Many of you know that I've been hiding in my cave focusing on Curcumin research....leaving me with time only for infrequent furtive lurks...
Our Neuro Oncologist told us that we are "losing the battle" in fighting Rajeev's Brain Tumor a GBM IV.
Since Rajeev received non-standard, aggressive treatment over the last 4.5 years and clinical trials are not an option, Rajeev is on the last GBMIV treatment available (Avastin, Accutane.Thalidomide). So, I'm digging deeper into supplements, nutrition, lifestyle, etc... in hopes of finding something to help preserve his quality of life for as long as possible and delaying the inevitable.
It is in amazement of and gratitude and awe for not only
each of you - strangers until I joined this group -
but also
all of the "non-BT list/group strangers" - such as Dr Aggarwal -
who have responded with kindness, empathy, compassion, information, advice, etc.... I share this summary with you.
Please note that this is a summary of the info/advice I received from Dr Aggarwal, a curcurmin expert at MD Anderson.
Dr Aggarwal has been so kind, compassionate, informative and helpful....
I simply cannot find words to express the depth of my appreciation and gratitude.
And it goes without saying that I'm not a doctor nor am I providing medical advice. And, you may want to consider discussing adding curcumin to your treatment with your NO.
In brief: CURCUMIN COMBINED W/ PIPERINE & EATEN WITH A FATTY FOOD IS BIO-AVAILABLE, CROSSES THE BBB & HAS SHOWN TO SUPPRESS GROWTH OF MALIGNANT GLIOMAS.
1. using regular font I'll indicate the questions I emailed to Dr Aggarwal
2. Dr Aggarwal's response is in bold
3. I've also included excerpts of research papers he sent to me (The titles of which are underlined & bold, the excerpt is in regular font w/ major points in bold). I suggest you read fully the attached research papers.
You may want to click on Bharat Aggarwal, Ph.D. to find many research papers he has authored.
Dr Aggarwal's email signature is:
Bharat B. Aggarwal, Ph.D.
Ransom Horne, Jr., Professor of Cancer Research
Professor of Cancer Medicine (Biochemistry) and
Chief, Cytokine Research Laboratory,
Department of Experimental Therapeutics,
The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, BOX 143
Houston, TX 77030, USA
Phone: 713-794-1817
Email: aggarwal@mdanderson.org
SUMMARY:
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EMAIL 1:
1. Can supplementation of turmeric (curcuma longa) root extract containing 95% curcuminoids (curcumin, demethoxycurcuin & bis-demethoxycurcumin) and piperine (from black pepper) cross the blood brain barrier (BBB)? OR does it require additional supplementation (DMSO (Dimethyl sulfoxide)?) to cross the BBB?
2. Do you believe that using curcumin/piperine supplements may be potentially helpful in fighting a glioblastoma multiforme grade IV.....OR..... do you suggest that instead of taking a supplement to fry the turmeric with black pepper in a little oil?
Rajeev takes Life Extension Foundation's Super Curcumin with Bioperine 4 times per day.
Each supplement includes
1.Curcumin 800 mg Turmeric (curcuma longa) root extract [containing 95% (760 mg curcuminoids {curcumin, demethoxycurcumin and bis-demethoxycurmin } AND 2.5 mg Bioperine piperine (from black pepper).
Thus, Rajeev gets 3200 mg Turmeric and 20 mg piperine per day
3. If you believe that supplementation may be efficacious in fighting a GBM, what daily dosage do you suggest?
4. Is there any indication that whilest taking Avastin (and Thalidomide) that curcurmin be reduced or eliminated since they may compete with one another in that they both inhibit VEGF and work along the same pathways?
My understanding is that Avastin has a half life of 21 days, thus simply foregoing supplementation a few days prior to and subsequent to receiving Avastin does not make sense.
Dr Aggarwal's Response to email #1 - Dear Julie: Please consider:
Please consider taking 8 gram curcumin per day; four times a day; for at least three months before you conclude its efficacy.
I suggest you gradually escalate the dose from 500 mg per day to 8 gram per day.
The potential sources of curcumin are as follows:
America’s Finest Inc.
800-350-3305
www.afisupplements.com <http://www.afisupplements.com/>
info@afisupplements.com
For nanocurcumin
Tadashi Hashimoto
Theravalues Corporation
8F Kioicho Bldg. 3-12 Kioicho Chiyoda-ku Tokyo Japan 102-0094
TEL：03-3234-7677 FAX ：03-3234-7680
Email：thashimoto@theravalues.com
HP：http://www.theravalues.com/ <http://www.theravalues.com>
For curcumin information, please visit:
http://www.curcuminresearch.org/ <http://www.curcuminresearch.org>
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EMAIL 2:
Thank you so much from the bottom of my heart for not only your quick reply but also your fine advice regarding the dosage, escalation schedule and potential sources of curcumin.
I'm assuming that curcumin can cross the BBB and that one can take the dosages of curcumin along with the Avastin and Thalidomide.
May I have your permission to post this valuable advice to the several brain tumor groups/lists to which I subscribe or would your prefer I keep your advice confidential? If you give me permission to post, please inform me if you want posted that I received this advice from you along with your contact information. I will honor your wishes to the fullest extent.
I received an email earlier today from a woman in Italy requesting your contact information and so I passed on your email address. My apologies for doing so without first gaining your permission and any inconvenience this may cause.
Dr Aggarwal's Response to email #2 - Dear Julie: Curcumin can cross the BBB. Please pass the info around to as many as you like. Best wishes
Enclosed paper may help.
Evidence That Curcumin Suppresses the Growth of Malignant Gliomas in Vitro and in Vivo through Induction of Autophagy: Role of Akt and Extracellular Signal-Regulated Kinase Signaling Pathways
Hiroshi Aoki, Yasunari Takada, Seiji Kondo, Raymond Sawaya, Bharat B. Aggarwal, and Yasuko Kondo
Departments of Neurosurgery (H.A., S.K., R.S., Y.K.) and Experimental Therapeutics (Y.T., B.B.A.), the University of Texas
M. D. Anderson Cancer Center, Houston, Texas; Department of Neurosurgery, the Baylor College of Medicine, Houston, Texas
(S.K., R.S.); and the Program in Molecular Pathology, the University of Texas Graduate School of Biomedical Sciences at
Houston, Houston, Texas (S.K.)
Received December 1, 2006; accepted March 28, 2007
ABSTRACT
Autophagy is a response of cancer cells to various anticancer therapies. It is designated as programmed cell death type II and characterized by the formation of autophagic vacuoles in the cytoplasm. The Akt/mammalian target of rapamycin (mTOR)/ p70 ribosomal protein S6 kinase (p70S6K) and the extracellular signal-regulated kinases 1/2 (ERK1/2) pathways are two major pathways that regulate autophagy induced by nutrient starvation. These pathways are also frequently associated with oncogenesis in a variety of cancer cell types, including malignant gliomas. However, few studies have examined both of these signal pathways in the context of anticancer therapy-induced autophagy in cancer cells, and the effect of autophagy on cell death remains unclear. Here, we examined the anticancer efficacy and mechanisms of curcumin, a natural compound with
low toxicity in normal cells, in U87-MG and U373-MG malignant glioma cells. Curcumin induced G2/M arrest and nonapoptotic autophagic cell death in both cell types. It inhibited the Akt/ mTOR/p70S6K pathway and activated the ERK1/2 pathway, resulting in induction of autophagy. It is interesting that activation of the Akt pathway inhibited curcumin-induced autophagy and cytotoxicity, whereas inhibition of the ERK1/2 pathway inhibited curcumin-induced autophagy and induced apoptosis, thus resulting in enhanced cytotoxicity. These results imply that the effect of autophagy on cell death may be pathway-specific. In the subcutaneous xenograft model of U87-MG cells, curcumin inhibited tumor growth significantly (P 0.05) and induced autophagy. These results suggest that curcumin has high anticancer efficacy in vitro and in vivo by inducing autophagy and warrant further investigation toward possible clinical application in patients with malignant glioma.
Discussion
The results of this study showed that curcumin induced G2/M cell cycle arrest and autophagy, but not apoptosis, in
U87-MG and U373-MG cells. Regarding signal pathways, curcumin inhibited the Akt/mTOR/p70S6K pathway and activated the ERK pathway, resulting in autophagy. The autophagy regulated by these two different pathways differently influenced the cytotoxicity of curcumin. Furthermore, curcumin effectively inhibited tumor growth and induced autophagy in the xenograft tumor model of U87-MG cells. These results demonstrate that curcumin may be a promising agent for the treatment of patients with malignant glioma. To the best of our knowledge, this study is the first to demonstrate that curcumin induces autophagy in cancer cells in vitro and in vivo.
This study clearly demonstrated that curcumin inhibits the Akt/mTOR/p70S6K pathway and activates ERK signaling,
resulting in the induction of autophagy (Figs. 2 and 3). Several other studies have also shown that curcumin inhibits
the Akt/mTOR/p70S6K pathway in various cancer cells including leukemia, renal cancer, breast cancer, and prostate
cancer cells (Woo et al., 2003; Bava et al., 2005; Aggarwal et al., 2006; Beevers et al., 2006). Some investigators reported the effect of curcumin on ERK signaling but with different results (Squires et al., 2003). Woo et al. (2005) showed that curcumin repressed the phorbol ester-induced activation of ERK, whereas Collett and Campbell (2004) found no effect of curcumin on ERK. Because curcumin modulates many pathways (Shishodia et al., 2005; Aggarwal et al., 2006), its detailed mechanisms may vary depending on the cancer cell type. In the context of induction of autophagy, Ellington et al. (2006) showed that the natural products triterpenoidB-group soyasaponins induced autophagy by inhibiting Akt signaling and enhancing ERK activity, in accord with our findings. This combination of Akt inhibition and ERK activation may be one of the common mechanisms of autophagy induction by anticancer agents.
Because the extent of autophagy increased in dose- and time-dependent manners, we concluded that autophagy is a response of U87-MG and U373-MG cells to curcumin. Our results clearly indicated that the cytotoxic effect of curcumin on these cells is caused by autophagy but not by apoptosis. Fig. 6. Curcumin inhibits the growth of malignant glioma cells in vivo byinducing autophagy. A, tumor growth on day 16 after the initiation of curcumin treatment. U87-MG cells (1 106) were inoculated subcutaneously into the nude mice. When the tumors reached 50 to 70 mm3 in volume, intratumoral injections of curcumin (100 mg/kg in DMSO/PBS) or DMSO/PBS (control) were administered every 24 h for 7 days. B,
Western blot analysis of excised tumors for LC3. Tumors were removed on day 16, and the proteins were isolated and subjected to Western blotting. Anti--actin antibody was used as a loading control. Results shown are representative of two independent experiments. C, representative micrographs of immunohistochemical staining using anti-LC3 antibody. Tumor-bearing animals were treated, and the tumors were removed as described above. Tumor samples were snap-frozen, sliced to10-m thickness, and subjected to immunohistochemical staining. Scalebars, 50 m.
Curcumin-Induced Autophagy in Glioma 37
The overall effect of curcumin is as an anticancer agent both in vitro and in vivo, as shown in other cancer cells (Shishodia et al., 2005; Aggarwal et al., 2006). Although autophagy is designated programmed cell death type II, whether autophagy actually leads cells to death or protects them from death has been a controversial issue (Gozuacik and Kimchi, 2004; Takada et al., 2004). Some investigators knocked down autophagy-related (Atg) genes using siRNA and specifically inhibited autophagy but reached opposite conclusions depending on their experimental system. For example, in an apoptosis-defective system in which Bax and Bak were both knocked out (i.e., Bax/Bak/), siRNA for Beclin 1 or Atg5 inhibited etoposide-induced autophagy and led cells to survival, whereas siRNA for Atg5 or Atg7 inhibited autophagy caused by interleukin-3 deprivation and killed more cells (Shimizu et al., 2004; Lum et al., 2005). One possibility is that autophagy kills or protects cells depending on how autophagy is induced. That is, interleukin-3 deprivation-induced autophagy is supposed to be a survival mechanism, so inhibition of this autophagy leads to death; etoposide induces cell death, so inhibition of this autophagy saves cells from death. In this study, we examined the role of autophagy by manipulating the regulatory pathways individually, because the Akt and ERK pathways are known to regulate autophagy, but with opposite effects: the Akt pathway regulates autophagy negatively, whereas the ERK pathway regulates it positively. Activation of the Akt pathway using rAkt1- inhibited curcumin-induced autophagy and cytotoxicity (Fig.4). On the other hand, inhibition of the ERK pathway using PD98059 inhibited autophagy and induced apoptosis, thus enhancing cytotoxicity (Fig. 5). These results imply that the role of autophagy on cell death is pathway-specific. That is, the autophagy the Akt pathway inhibits confers cell death, and the autophagy the ERK pathway induces confers cell survival. This hypothesis can explain the double effect autophagy has on cell death, and it is worth being evaluated in different experimental systems. NF-B is one of the main targets of curcumin for its anticancer effect (Singh and Aggarwal, 1995; Bharti et al., 2003; Aggarwal et al., 2004). However, we found that U87-MG and U373-MG cells had very little or no constitutively active NF-B. Furthermore, when we completely knocked down NF-B p65, the viability of these cell types did not change (Supplementary Fig. S1). These results indicate that the anticancer effect of curcumin and the autophagy we detected in these cell types are not caused by inhibition of NF-B. However, curcumin can be used to inhibit active NF-B that is induced by chemokines or other anticancer treatments, as shown in leukemia and cervical cancer cells (Xia et al., 1995; Bava et al., 2005). For example, radiation induces NF-B activity in malignant glioma cells, which implies a resistant mechanism (Raju et al., 1997). Thus, curcumin may need to be used in combination with radiation or other chemotherapeutic agents for treating malignant glioma to demonstrate its inhibitory effect of NF-B.Our results showed that curcumin significantly inhibited the growth of malignant glioma both in vitro and in vivo.
An increasing number of studies have shown the anticancer efficacy of curcumin in preclinical and clinical settings. In subcutaneous animal models of various cancer cell types, curcumin effectively inhibited the growth of tumors (Shishodia et al., 2005; Aggarwal et al., 2006). Furthermore, a recent study reported that curcumin suppressed lung metastasis of breast cancer cells when used as a single agent or in combination with paclitaxel (Aggarwal et al., 2005). Several phase I clinical studies have demonstrated that curcumin was well tolerated up to 12 g/day without major adverse effects (Sharma et al., 2001, 2004; Lao et al., 2006). A phase II clinical trial for patients with pancreatic cancer is ongoing at our institute. However, absorption and bioavailability
of curcumin outside the colon is very problematic. Therefore, the intratumoral injection of rather large concentrations of curcumin that we used in this study might be not very useful clinically for human gliomas. Convection-enhanced delivery has been developed as a new technique of direct injection to increase drug uptake and distribution to large regions of the brain tumor by applying a pressure gradient (Lopez et al., 2006). With this method, curcumin can be delivered to malignant gliomas directly and efficiently while limiting toxicity to surrounding normal tissues. In summary, we have shown for the first time that curcumin induces autophagy in malignant glioma cells both in vitro and in vivo. The Akt/mTOR/p70S6K and ERK1/2 pathways are involved in curcumin-induced autophagy. Our results suggest that effect of autophagy on cell death may be dependent on its regulatory pathways. We recommend that the use of curcumin as a new anticancer agent for malignant glioma should be pursued further because of its prominent effect and its new anticancer mechanism of inducing autophagy.
Curcumin Blocks Brain Tumor Formation
A B S T R A C T
Turmeric, an essential ingredient of culinary preparations of Southeast Asia, contains a major
polyphenolic compound, named curcumin or diferuloylmethane, which eliminates cancer cells
derived from a variety of peripheral tissues. Although in vitro experiments have
addressed its anti-tumor property, no in vivo studies have explored its anti-cancer activity in
the brain. Oral delivery of this food component has been less effective because of its low
solubility in water.We show that a soluble formulation of curcumin crosses the blood–brain
barrier but does not suppress normal brain cell viability. Furthermore, tail vein injection, or
more effectively, intracerebral injection through a cannula, blocks brain tumor formation in
mice that had already received an intracerebral bolus of mouse melanoma cells (B16F10).
While exploring the mechanism of its action in vitro we observed that the solubilized
curcumin causes activation of proapoptotic enzymes caspase 3/7 in human
oligodendroglioma (HOG) and lung carcinoma (A549) cells, and mouse tumor cells N18
(neuroblastoma), GL261 (glioma), and B16F10. A simultaneous decrease in cell viability is
also revealed by MTT [3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide]
assays. Further examination of the B16F10 cells showed that curcumin effectively
suppresses Cyclin D1, P-NF-kB, BclXL, P-Akt, and VEGF, which explains its efficacy in
blocking proliferation, survival, and invasion of the B16F10 cells in the brain. Taken together,
solubilized curcumin effectively blocks brain tumor formation and also eliminates brain
tumor cells. Therefore, judicious application of such injectable formulations of curcumin
could be developed into a safe therapeutic strategy for treating brain tumors.
Discussion
A major difficulty in using orally-administered curcumin as a therapeutic agent stems from its low solubility, poor absorption, and high rate of metabolism of this compound (Anand et al., 2007). Therefore, as a first step, we have increased its solubility by using DMSO in sterile PBS to solubilize curcumin. The final concentration of DMSO in the body was expected to be 0.15% after tail-vein injections and less than 0.2% in the brain following intracranial delivery through a cannula. Thorough analyses of human toxicology of DMSO have been reported (http://www.dmso.org/...rmation/brobyn. html), and all these studies and human trials using relatively higher amounts of DMSO (0.5% of the body weight) confirmed that it was a “safe drug”. Thus, our solubilized formulation of curcumin is expected to have no adverse effect in humans. Our experiments indicate that the observed efficacy of curcumin as a prophylactic agent against cancer depends on its method of delivery in this solvent at an optimum concentration via intravenous or more effectively, intracranial injection. Studies from other groups have shown that curcumin eliminates human tumor cells such as melanoma, glioma, and others (Chen et al., 2005; Deeb et al., 2004; Dhandapani et al., 2007; Karmakar et al., 2006; Marin et al., 2007; Shishodia et al., 2007). A few in vivo studies have demonstrated that curcumin suppresses carcinogenesis of peripherally derived tissues,such as skin (Huang et al., 1997), the stomach (Huang et al., 1994), the colon (Huang et al., 1997; Kim et al., 1998), the breast (Mehta et al., 1997), and the liver (Chuang et al., 2000), but not the brain. Thus, this is the first in vivo demonstration of the anti-carcinogenic and anti-metastatic activity of curcumin in the brain. It demonstrates that our formulation is harmless to normal brain cells and attests to the chemopreventive and anti-tumor properties of curcumin.
The mechanisms by which curcumin selectively eliminates the tumor cells have yet to be elucidated. Although this
study does not establish the exact pathway through which curcumin blocks tumor formation in mouse brain, in vitro data presented here indicate that the chemopreventive and anticarcinogenic action of curcumin might be due to its ability to inhibit proteins that initiate protective signals, such as NF-kB, Akt, BclXL, or those that enhance cell proliferation, e.g. cyclin D1, and angiogenesis (VEGF) (Anto et al., 2002; Ellis and Hicklin, 2008; Franke and Cantley, 1997; Hengartner, 2000; Mukhopadhyay et al., 2001; Saile et al., 2001). Thus, curcumin inhibits multiple pathways that promote proliferation, survival, migration, and other functions of the cancerous B16F10 cells.
Once applied to humans, this treatment could eliminate chances of reappearance of cancer after tumor resection.
Intracranial delivery of solubilized curcumin would allow its quick permeation into all parts of the brain, thereby ablating residual cancer cells. Such a strategy could potentially eliminate the need for chemotherapy and radiation therapy, which have adverse side effects and often enhance angiogenesis and cancer cell proliferation. However, the rapid metabolic breakdown of curcumin in vivo is a significant challenge, which we expect to overcome by designing effective strategies of targeting this compound to the cancer cells.
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EMAIL 3:
Not sure I understand how they can create a soluable curcumin using DSMO which as a solvent can be used to remove paint, etc.....
I realize the authors state that there is no toxicity to humans in appropriate dosages, but it surprizes me that such a solvent can be ingested safely. Thus, I read the MSDS (Material Safety Data Sheet) for DSMO.
Dr Aggarwal's Response to email #3 - Dear Julie: Curcumin is soluble in milk or yogurt. You do not need to use DMSO. Best wishes
Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets
Curcumin (diferuloylmethane), a yellow pigment in the spice turmeric (also called curry powder), has been used for centuries as a treatment for inflammatory diseases. Extensive research within the past two decades has shown that curcumin mediates its antiinflammatoryeffects through the downregulation of
inflammatory transcription factors (such as nuclear factor kB), enzymes (such as cyclooxygenase 2 and 5
lipoxygenase) and cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6). Because of the
crucial role of inflammation in most chronic diseases, the potential of curcumin has been examined in neoplastic,
neurological, cardiovascular, pulmonary and metabolic diseases. The pharmacodynamics and pharmacokinetics
of curcumin have been examined in animals and in humans. Various pharmacological aspects of curcumin in vitro and in vivo are discussed in detail here.
Traditional medicine is known to be fertile ground for the source of modern medicines. One medicine in that
category is curcumin, a yellow coloring agent present in the spice turmeric (Curcuma longa) that belongs to the
ginger (Zingiberaceae) family. Besides its use in Indian cooking to add color and as a preservative, turmeric is used
in Ayurveda (Indian traditional medicine) to treat various common ailments including stomach upset, flatulence, dysentery, ulcers, jaundice, arthritis, sprains, wounds, acnes, and skin and eye infections. Curcumin was first isolated in 1815 by Vogel and Pelletier. Its chemical structure was determined in 1910 by J. Milobedzka and V. Lampe (Germany), its use in biliary diseases was documented in 1937 (67 patients treated), its antibacterial action in 1949 and its ability to decrease blood sugar levels in human subjects (i.e. its use as an antidiabetic) in 1972. Chemically, although curcumin is diferuloylmethane [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3, 5 dione], commercially available curcumin also contains 17% and 3% demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), respectively. Curcumin has been, however, shown to be more active than DMC or BDMC . These studies indicate that bis-a,b-unsaturated b-diketone, two methoxy groups, two phenolic hydroxy groups and two double-conjugated bonds might play an essential part in the antiproliferativeand anti-inflammatory activities assigned to curcumin. Various preclinical and clinical studies indicate that curcumin has potential therapeutic value against mostchronic diseases including neoplastic, neurological, cardiovascular, pulmonary, metabolic and psychological diseases. How curcumin manifests these pharmacological effects in vitro and in vivo is discussed here.
Our gain in knowledge about curcumin has been exponential over recent years. Curcumin has been shown to inhibit the proliferation and survival of almost all types of tumor cells examined up to now.
This phytochemical has been shown to selectively kill tumor cells and not normal cells. How does curcumin selectively mediate toxicity to tumor cells? Absorption and fluorescence spectroscopic methods showed that cellular uptake of curcumin is higher in tumor cells than in normal cells. Curcumin is also a potent chemosensitizer and radiosensitizer against tumor cells. Curcumin has been shown to be a more potent antioxidant than even vitamin E. Whether most of the activities described earlier are through antioxidant mechanisms is not fully understood. Evidence from our laboratory, however, indicates that both antiproliferative and anti-inflammatory activities of curcumin are mediated through its prooxidant mechanisms
Evidence is also accumulating that indicates that curcumin not only can prevent cancer but also has potential in the treatment of established tumors.
Three different Phase I clinical trials performed to determine safety have indicated that curcumin given at doses as
high as 15 g/day orally for 3 months is safe. No dose limiting toxicity was reported.
The effect of curcumin has been examined in various inflammatory chronic diseases in humans. We concluded that oral curcumin is well tolerated and had biological activity in some patients with pancreatic cancer despite limited absorption.
Although curcumin has been shown to modulate several targets that have been linked with cancer and various
other chronic diseases, one of the most important limitations with curcumin is its bioavailability.
Curcumin seems to be metabolized through conjugation and reduction. The low bioavailability of curcumin
is due to the hydrophobic nature of the molecule.For instance, Shoba et al. examined the effect of piperine on the pharmacokinetics of curcumin in animals and human volunteers. By contrast, in humans after a dose
of 2 g curcumin alone, serum levels were either undetectable or very low. However, piperine (20 mg) produced
much higher concentrations from 0.25–1 h post-drug; the increase in bioavailability was 2000%. The
Conclusion
Basic requirement for any chemopreventive agent demands that it should be non-toxic to normal and healthy
people, have high efficacy against multiple sites, should be orally bioavailable, should have a known mechanism of
action, should be easily available, should be low cost and should be acceptable to most of the human population.
Curcumin meets several, if not all, of these requirements. The aforementioned description demonstrates that curcumin can modulate multiple cell-signaling pathways known to be crucial for most chronic diseases, yet it is pharmacologically safe. Because most chronic diseases are mediated through dysregulated inflammation, curcumin has potential use in the prevention of these diseases. Despite the lower bioavailability, curcumin has potential therapeutic value against various human diseases including cancer, cardiovascular diseases, diabetes, arthritis and neurological diseases. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for the treatment of human disease. Because most of the therapeutic effects of curcumin are based on cell culture and animal studies, more clinical trials are needed to fully realize its potential.
Cancer is a Preventable Disease that Requires Major Lifestyle Changes
Preetha Anand,1 Ajaikumar B. Kunnumakara,1 Chitra Sundaram,1 Kuzhuvelil B. Harikumar,1
Sheeja T. Tharakan,1 Oiki S. Lai,1 Bokyung Sung,1 and Bharat B. Aggarwal1,2
Received May 14, 2008; accepted June 9, 2008; published online July 15, 2008
Abstract. This year, more than 1 million Americans and more than 10 million people worldwide are
expected to be diagnosed with cancer, a disease commonly believed to be preventable. Only 5–10% of all
cancer cases can be attributed to genetic defects, whereas the remaining 90–95% have their roots in the
environment and lifestyle. The lifestyle factors include cigarette smoking, diet (fried foods, red meat),
alcohol, sun exposure, environmental pollutants, infections, stress, obesity, and physical inactivity. The
evidence indicates that of all cancer-related deaths, almost 25–30% are due to tobacco, as many as 30–
35% are linked to diet, about 15–20% are due to infections, and the remaining percentage are due to
other factors like radiation, stress, physical activity, environmental pollutants etc. Therefore, cancer
prevention requires smoking cessation, increased ingestion of fruits and vegetables, moderate use of
alcohol, caloric restriction, exercise, avoidance of direct exposure to sunlight, minimal meat consumption,
use of whole grains, use of vaccinations, and regular check-ups. In this review, we present evidence that
inflammation is the link between the agents/factors that cause cancer and the agents that prevent it.
In addition, we provide evidence that cancer is a preventable disease that requires major lifestyle changes.
A more detailed discussion of dietary agents that can block inflammation and thereby provide chemopreventive
effects is presented in the following section.
How diet contributes to cancer is not fully understood. Most carcinogens that are ingested, such as
nitrates, nitrosamines, pesticides, and dioxins, come from food or food additives or from cooking.
Various phytochemicals have been identified in fruits, vegetables, spices, and grains that exhibit
chemopreventive potential. More than 25,000 different phytochemicals have been identified that may have potential
against various cancers.These phytochemicals have advantages because they are safe and usually target
multiple cell-signaling pathways. Major chemopreventive compounds identified from fruits and vegetables includes
carotenoids, vitamins, resveratrol,quercetin, silymarin, sulphoraphane and indole-3-carbinol.
Various natural carotenoids present in fruits and vegetables were reported to have anti-inflammatory
and anticarci-nogenic activity. The anticancer activity of lycopene has been demonstrated in both
in vitro and in vivo tumor models as well as in humans. Other carotenoids reported to have anticancer activity
include beta-carotene, alpha-carotene, lutein, zeaxanthin, beta-cryptoxanthin, fucoxanthin, astaxanthin,
capsanthin, crocetin, and phytoene.
The stilbene resveratrol has been found in fruits such as grapes, peanuts, and berries.
Resveratrol exhibits anticancer properties against a wide variety of tumors.....
The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; induction of apoptosis
via Fas/CD95, p53, ceramide activation, tubulin polymerization, mitochondrial and adenylyl cyclase
pathways; up-regulationof p21 p53 and Bax; down-regulation of survivin, cyclin D1,
cyclin E, Bcl-2, Bcl-xL, and cellular inhibitor of apoptosis proteins; activation of caspases; suppression of
nitric oxide synthase; suppression of transcription factors such as NF-κB, AP-1, and early growth response-1;
inhibition of cyclooxygenase- 2 (COX-2) and lipoxygenase; suppression of adhesion molecules; and inhibition
of angiogenesis, invasion, and metastasis. Limited data in humans have revealed that resveratrol is
pharmacologically safe. As a nutraceutical, resveratrol is commercially available in the USA and Europe
in 50 μg to 60 mg doses. Currently, structural analogues of resveratrol with improved bioavailability
are being pursued as potential chemopreventive and therapeutic agents for cancer.
The flavone quercetin,one of the major dietary flavonoids, is found in a broad range of fruits, vegetables,
and beverages such as tea and wine.The antioxidant, anti-inflammatory, antiproliferative, and apoptotic
effects of the molecule have been largely analyzed in cell culture models, and it is known to block NF-κB activation.
In animal models, quercetin has been shown to inhibit inflammation. A phase 1 clinical trial indicated that the
molecule can be safely administered and that its plasma levels are sufficient to inhibit lymphocyte tyrosine
kinase activity. Consumption of quercetin in onions and apples was found to be inversely associated with
lung cancer risk in Hawaii. In another study, an increased plasma level of quercetin after a meal of onions was
accompanied by increased resistance to strand breakage in lymphocytic DNA and decreased levels
of some oxidative metabolites in the urine.
The flavonoid silymarin (silybin, isosilybin, silychristin, silydianin, and taxifolin) is commonly found in
the dried fruit of the milk thistle plant Silybum marianum. Although silymarin’s role as an antioxidant
and hepatoprotective agent is well known, its role as an anticancer agent is just emerging.
The anti-inflammatory effects of silymarin are mediated through suppression of NF-κB-regulated
gene products, including COX-2, lipoxygenase (LOX), inducible NO synthase, TNF, and IL-1.
Numerous studies have indicated that silymarin is a chemopreventive agent in vivo against various
carcinogens/tumor promoters. Silymarin has also been shown to sensitize tumors to chemotherapeutic
agents through downregulation of the MDR protein and other mechanisms. It binds to both estrogen and androgen
receptors and downregulates prostate specific antigen. In addition to its chemopreventive effects,
silymarin exhibits activity against tumors (e.g., prostate and ovary) in rodents. Various clinical trials have
indicated that silymarin is bioavailable and pharmacologically safe. Studies are now in progress to
demonstrate the clinical efficacy of silymarin against various cancers.
The flavonoid indole-3-carbinol (I3C) is present in vegetables such as cabbage, broccoli,
brussels sprout, cauliflower, and daikon artichoke.
Sulforaphane (SFN) is an isothiothiocyanate found in cruciferous vegetables such as broccoli.
Its chemopreventive effects have been established in both in vitro and in vivo studies. The mechanisms of
action of SFN include inhibition of phase 1 enzymes, induction of phase 2 enzymes to detoxify carcinogens,
cell-cycle arrest, induction of apoptosis, inhibition of histone deacetylase, modulation of the MAPK pathway,
inhibition of NF-κB, and production of ROS. Preclinical and clinical studies of this compound have suggested
its chemopreventive effects at several stages of carcinogenesis.
Teas and Spices
Spices are used all over the world to add flavor, taste, and nutritional value to food. A growing body of research
has demonstrated that phytochemicals such as catechins (green tea), curcumin (turmeric),
diallyldisulfide (garlic), thymoquinone (black cumin) capsaicin (red chili), gingerol (ginger),
anethole (licorice), diosgenin (fenugreek) and eugenol (clove, cinnamon) possess therapeutic
and preventive potential against cancers of various anatomical origins. Other phytochemicals with
this potential include ellagic acid (clove), ferulic acid (fennel, mustard, sesame), apigenin (coriander, parsley),
betulinic acid (rosemary), kaempferol (clove, fenugreek), sesamin (sesame), piperine (pepper),
limonene (rosemary), and gambogic acid (kokum). Below is a description of some important phytochemicals
associated with cancer.
More than 3,000 studies have shown that catechins derived from green and black teas have potential
against various cancers. The consumption of green tea appears to be relatively safe. Among patients
with established premalignant conditions, green tea derivatives have shown potential efficacy against
cervical, prostate, and hepatic malignancies without inducing major toxic effects. One novel study determined
that even persons with solid tumors could safely consume up to 1 g of green tea solids, the equivalent
of approximately 900 ml of green tea, three times daily. This observation supports the use of green tea
for both cancer prevention and treatment.
Curcumin is one of the most extensively studied compounds isolated from dietary sources for
inhibition of inflammation and cancer chemoprevention, as indicated by almost 3000 published studies.
Studies from our laboratory showed that curcumin inhibited NF-κB and NF-κB-regulated gene expression in various
cancer cell lines. In vitro and in vivo studies showed that this phytochemical inhibited inflammation
and carcinogenesis in animal models........
Results showed that oral Curcuma extract was well tolerated, and dose-limiting toxic effects were
not observed. Results from another study conducted by our group showed that curcumin inhibited constitutive
activation of NF-κB, COX-2, and STAT3 in peripheral blood mononuclear cells ...... Curcumin down-regulated
the expression of NF-κB, COX-2, and phosphorylated STAT3 in peripheral blood mononuclear cells from patients.
These studies showed that curcumin is a potent anti-inflammatory and chemopreventive agent.
Diallyldisulfide, isolated from garlic, inhibits the growth and proliferation of a number of cancer cell lines
including colon, breast, glioblastoma, melanoma, and neuroblastoma cell lines. Recent studies showed that this
compound induces apoptosis in Colo 320 DM human colon cancer cells by inhibiting COX-2, NF-κB, and ERK-2.
It has been shown to inhibit a number of cancers .....
Diallyldisulfide is believed to bring about an anticarcinogenic effect through a number of mechanisms,
such as scavenging of radicals; increasing gluathione levels; increasing the activities of enzymes such as glutathione
S-transferase and catalase; inhibiting cytochrome p4502E1 and DNA repair mechanisms; and preventing chromosomal
damage.
The chemotherapeutic and chemoprotective agents from black cumin include thymoquinone (TQ),
dithymoquinone (DTQ), and thymohydroquinone, which are present in the oil of this seed. TQ has antineoplastic
activity against various tumor cells. DTQ also contributes to the chemotherapeutic effects of Nigella sativa. In vitro
study results indicated that DTQ and TQ are equally cytotoxic to several parental cell lines and to their
corresponding multidrug-resistant human tumor cell lines. TQ induces apoptosis by p53-dependent and
p53-independent pathways in cancer cell lines. It also induces cell-cycle arrest and modulates the levels of
inflammatory mediators. To date, the chemotherapeutic potential of TQ has not been tested, but numerous studies
have shown its promising anticancer effects in animal models. Moreover, the combination of TQ and clinically used
anticancer drugs has been shown to improve the drug’s therapeutic index, prevents nontumor tissues
from sustaining chemotherapy-induced damage, and enhances the antitumor activity of drugs such as
cisplatin and ifosfamide. A very recent report from our own group established that TQ affects the NF-κB signaling pathway
by suppressing NF-κB and NF-κB-regulated gene products.
The phenolic compound capsaicin, a component of red chili, has been extensively studied.
Although capsaicin has been suspected to be a carcinogen, a considerable amount of evidence suggests
that it has chemopreventive effects. The antioxidant, anti-inflammatory, and antitumor properties of
capsaicin have been established in both in vitro and in vivo systems. For example, showed that capsaicin can
suppress the TPA-stimulated activation of NF-κB and AP-1 in cultured HL-60 cells. In addition, capsaicin inhibited
the constitutive activation of NF-κB in malignant melanoma cells. Furthermore, capsaicin strongly suppressed the
TPA-stimulated activation of NF-κB and the epidermal activation of AP-1 in mice. Another proposed mechanism ofaction
of capsaicin is its interaction with xenobiotic metabolizing enzymes, involved in the activation and detoxification of
various chemical carcinogens and mutagens. Metabolism of capsaicin by hepatic enzymes produces reactive phenoxy
radical intermediates capable of binding to the active sites of enzymes and tissue macromolecules.
Capsaicin can inhibit platelet aggregation and suppress calcium-ionophore–stimulated proinflammatory
responses, such as the generation of superoxide anion, phospholipaseA2 activity, and membrane lipid peroxidation
in macrophages. It acts as an antioxidant in various organs of laboratory animals. Anti-inflammatory properties
of capsaicin against carcinogen-induced inflammation have also been reported in rats and mice. Capsaicin has
exerted protective effects against ethanol-induced gastric mucosal injury, hemorrhagic
erosion, lipid peroxidation, and myeloperoxidase activity in rats that was associated with suppression of COX-2.
Gingerol, a phenolic substance mainly present in the spice ginger (Zingiber officinale Roscoe), has diverse
pharmacologic effects including antioxidant, antiapoptotic, and anti-inflammatory effects.
Gingerol has been shown to have anticancer and chemopreventive properties, and the proposed
mechanisms of action include the inhibition of COX-2 expression by blocking of the p38 MAPK–NF-κB
signaling pathway. A detailed report on the cancer-preventive ability of gingerol was presented in a recent
review by Shukla and Singh.
Anethole, the principal active component of the spice fennel, has shown anticancer activity.
In 1995, Al-Harbi et al. studied the antitumor activity of anethole against Ehrlich ascites carcinoma induced in
a tumor model in mice. The study revealed that anethole increased survival time, reduced tumor weight,
and reduced the volume and body weight of the EAT-bearing mice. It also produced a significant cytotoxic effect i
n the EAT cells in the paw, reduced the levels of nucleic acids and MDA, and increased NP-SH concentrations.
In 1996, Sen et al.,studied the NF-κB inhibitory activity of a derivative of anethole and anetholdithiolthione.
Their study results showed that anethole inhibited H2O2, phorbol myristate acetate or TNF alpha induced NF-κB
activation in human jurkat T-cells....
Diosgenin, a steroidal saponin present in fenugreek, has been shown to suppress inflammation, inhibit proliferation,
and induce apoptosis in various tumor cells. Research during the past decade has shown that diosgenin
suppresses proliferation and induces apoptosis in a wide variety of cancer cells lines. Antiproliferative effects
of diosgenin are mediated through cell-cycle arrest, disruption of Ca2+ homeostasis, activation of p53, release of
apoptosis-inducing factor, and modulation of caspase-3 activity. Diosgenin also inhibits
azoxymethane-induced aberrant colon crypt foci, has been shown to inhibit intestinal inflammation, and modulates the
activity of LOX and COX-2. Diosgenin has also been shown to bind to the chemokine receptor CXCR3, which mediates
inflammatory responses. Results from our own laboratory have shown that diosgenin inhibits osteoclastogenesis,
cell invasion, and cell proliferation through Akt down-regulation, IκB kinase activation, and NF-κB-regulated gene expression.
Eugenol is one of the active components of cloves. Studies conducted by Ghosh et al. showed that eugenol
suppressed the proliferation of melanoma cells. In a B16 xenograft study, eugenol treatment produced a
significant tumor growth delay, an almost 40% decrease in tumor size, and a 19% increase in the
median time to end point. Of more importance, 50% of the animals in the control group died of metastatic growth,
whereas none in the eugenol treatment group showed any signs of cell invasion or metastasis. The same study showed
that eugenol inhibited superoxide formation and lipid peroxidation and the radical scavenging activity that may be responsible
for its chemopreventive action. Another study conducted by Pisano et al. demonstrated that eugenol and related biphenyl
(S)-6,6′-dibromo-dehydrodieugenol elicit specific antiproliferative activity on neuroectodermal tumor cells, partially
triggering apoptosis. In 2003, Kim et al. showed that eugenol suppresses COX-2 mRNA expression (one of the main
genes implicated in the processes of inflammation and carcinogenesis) in HT-29 cells and lipopolysaccharide-stimulated
mouse macrophage .7 cells.
The major wholegrain foods are wheat, rice, and maize; the minor ones are barley, sorghum, millet, rye, and oats.
Whole grains contain chemopreventive antioxidants such as vitamin E, tocotrienols, phenolic acids, lignans, and phytic acid. The but is greatantioxidant content of whole grains is less than that of some berries but is greater than that of common fruits or vegetables. The refining process concentrates the carbohydrate and reduces the amount of other macronutrients, vitamins,
and minerals because the outer layers are removed. In fact, all nutrients with potential preventive actions against cancer are reduced.
For example, vitamin E is reduced by as much as 92%. How do whole grains reduce the risk of cancer? Several potential mechanisms
have been described. For instance, insoluble fibers, a major constituent of whole grains, can reducethe risk of bowel cancer.
Additionally, insoluble fiber undergoes fermentation, thus producing short-chain fatty acids such as butyrate, which is an important suppressor of tumor formation. Whole grains also mediate favorable glucose response...Also, several phytochemicals from grains and pulses were reported to have chemopreventive action against a wide variety of cancers. For example, isoflavones
(including daidzein, genistein, and equol) are nonsteroidal diphenolic compounds that are found in leguminous plants
and have antiproliferative activities. Findings from several, but not all, studies have shown significant
correlations between an isoflavone-rich soy-based diet and reduced incidence of cancer or mortality
from cancer in humans. Our laboratory has shown that tocotrienols, but not tocopherols, can suppress
NF-κB activation induced by most carcinogens, thus leading to suppression of various genes linked
with proliferation, survival, invasion, and angiogenesis of tumors.
Observational studies have suggested that a diet rich in soy isoflavones (such as the typical Asian diet) is
one of the most significant contributing factors for the lower observed incidence and mortality of prostate
cancers in Asia. On the basis of findings about diet and of urinary excretion levels associated with daidzein, genistein,
and equol in Japanese subjects compared with findings in American or European subjects, the isoflavonoids in soy
products were proposed to be the agents responsible for reduced cancer risk. In addition to its effect on breast cancer, genistein and related isoflavones also inhibit cell growth or the development of chemically induced cancers
in the stomach, bladder, lung, prostate, and blood.
Although controversial, the role of vitamins in cancer chemoprevention is being evaluated increasingly.
ruits and vegetables are the primary dietary sources of vitamins except for vitamin D. Vitamins,
especially vitamins C, D, and E, are reported to have cancer chemopreventive activity without apparent
toxicity. Epidemiologic study findings suggest that the anticancer/ chemopreventive effects of vitamin C
against various types of cancers correlate with its antioxidant activities and with the inhibition of inflammation
and gap junction intercellular communication. Findings from a recent epidemiologic study showed that a
high vitamin C concentration in plasma had an inverse relationship with cancer-related mortality.
In 1997, expert panels at the World Cancer Research Fund and the American Institute for Cancer
The protective effects of vitamin D result from its role as a nuclear transcription factor that regulates
cell growth, differentiation, apoptosis, and a wide range of cellular mechanisms central to the
development of cancer
There is extensive evidence suggesting that regular physical exercise may reduce the incidence of
various cancers. A sedentary lifestyle has been associated with most chronic illnesses.
Fasting is a type of caloric restriction (CR) that is prescribed in most cultures.
Dietary restriction, especially CR, is a major modifier in experimental carcinogenesis and is known to
significantly decrease the incidence of neoplasms. Gross and Dreyfuss reported that a 36% restriction
in caloric intake dramatically decreased radiation-induced solid tumors and/or leukemias.
How CR reduces the incidence of cancer is not fullyunderstood. CR in rodents decreases the levels of
plasma glucose and IGF-1 and postpones or attenuates cancer and inflammation without irreversible
adverse effects. Most of the studies done on the effect of CR in rodents are longterm; however, that is not
possible in humans, who routinely practice transient CR. The effect that transient CR has on cancer in
humans is unclear.
CONCLUSIONS
On the basis of the studies described above, we propose a unifying hypothesis that all lifestyle factors
hat cause cancer (carcinogenic agents) and all agents that prevent cancer (chemopreventive agents)
tare linked through chronic inflammation The fact that chronic inflammation is closely linked to the
tumorigenic pathway is evident from numerous lines of evidence.
First, inflammatory markers such as cytokines (such asTNF, IL-1, IL-6, and chemokines), enzymes
(such as COX-2, 5-LOX, and matrix metalloproteinase-9 [MMP-9]), and adhesion molecules (such as intercellular
adhesion molecule 1, endothelium leukocyte adhesion molecule 1, and vascular cell adhesion molecule 1)
have been closely linked with tumorigenesis.
Second, all of these inflammatory gene products have been shown to be regulated by the nuclear
transcription factor, NF-κB.
Third, NF-κB has been shown to control the expression of other gene products linked with tumorigenesis
such as tumor cell survival or antiapoptosis (Bcl-2, Bcl-xL, IAP-1, IAP-2, XIAP, survivin, cFLIP, and TRAF-1),
proliferation (such as c-myc and cyclin D1), invasion (MMP-9), and angiogenesis (vascular endothelial growth
factor).
Fourth, in most cancers, chronic inflammation precedes tumorigenesis.
Fifth, most carcinogens and other risk factors for cancer, including cigarette smoke, obesity, alcohol,
hyperglycemia, infectious agents, sunlight, stress, food carcinogens, and environmental pollutants, have been
shown to activate NF- κB.
Sixth, constitutive NF-κB activation has been encountered in most types of cancers.
Seventh, most chemotherapeutic agents and γ-radiation, used for the treatment of cancers, lead to
activation of NF-κB.
Eighth, activation of NF-κB has been linked with chemoresistance and radioresistance.
Ninth, suppression of NF-κB inhibits the proliferation of tumors, leads to apoptosis, inhibits invasion,
and suppresses angiogenesis.
Tenth, polymorphisms of TNF, IL-1, IL-6, and cyclin D1 genes encountered in various cancers are all
regulated by NF-κB. Also, mutations in genes encoding for inhibitors of NF-κB have been found in certain
cancers.
Eleventh, almost all chemopreventive agents described above have been shown to suppress NF-κB activation.
Fruits Spices & condiments Vegetables Cereals
Fruits, vegetables, spices, condiments and cereals with potential to prevent cancer.
Fruits include apple, apricot, banana, blackberry, cherry, citrus fruits, dessert date, durian, grapes,
guava, Indian gooseberry, mango, malay apple, mangosteen, pineapple, pomegranate.
Vegetables include artichoke, avocado, brussels sprout, broccoli, cabbage, cauliflower, carrot, daikon,
kohlrabi, onion, tomato, turnip, ulluco, water cress, okra, potato, fiddle head, radicchio, komatsuna, salt bush,
winter squash, zucchini, lettuce, spinach.
Spices and condiments include turmeric, cardamom, coriander, black pepper, clove, fennel, rosemary,
sesame seed, mustard, licorice, garlic, ginger, parsley, cinnamon, curry leaves, kalonji, fenugreek, camphor,
pecan, star anise, flax seed, black mustard, pistachio, walnut, peanut, cashew nut.
Cereals include rice, wheat, oats, rye, barley, maize, jowar, pearl millet, proso millet, foxtail millet, little millet,
barnyard millet, kidney bean, soybean, mung bean, black bean, pigeon pea, green pea, scarlet runner bean,
black beluga, brown spanish pardina, green, green (eston), ivory white, multicolored blend, petite crimson, petite golden,
red chief.
Attached Files
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Curcumin___Cancer_is_a_preventable_Disease.pdf 1011.99KB
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Curcumin_Blocks_Brain_Tumor_Formation.pdf 1.77MB
125 downloads
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Curcumin_Pharmacological_Basis_for_the_role_of_Curcumin_in_chronic_diseases.pdf 1.09MB
135 downloads
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Curcumin_Suppresses_Growth_of_Malignant_Gliomas.pdf 648.28KB
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