acetylated histone H4 (Liu et al. 2005). Similarly, significant decreases in the amounts of HDAC1 and HDAC3 were detected by Chen et al. (2007) after treatment with curcumin.
By contrast, HDAC2, a critical component of corticosteroid anti-inflammatory action and impaired in lungs of patients with chronic obstructive pulmonary disease and by cigarette smoke extract, was restored by curcumin (Meja et al. 2008). Because of the differing effect of curcumin on the different subtypes of HDAC enzymes, further research is required to understand the mechanism of curcumin on HDAC expression.
HATs, enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyl lysine, are other important targets for dietary components. HATs include at least 25 members and are organized into 4 families based on primary structure homology (Lee and Workman 2007). Several studies have recently reported that curcumin is a potent HAT inhibitor. In 2004, Balasubramanyam et al. (2004) reported that curcumin is a specific inhibitor of p300/CREB-binding protein (CBP) HAT activity in vitro and in vivo but not of p300/CBP-associated factor. Furthermore, they showed that curcumin inhibited the p300-mediated acetylation of p53 in vivo and significantly repressed acetylation of HIV-Tat protein in vitro as well as proliferation of the virus (Balasubramanyam et al. 2004).
Another group that identified curcumin as a specific inhibitor of p300/CBP HAT activity in vitro and in vivo discovered that inhibition of p300 HAT activity by curcumin prevented also against heart failure in rats (Morimoto et al. 2008). Marcu et al. (2006) found that curcumin’s binding site on p300/CBP was specific and that binding led to a conformational change, resulting in a decrease in the binding efficiency of histones H3 and H4 and acetyl CoA.
It is well known that curcumin induces apoptosis of numerous cancer cell lines, but its mechanism may vary. Induction of apoptosis by curcumin in cervical cancer cells, for example, was associated with inhibition of histone and p53 acetylation through specific inhibition of p300/CBP (Balasubramanyam et al. 2004). For example, curcumin activated poly (ADP) ribose polymerase- and caspase-3–mediated apoptosis in brain glioma cells through induction of histone hypoacetylation (Kang et al. 2006).
Histones are acetylated and deacetylated on lysine residues, but HATs and HDACs can also modify the acetylation status of non-histone proteins (Sadoul et al. 2008). The regulation of transcription factors, effector proteins, molecular chaperones, and cytoskeletal proteins by acetylation/deacetylation is emerging as a significant post-translational regulatory mechanism (Glozak et al. 2005).
NF-κB, a pro-inflammatory transcription factor, undergoes acetylation before it activates hundreds of genes involved in different cellular processes (Chen et al. 2001; Gupta et al. 2010a). Acetylation of NF-κB takes place at multiple lysine residues with the p300/CBP acetyltransferases. Curcumin inhibited p300-mediated acetylation of RelA, an isoform of NF-κB, which attenuated interaction with IκBα, leading to decreased IκBα-dependent nuclear export of the complex through a chromosomal region maintenance-1–dependent pathway (Chen et al. 2001). In the same way, Yun et al. (2010) found that curcumin treatment significantly reduced HAT activity, p300 levels, and acetylated CBP/p300 gene expression and consequently suppressed NF-κB binding. Thus, curcumin’s ability to suppress p300/CBP HAT activity may be responsible, at least in part, for its potent NF-κB inhibitory activity.
Curcumin also inhibited the hypertrophy-induced acetylation and DNA-binding abilities of GATA4, a hypertrophy-responsive transcription factor, in rat cardiomyocytes, which indicates that inhibition of p300 HAT activity by curcumin may also provide a novel therapeutic strategy for heart failure in humans (Morimoto et al. 2008). Finally, curcumin also induced recontrolling of neural stem cell fates by decreasing histone H3 and H4 acetylation (Kang et al. 2006).
Since curcumin can modulate both HDAC and HAT, a common mechanism may be underlying. For example, oxidative stress can activate NF-κB through the activation of intrinsic HAT activity, resulting in the expression of pro-inflammatory mediators, but it can also inhibit HDAC activity (Rahman et al. 2004). As such, curcumin, a known antioxidant, may regulate both acetylation and deacetylation through the modulation of oxidative stress.
Effect of curcumin on DNA methylation
DNA methylation plays an essential role in regulating normal biological processes in addition to carcinogenesis (Esteller 2007). DNA methylation is a heritable modification of the DNA structure that does not alter the specific sequence of base pairs responsible for encoding the genome but that can directly inhibit gene expression (Das and Singal 2004). Two patterns of DNA methylation have been observed in cancer cells: global hypomethylation, or decreased methylation that can facilitate the expression of quiescent proto-oncogenes and prometastatic genes and promote tumor progression, or localized hypermethylation, an increased methylation at specific CpG islands within the gene promoter regions of specific genes, such as tumor suppressor genes, that can result in transcriptional silencing and an inability to control tumorigenesis (Ehrlich 2009). DNA methylation is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosyl-methionine, which serves as a methyl donor for methylation of cytosine residues at the C-5 position to yield 5-methylcytosine (Herman and Baylin 2003).
Only a few reports have so far investigated the effect of curcumin on DNA methylation. Molecular docking of the interaction between curcumin and DNMT1 suggested that curcumin covalently blocks the catalytic thiolate of DNMT1 to exert its inhibitory effect on DNA methylation (Liu et al. 2009). However, a more recent study showed no curcumin-dependent demethylation, which suggested that curcumin has little or no pharmacologically relevant activity as a DNMT inhibitor (Medina-Franco et al. 2010). To clarify these contradictions, more research is urgently needed.
Given that 5-azacitidine and decitabine, two FDA-approved hypomethylating agents for treating myelodysplastic syndrome, have a demonstrated ability to sensitize cancer cells to chemotherapeutic agents, it would be worthwhile to explore whether the hypomethylation effect of curcumin can also induce cancer cell chemosensitization. Interestingly, a phase 1 trial with curcumin administered several days before docetaxel in patients with metastatic breast cancer resulted in 5 partial remissions and stable disease in 3 of 8 patients (Bayet-Robert et al. 2011). This unexpected high response might have resulted from the clever sequential delivery of these two agents, which capitalized on and maximized curcumin’s epigenetic activity for cancer treatment.
Effect of curcumin on miRNA expression
miRNAs, small noncoding regulatory RNAs, range in size from 17 to 25 nucleotides (Croce 2009) and are responsible for a reduced translation rate and/or increased degradation of mRNAs if aberrantly expressed. miRNAs play important roles in cell cycling, programmed cell death, cell differentiation, tumor development, invasion, metastasis, and angiogenesis (Negrini et al. 2007). To date, more than 500 human miRNA genes have been identified, and it is believed that at least 500 have yet to be discovered within the human genome (Bentwich et al. 2005). The specific function of most mammalian miRNAs is still unknown (Bentwich et al. 2005), but it is speculated that miRNAs could regulate ~30% of the human genome (Bartel 2004). Disturbances in the expression of miRNAs, processing of miRNA precursors, or mutations in the sequence of the miRNA, its precursor, or its target mRNA may have detrimental effects on cellular function and have been associated with cancer (Davis and Ross 2008). Some miRNAs could, for example, regulate the formation of cancer stem cells and the epithelial-mesenchymal transition (EMT) phenotype of cancer cells, which are typically drug resistant (Li et al. 2010).
It is known that curcumin regulates the expression of genes that are critically involved in the regulation of cellular signaling pathways, including NF-κB, Akt, MAPK, and other pathways (Mukhopadhyay et al. 2001; Sarkar and Li 2004). These signaling pathways could be regulated by miRNAs.
Recently, Sun et al. (2008) reported that curcumin altered miRNA expression in human pancreatic cancer cells. After 72 h of incubation, 11 miRNAs were significantly up-regulated and 18 were down-regulated by curcumin. Among these, miRNA-22 was the most significantly up-regulated and miRNA-199a* the most down-regulated. Those researchers also found that up-regulation of miR-22 expression by curcumin suppressed the expression of its target genes Sp1 and estrogen receptor 1 (Sun et al. 2008). These results suggest that curcumin could inhibit the proliferation of pancreatic cancer cells through the regulation of specific miRNAs. In addition, curcumin has been shown to promote apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway (Zhang et al. 2010). In these cells, curcumin significantly down-regulated the expression of miR-186* (Zhang et al. 2010). A major challenge for current miRNA studies is to identify the biologically relevant downstream targets that they regulate. In the study by Sun et al. (2008) at least 50 target genes for miRNA-22 were found, showing that a key effect of curcumin on pancreatic cancer cells could be mediated by epigenetic modulation of miRNAs.
In addition, a recent report showed that gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin (Ali et al. 2010). The miR-200 family has been shown to inhibit the EMT, the initiating step of metastasis, by maintaining the epithelial phenotype through direct targeting of the transcriptional repressors of E-cadherin, ZEB1, and ZEB2 (Korpal and Kang 2008). Therefore, targeting specific miRNAs could be a novel therapeutic approach for the treatment of cancers, especially by eliminating cancer stem cells or EMT-type cells that are typically drug resistant. In contrast, miR-21 is an oncomiR and is overexpressed in many tumors, thereby promoting cancer progression and metastasis. Curcumin treatment has been shown to reduce miR-21 promoter activity and expression in primary tumors by inhibiting AP-1 binding to the promoter and to induce expression of the tumor suppressor Pdcd4, a target of miR-21 (Mudduluru et al. 2011).
These novel findings suggest that the use of natural agents could open new avenues for the successful treatment of cancers, especially by combining conventional therapeutics with natural chemopreventive agents that are known to be nontoxic to humans (Li et al. 2010).
Curcumin and DNA binding
Curcumin’s antioxidant (Miquel et al. 2002), anti-inflammatory (Surh 1999), antimicrobial (Saleheen et al. 2002; Taher et al. 2003), and chemopreventive (Aggarwal et al. 2003) properties are attributed to various mechanisms, including an anti-angiogenic action; up-regulation of enzymes detoxifying carcinogens, such as glutathione S-transferase; inhibition of signal transduction pathways critical for tumor cell growth (e.g., NF-κB); suppression of cyclooxygenase expression; and neutralization of carcinogenic free radicals (Aggarwal et al. 2003; Chauhan 2002; Itokawa et al. 2008). However, the molecular basis of curcumin’s various therapeutic actions is far from established, perhaps because research has focused so far only on proteins as the potential macromolecular targets of curcumin and less on its ability to bind directly to the DNA and to modulate epigenetic mechanisms directly as a DNA binding agent.
In 2004, a direct interaction between curcumin and both natural and synthetic DNA duplexes was demonstrated by using circular dichroism and absorption spectroscopy techniques (Zsila et al. 2004). Evaluation of the spectral data and molecular modeling calculations suggested that curcumin binds to the minor groove of the double helix and that it is also a promising molecular probe to study biologically important pH- and cation-induced conformational polymorphisms of nucleic acids (Zsila et al. 2004). Based on these results, curcumin has to be considered as a new phenolic minor groove-binding agent, which may explain the observed anticancer potential and other pharmacological effects of this natural compound.
In the same way, Fourier transform infrared (FTIR) and UV analysis of the binding of curcumin to the DNA showed that curcumin can bind to the major and minor grooves of the DNA duplex, to RNA bases, and to the backbone phosphate group (Nafisi et al. 2009). No conformational changes were observed upon the interaction between curcumin and these biopolymers. Instead, Nafisi et al. (2009) found that curcumin binds to DNA through thymine O2 in the minor groove and through guanine and adenine N7 in the major groove, as well as to the backbone PO2 group. RNA binding occurs via uracil O2 and guanine and adenine N7 atoms as well as the backbone phosphate group. Interestingly, the interaction of curcumin was stronger with DNA than RNA.
Pentamidine, a diarylamidine antibiotic that is currently in clinical use for treatment of leishmaniasis, trypanosomiasis, and Pneumocystis carinii pneumonia (Fairlamb 2003), has been suggested to interact directly with the pathogenic genome. It binds selectively to the minor groove of the DNA, similar to curcumin, and interferes with the normal functioning of the pathogen topoisomerases (Reddy et al. 1999; Neidle 2001; Bischoff and Hoffmann 2002). Interestingly, curcumin was also found to be effective against trypanosomiasis (Saleheen et al. 2002; Araujo and Leon 2001), which could be due to its binding ability to the minor groove of the DNA.
Effect of curcumin on transcription factors
Extensive research over the past five decades has indicated that curcumin reduces blood cholesterol levels; prevents low-density lipoprotein oxidation; inhibits platelet aggregation; suppresses thrombosis and myocardial infarction; suppresses symptoms associated with type II diabetes, rheumatoid arthritis, multiple sclerosis, and Alzheimer disease; inhibits HIV replication; suppresses tumor formation; enhances wound healing; protects against liver injury; increases bile secretion; protects against cataract formation; and protects against pulmonary toxicity and fibrosis (Shishodia et al. 2007). These divergent effects of curcumin seem to depend on its pleiotropic molecular effects, including the regulation of signal transduction pathways, and direct modulation of several enzymatic activities. Most of these signaling cascades lead to the activation of transcription factors.
Transcription factors are proteins that bind to DNA at a specific promoter or enhancer region, probably at histone tails, which are considered to be the platform for transcription factors (Fig. 1b), and thus regulate the expression of various genes. Hundreds of transcription factors with functionally different domains essential for DNA binding and activation have been identified and characterized in several organisms—some of the transcription factors are important targets for therapeutic intervention in several types of disease (Shishodia et al. 2007). For example, the transcription factors NF-κB, activator protein (AP)–1, and Signal transducer and activator of transcription (STAT) control the expression of genes that affect cell transformation, proliferation, cell survival, invasion, metastasis, adhesion, angiogenesis, and apoptosis (Aggarwal 2004; Aggarwal et al. 2009; Gupta et al. 2010b; Shishodia and Aggarwal 2004). Other transcription factors involved in cancer are early growth response-1 (Egr-1), peroxisome proliferator-activated receptor-γ (PPAR- γ), electrophile response element (EpRE), β-catenin, NF-E2-related factor 2 (Nrf2), and androgen receptor (AR).
Our laboratory has previously shown that curcumin down-regulates the activation of NF-κB by various tumor promoters, including phorbol ester, tumor necrosis factor, hydrogen peroxide, and cigarette smoke (Shishodia et al. 2003; Singh and Aggarwal 1995). Curcumin-induced down-regulation of NF-κB was shown to be mediated through suppressed activation of IκBα kinase (IKK) (Shishodia et al. 2003; Jobin et al. 1999; Plummer et al. 1999). Moreover, curcumin can suppress constitutively active NF-κB in mantle cell lymphoma through the suppression of IKK (Shishodia et al. 2005). This leads to the down-regulation of cyclin D1, cyclooxygenase-2, and matrix metalloproteinase–9. Also, we found that curcumin suppressed the paclitaxel-induced NF-κB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice (Aggarwal et al. 2005).
AP-1 has also been closely linked with the proliferation and transformation of tumor cells (Karin et al. 1997). Curcumin has been shown to inhibit the activation of AP-1 induced by tumor promoters (Huang et al. 1991) and JNK activation by carcinogens (Chen and Tan 1998). Bierhaus et al. (1997) demonstrated that curcumin-induced inhibition of AP-1 was due to its direct interaction with the AP-1 DNA-binding motif.
Curcumin was also shown to modulate STATs, and constitutive STAT activation can be observed in a large number of tumors. Curcumin inhibited both NF-κB and STAT3 activation, leading to decreased expression of proteins involved in cell proliferation and apoptosis, such as Bcl-2, Bcl-xL, c-FLIP, XIAP, c-IAP1, survivin, c-Myc, and cyclin D1 (Mackenzie et al. 2008). The constitutive phosphorylation of STAT3 found in certain multiple myeloma cells was abrogated by treatment with curcumin (Bharti et al. 2003), and inhibition of STAT3 by curcumin led to the induction of apoptosis (Bharti et al. 2004). In addition, curcumin has been shown to modulate the Egr-1, PPAR-γ, EpRE, β-catenin, Nrf-2, and AR signaling pathways (Shishodia et al. 2003).
The evidence that curcumin modulates many important transcription factors, which are either constitutively expressed or overexpressed in cancer cells, might explain in part the molecular basis of the wide and complex effects of this phytochemical. The versatile chemical structure of curcumin enables it to interact with a large number of molecules inside the cell, leading to a variety of biological effects, such as modulation of the cell cycle, suppression of growth, induction of differentiation, up-regulation of proapoptotic factors, and inhibition of reactive oxygen species production.
Effect of other natural compounds on epigenetics
Evidence in the past decade has provided important clues that natural compounds present in plants and/or in the diet directly influence epigenetic mechanisms in humans (Table 1). Indeed, some dietary polyphenols may exert their chemopreventive effects in part by modulating various components of the epigenetic machinery in humans (Link et al. 2010).
Table 1
Table 1

Common HDAC, HAT and DNMT modulators derived from natural sources
EGCG, the ester of epigallocatechin and gallic acid and the major polyphenol in green tea, has been extensively studied as a potential demethylating agent. It has been hypothesized that generation of S-adenosyl-s-homocysteine, a potent inhibitor of DNA methylation, is one of the mechanisms for the demethylating properties of this compound. EGCG can form hydrogen bonds with different residues in the catalytic pocket of DNMT and thus act as a direct inhibitor of DNMT1 (Fang et al. 2003; Lee et al. 2005). EGCG has also been recently found to modulate miRNA expression in human hepatocellular carcinoma HepG2 cells. Tsang and Kwok performed microarray analysis in this cell line after EGCG treatment and found that the compound modified the expression of 61 miRNAs (Tsang and Kwok 2010).
Choi et al. found that another compound, gallic acid—an organic acid found in gallnuts, sumac, witch hazel, tea leaves, oak bark, and other plants can inhibit p300-induced p65 acetylation, increase the level of cytosolic IκBα, prevent lipopolysaccharide (LPS)–induced p65 translocation to the nucleus, and suppress LPS-induced NF-κB activation in A549 lung cancer cells (Choi et al. 2009b). In addition, gallic acid inhibits the acetylation of p65 and LPS-induced serum levels of interleukin-6 in vivo.
Sanguinarine, an extract from several plants such as bloodroot (Sanguinaria canadensis) and in the root, stem, and leaves of the opium poppy, has been shown to induce conformational changes by interacting with chromatin (Selvi et al. 2009). Sanguinarine potently inhibited HAT activity in rat liver and cervical cancer cell lines, and this was associated with a dose-dependent decrease in H3/H4 acetylation.
Resveratrol, a natural compound found in the skin of red grapes and a constituent of red wine, is believed to play a significant role in the reduction of cardiovascular events (Artaud-Wild et al. 1993; Gupta et al. 2011). Multiple studies have shown that resveratrol can activate sirtuin 1 (SIRT1), a histone deacetylase, and inhibit p300 (Howitz et al. 2003; Gracia-Sancho et al. 2010). Sirtuins, the class III HDACs, are widely distributed and have been shown to regulate a variety of physiopathologic processes, such as inflammation, cellular senescence and aging, cellular apoptosis and proliferation, differentiation, metabolism, stem cell pluri-potency, and cell cycle regulation. Polyphenols, including not only resveratrol but also quercetin and catechins, have been shown to activate SIRT1, the best characterized of the seven mammalian sirtuins, SIRT1–7 (Kaeberlein et al. 2005; Borra et al. 2005; de Boer et al. 2006).
Similar to EGCG, resveratrol showed weak inhibition of DNMT activity in nuclear extracts from MCF7 cells (Paluszczak et al. 2010). In these cells, resveratrol improved the action of adenosine analogues to inhibit methylation and to increase expression of the retinoic acid receptor beta 2 gene (Stefanska et al. 2010). In addition, resveratrol decreased the levels of the miR-155 by up-regulating miR-663, an miRNA targeting JunB and JunD (Tili et al. 2010a), and modulated expression levels of miRNA target genes, such as tumor suppressors and effectors of the transforming growth factor–β signaling pathway, in SW480 cells (Tili et al. 2010b).
Anacardic acid, an active compound found in cashew nuts, has also been shown to be a specific HAT inhibitor (Balasubramanyam et al. 2003; Sun et al. 2006). Anacardic acid can inhibit p300, PCAF, and Tip60 HAT factors.
Garcinol, a highly cytotoxic polyisoprenylated benzophenone derived from garcinia fruit rinds, is also a potent inhibitor of different HATs, such as p300 and PCAF (Mai et al. 2006; Chandregowda et al. 2009; Balasubramanyam et al. 2004).
Plumbagin is another agent, derived from Plumbago rosea root extract, that has been found to potently inhibit HAT activity (Ravindra et al. 2009). Plumbagin derivatives without a hydroxyl group lost HAT inhibitory activity, indicating that the hydroxyl group is required for this activity.
Finally, genistein, one of the many phytoestrogens present in soybeans, has been recently studied as a demethylating agent. Genistein induced a dose-dependent inhibition of DNMT activity stronger than that of other soy isoflavones (biochanin A or diadzein) (Fang et al. 2005; Li et al. 2009). The continuously growing list of natural compounds (Table 1) that modulate epigenetic mechanisms shows the great interest in this exciting field and clinical trials performed with several of these compounds (Table 2) confirm their efficiency.
Table 2
Table 2

Clinical studies with curcumin and other natural compounds
Conclusion
Experimental evidence accumulated in the recent years clearly supports the idea that dietary nutraceuticals such as curcumin have great potential as epigenetic agents. Unlike genetic changes, epigenetic changes can be modified by the environment, diet, or pharmacological intervention. This characteristic has increased enthusiasm for developing therapeutic strategies by targeting the various epigenetic factors, such as HDAC, HAT, DNMTs, and miRNAs, by dietary polyphenols such as curcumin (Fig. 2). Further investigation of phytochemicals as epigenetic agents is, however, urgently needed to fully explore the potential of these nutraceuticals in the treatment of cancer and other diseases.
Acknowledgments
We thank Virginia Mohlere for carefully editing this article. This work was supported by MD Anderson’s Cancer Center Support Grant from the National Institutes of Health (NIH CA-16672), a program project grant from the National Institutes of Health (NIH CA-124787-01A2), and a grant from the Center for Targeted Therapy at The University of Texas MD Anderson Cancer Center, where Dr. Aggarwal is the Ransom Horne, Jr., Professor of Cancer Research. Simone Reuter was supported by a grant from the Fonds National de la Recherche Luxembourg (PDR-08-017).
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Curcumin is Key to Unlocking Cancer Epigenetic Code – EuroPharma

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Posted 23 Jun 2011 — by James Street
Category CURCUMIN, curcumin, Epigenetics, genetic research

Research at Baylor University shows curcumin awakens sleeping genes and reignites tumor suppression activity

GREEN BAY, Wis., June 23, 2011 /PRNewswire/ – Dr. Ajay Goel, Ph.D., Director of Epigenetics and Cancer Prevention at the Gastrointestinal Research Center at Baylor University Medical Center in Dallas, TX, has announced plans for a series of upcoming studies to continue to unlock the mechanisms by which curcumin prevents cancer via its influence on epigenetic activity. While many people believe there is a strong genetic influence in the development of cancer, Dr. Goel states this is untrue. “Less that 5% of cancers arise from broken or damaged genes. The vast majority (more than 95%) are due to epigenetic influences. ‘Epigenetics’ is the study of the complex ways in which our genes are influenced by various dietary and environmental factors. Some factors turn genes on, and other factors subdue them or turn them off. This is good news. That means that you can influence 95% of all cancers with environment and lifestyle changes.”

In a study published in the journal Gastroenterology, entitled “Novel Evidence for Curcumin-induced DNA Methylation Changes in Colon Cancer Cells,”(1) Dr. Goel examined epigenetic expression in colon cancer cells and the influence of curcumin on cancer prevention.

“It was a very technical study,” reports Dr. Goel. “But in essence, we looked at a process in the body called methylation and how that process silences certain genes that are designed to suppress tumors. Curcumin was able to ‘reawaken’ the sleeping genes and reignite the body’s own tumor suppression activity. This process keeps the cancerous tumor from growing and spreading, and is vitally important. Though we used colon cancer cells in this study, we suspect that this is one mechanism of action for cancer suppression in many other types of cancer as well. It is exciting new research and holds great promise for human health as the science continues to unfold. That is why our upcoming studies will continue to explore the epigenetic connection.”

BCM-95® curcumin was used in this study. “I selected this form of curcumin because of its purity and lack of unfavorable solvents that can interfere with research results. This type of curcumin is of interest in human studies as well, because it has 7 to 10 times the absorption of plain curcumin, which means we can achieve more significant serum curcuminoid levels with fewer capsules for the study participant,” states Dr. Goel.

EuroPharma, Inc. is the exclusive distributor of BCM-95® curcumin products in the U.S. through both the health food store and professional distribution channels. EuroPharma offers clinically proven and effective nutritional supplements and natural remedies that improve the health of America. Terry Lemerond, founder and president of EuroPharma, is well-known for innovation, as he is credited as the first to introduce glucosamine sulfate, standardized Ginkgo biloba, and the award winning natural pain product, Curamin®, to the U.S. natural products market. At EuroPharma, Our Passion is Your Health™.  For more information on EuroPharma, visit www.EuroPharmaUSA.com.

(1) A. Link, F. Balaguer, Y. Shen, J. Jose Lozano, HE. Leung, C.R. Boland, A. Goel. M1182 Novel Evidence for Curcumin-Induced DNA Methylation Changes in Colon Cancer Cells. Gastroenterology. May 2010 (Vol. 138, Issue 5, Supplement 1, Page S-349, DOI: 10.1016/S0016-5085(10)61608-3).

SOURCE EuroPharma, Inc.

Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer

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Posted 20 Jun 2011 — by James Street
Category Breast Cancer, CURCUMIN, curcumin, docetaxel, Docetaxel (deoxycytidine drug)
Cancer Biol Ther. 2010 Jan;9(1):8-14. Epub 2010 Jan 21.

Source

Centre Jean Perrin, Division de Recherche Clinique, Université d’Auvergne, Centre d’Investigation Clinique, Clermont-Ferrand, France. Mathilde.Bayet-Robert@u-clermont1.fr

Abstract

BACKGROUND:

Since the improvement of chemotherapy with safe molecules is needed for a better efficacy without supplementary toxicity, we investigated the feasibility and tolerability of the combination of docetaxel and curcumin, a polyphenolic derivative extracted from Curcuma longa root.

RESULTS:

Fourteen patients were accrued in this open-label phase I trial. At the last dose level of curcumin, three dose-limiting toxicities were observed and two out of three patients at this dose level refused to continue treatment, leading us to define the maximal tolerated dose of curcumin at 8,000 mg/d. Eight patients out of 14 had measurable lesions according to RECIST criteria, with five PR and three SD. Some improvements as biological and clinical responses were observed in most patients.

PATIENTS AND METHODS:

Patients with advanced or metastatic breast cancer were eligible. Docetaxel (100 mg/m(2)) was administered as a 1 h i.v. infusion every 3 w on d 1 for six cycles. Curcumin was orally given from 500 mg/d for seven consecutive d by cycle (from d-4 to d+2) and escalated until a dose-limiting toxicity should occur. The primary endpoint of this study was to determine the maximal tolerated dose of the combination of dose-escalating curcumin and standard dose of docetaxel chemotherapy in advanced and metastatic breast cancer patients. Secondary objectives included toxicity, safety, vascular endothelial growth factor and tumor markers measurements and assessment of objective and clinical responses to the combination therapy.

CONCLUSION:

The recommended dose of curcumin is 6,000 mg/d for seven consecutive d every 3 w in combination with a standard dose of docetaxel. From the encouraging efficacy results, a comparative phase II trial of this regimen plus docetaxel versus docetaxel alone is ongoing in advanced and metastatic breast cancer patients.

PMID:
19901561
[PubMed - indexed for MEDLINE]