CURCUMIN: Master Healer

Cancer

It’s rare to see a drug that is shown, in study after study, to have remarkable and significant anti-cancer properties both in vivo and in vitro. But curcumin is such a drug, and it induces tumor apoptosis with no apparent toxicity.

To get just a sampling of how thoroughly curcumin has been studies in cancer over the past few years, consider the following.

(PMID: 20145189) Curcumin has shown activity against oral cancers. Remarkably, curcumin arrests the growth of immortalized normal cells and malignant cells, but not normal oral cells.

(PMID: 20127174) Curcumin sensitizes lung cancer cells to apoptosis by reducing expression of Bcl-2, an anti-apoptotic signaling molecule.

(PMID: 19898931) Curcumin and piperine, both separately and in combination, inhibit breast stem cell self-renewal, but do not cause toxicity to differentiated cells. This action may prevent breast cancer.

(PMID: 16584595) Curcumin reduces BDNF, inhibits TrkB expression, and reduces angiogenesis (which is stimulated by BDNF) in multiple myeloma cells. This is the first of many paradoxical results, as curcumin has been shown to increase BDNF in chronic stress.

(PMID: 20387230) Curcumin induces apoptosis in oral cancer cells.

(PMID: 20358476) Curcumin causes mitochondrial damage to prostate cancer cells, leading to apoptosis.

(PMID: 20305684) Curcumin treatment enhanced the ability of effector T cells to kill cancer cells in vitro.

(PMID: 20332461) Curcumin induces apoptosis in brain cancer cells.

(PMID: 20044614) Curcumin induces cell death in bone cancer cells.

(PMID: 20032896) Curcumin is effective against leukemia; abstract notes that tumor cells are more sensitive to the effects of curcumin than are normal cells.

(PMID: 19901561) Phase I trial of curcumin, combined with chemotherapy, in breast cancer in humans. Curcumin given orally at 500mg/day and escalated from there. 6000mg/day was most effective, and curcumin seemed to improve efficacy.

(PMID: 20373902) Curcumin induces apoptotis in melanoma cells through a mitochondrial pathway.

(PMID: 20393484) Curcumin induces apoptotis in T-cell lymphoma cells by inhibiting STAT-3 and NF-kappaB.

(PMID: 20077433) Curcumin inhibits lung cancer growth in vivo.

(PMID: 20363232) Curcumin restrains cancer cell growth by suppressing activity of telomerase, and this study suggests it does so by (paradoxical) ROS production.

(PMID: 20360934) Curcumin promotes apoptosis in esophageal cancer.

(PMID: 20057137) Curcumin inhibits inosine monophosphate dehydrogenase, a therapeutic target for anti-cancer therapy and key step in DNA synthesis.

Summary Curcumin shows activity (in a mix of in vivo and in vitro studies) in esophageal cancer, lung cancer, melanoma, lymphoma, breast cancer, leukemia, bone cancer, brain cancer, prostate cancer, and oral cancer. And this is just a sampling of the literature.

It seems that curcumin’s effects are mediated by a variety of factors, ranging from a reduction in Bcl-2 (an anti-apoptotic protein), inhibition of STAT-3 and NF-kappaB, increased ROS production in cancer cells, suppression of telomerase activity, and increased T cell efficacy.

Anti-ROS, Injury, Inflammation, and Inflammation-related Disease

Inhibiting NF-kappaB and TNF-alpha is just the beginning for curcumin, as the compound seems to have widespread anti-inflammatory effects.

(PMID: 20227282) Curcumin induces glutathione synthesis.

(PMID: 20132469) Clinically achievable concentrations of curcumin reduced glial activation, inflammation, and cerebral edema following traumatic brain injury in mice.

(PMID: 20018302) In rats with spinal cord injury, curcumin inhibited apoptosis and neuron loss and also “quenched astrocyte activation”, improving neural deficit. By attenuating astrocyte activation, curcumin improves neuron survival.

(PMID: 19917353) Curcumin is known to be a potent inhibitor of NF-kappaB and attenuates ischemia-reperfusion injury. In reperfusion injury, curcumin increases glutathione and reduced NO levels (among other effects), reducing inflammatory damage.

(PMID: 16364299) Pre-supplementation (and post-supplementation, possibly to a lesser extent) with curcumin dramatically reduced effects of traumatic brain injury, normalizing levels of BDNF, CREB, and synapsin I.

(PMID: 20214332) Curcumin inhibits fibroblast proliferation, potentially indicating effectiveness against fibrotic disease.

(PMID: 20180411) In rat chronic nonbacterial prostatitis, curcumin lowers TNF-alpha and IL-8, leading to amelioration of symptoms.

(PMID: 20125031) Curcumin protects myocardium against ischemic injury.

(PMID: 20056736) Curcumin protects against arsenic-induced DNA damage by reducing ROS generation and lipid peroxidation and increasing antioxidant activity.

(PMID: 19878610) Curcumin may have efficacy against inflammatory bowel disease. Curcumin enhances IL-10 and reduces IL-1beta.

(PMID: 20112103) Curcumin has hepatoprotective potency by reducing lipid peroxidation and increasing GSH, CAT, and SOD. Indeed, curcumin (but not resveratrol) is effective against aflatoxin-induced liver injury.

(PMID: 20056776) Curcumin inhibits pneumonia-related lung inflammation without decreasing bacterial load, and may combine very well with antibiotics. (Curcumin reduced TNF-alpha, NO, and other inflammatory mediators.)

(PMID: 19932168) Curcumin may help prevent cataracts by limiting free-radical induced Ca2+ influx in the eye.

(PMID: 20188213) At least in mice, curcumin may treat arthritis by reducing TNF-alpha, IL-1beta, and serum IgG2. By inhibiting NF-kappaB, curcumin also inhibited PGE2 production and COX-2 expression.

(PMID: 20080166) Curcumin exerts hepatoprotective actions against ethanol.

(PMID: 20229497) In merucury-exposed rats, curcumin reduces mercury-associatd oxidative stress and its serum markers. Curcumin also reduced tissue mercury concentrations. Curcumin may be both an effective treatment and pre-treatment to mercury exposure.

(PMID: 20026275) In rats given streptozotocin (a toxin), curcumin prevents memory deficit and normalizes elevated AChE levels in the hippocampus. Curcumin also attenuated reduced glutathione levels in the cortex and hippocampus due to the toxin. Finally, curcumin also restored insulin receptor protein levels altered by the toxin.

(PMID: 20025056) Curcumin is protective against selenium toxicity in the liver and kidney by means of regulating iNOS expression.

(PMID: 16387899) A good review summarizing effects of curcumin. Curcumin inhibits NF-kappaB, COX-2, LOX, and iNOS.

(PMID: 19919835) Curcumin can prevent acetominophen overdose-induced damage to kidney and renal cells.

(PMID: 20026325) Curcumin may have therapeutic potential in dry eye disease.

Summary Curcumin protects the liver against ethanol, may heal dry eye disease, prevents acetominophen toxicity, protects against selenium, mercury, and arsenic toxicity, has shown efficacy against arthritis, may prevent cataracts, may reduce sickness-associated inflammation, reduces liver inflammation, may have efficacy against inflammatory bowel disease, reduces inflammation in prostatitis, reduces damage due to ischemia/reperfusion, reduces the effects of traumatic brain injury (both in preventative and treatment capacities), increases glutathione, and improves neuron survival in spinal cord injury.

It accomplishes these remarkable and diverse feats by increasing glutathione, inhibiting NF-kappaB, inhibiting PGE2 and COX-2, reducing TNF-alpha, IL-8, and IL-1beta, scavenging ROS, reducing iNOS and nitric oxide, increases catalase and superoxide dismutase expression, increasing IL-10, reducing TGF-beta1 activation, reducing astrocyte activation in traumatic brain injury, and normalizing brain levels of BDNF and CREB.

Stress and Depression
Curcumin has shown remarkable efficacy in reducing the neurological consequences of chronic stress. Many of these benefits seem to derive from increased BDNF expression, but there may also be other mechanisms at work. At any rate, curcumin may have potential as both an antidepressant and an “adaptogen”.

(PMID: 19879308) Curcumin increases BDNF and CREB.

(PMID: 17022948) Chronic stress increased plasma corticosterone and reduced GR expression, and these changes were reversed by curcumin administration. Chronic stress also reduced BDNF levels and pCREB/CREB ratio in the hippocampus and frontal cortex of rats. Curcumin blocked these effects.

(PMID: 18766332) Curcumin showed antidepressant effects in mice, increased 5-HT and DA (at higher doses) levels, and (at higher doses) inhibited both MAO-A and MAO-B. Curcumin also appears to synergize with SSRI and NRI antidepressants, but not tricyclics. Coadministration of piperine (known to increase bioavailability) enhanced effects.

(PMID: 17942093) Curcumin has anti-depressant like effects in the forced swimming test. These effects appear to be mediated by alterations in 5-HT1A/1B and 5-HT2C. More specifically, both 5-HT1A and 5-HT1B antagonism separately blocks the effects of curcumin, but 5-HT1A agonism, 5-HT1B agonism, and 5-HT2C antagonism synergize with the effects of curcumin. Thus curcumin may act, directly or indirectly, as a 5-HT1A/1B agonist and a 5-HT2C antagonist. This is very good.

(PMID: 17846884) Ethanol withdrawal did not restore rhythmicity or levels of 5-HT or 5-HIAA in the SCN of male rats, but curcumin administration partially restored 5-HT/5-HIAA ratio and daily phase shifts. This may have relevance for circadian rhythm disruptions.

(PMID: 17846884) Rats subjected to chronic mild stress developed increased TNF-alpha and IL-6 levels, as well as reduced NK cell counts. These rats also showed increased CRH and serum cortisol, without an elevation in ACTH. Administration of curcumin reversed these effects, demonstrating antidepressant-like effects.

(PMID: 17617388) Curcumin increases hippocampal neurogenesis in chronically stressed rats in a way similar to imipramine. Curcumin also prevented stress-induced reductions in 5-HT1A mRNA and BDNF levels in the hippocampus.

These last two studies are strange; they are in vitro studies in bovine adrenocortical cells, but show largely opposite actions of curcumin on cortisol. Not sure what to think, and haven’t had time to analyze them.

(PMID: 18406348) In bovine adrenocortical cells, curcumin increased cortsiol secretion, and this increase lasted for 24 hours. Secretion was increased as much as 10-fold. This was accomplished by curcumin inhibition of bTREK1 K+ channels.

(PMID: 19653644) Also in bovine adrenocortical cells, curcumin decreased ACTH-induced cortisol secretion as well as angiotensin-II-induced cortisol secretion. (Contradicts another study.)

Summary Curcumin prevents stress-induced reductions in 5-HT1A and BDNF in the cortex and hippocampus, normalizes stress-induced increases in TNF-alpha and IL-6, reduces stress-induced increases in serum corticosterone, negates stress-induced downregulation of GR expression, restores disturbed 5-HT circadian rhythm consequent to ethanol withdrawal, increases BDNF and CREB, shows considerable antidepressant efficacy, and may directly or indirectly be a 5-HT1A/1B agonist and 5-HT2C antagonist.

Insulin, Skeletal Muscle, Fat, and Metabolism

Though the data are, my comparison, scant, curcumin also seems to have positive effects on blood lipids, insulin sensitivity, fat cells, and skeletal muscle.

(PMID: 20227862) Curcumin dose-dependently decreases lipids and glucose in diabetic rats. Curcumin also increased AMPK both in vivo and in vitro. Thus curcmin improves insulin resistance in rat skeletal muscle.

(PMID: 20222050) Curcumin reduced insulin and leptin in frucrose-fed rats. Thus curcumin led to improved leptin and insulin signaling as well as PPAR alpha expression. It also reduced LDL cholesterol and tryglycerides.

(PMID: 20205235) Another study noting curcumin activates AMPK in skeletal muscle, leading to increased glucose uptake.

(PMID: 10444409) Curcumin acts directly on muscle cells to stimulate proliferation. Inhibitors of NF-kappaB, like curcumin, also stimulate muscle differentiation in vitro. Curcumin has a “striking” effect on myogenesis and accelerated healing after injury.

(PMID:19093868) AMPK activation by curcumin may inhibit both cancer cell and adipocyte differentiation.

(PMID: 20357182) Curcumin suppresses adipogenesis.

(PMID: 20395228) Curcumin appears to have hypoglycemic action and stimulates insulin secretion from pancreatic cells, suggesting potential efficacy in diabetes.

Summary Curcumin has hypoglycemic action, likely by a combination of reducing insulin sensitivity and increasing pancreatic insulin output; the compound may thus have anti-diabetic activity. Moreover, curcumin activates AMPK (leading to improved glucose uptake in muscle), suppresses adipogenesis, inhibits adipocyte differentiation, stimulates skeletal muscle proliferation (with a “striking” effect on myogenesis), speeds healing after injury, improves insulin and leptin signaling, increases PPAR-alpha expression, and reduces both LDL cholesterol and triglycerides.

Other Good Stuff

And yet, curcumin has further positive effects.

(PMID: 20040737) Curcumin inhibits TRPV1-mediated hyperalgesia/pain hypersensitivity, but does not inhibit heat-induced TRPV1 currents. (Curcumin may have direct action at TRPV1.)

(PMID: 20153625) Curcumin activates the nuclear vitamin D receptor, and this receptor has been associated with chemoprotection against intestinal cancers.

(PMID: 20026048) Curcumin has anti-viral activity against influenza, adenovirus, coxsackievirus, and HIV. This study further showed that curcumin reduces hepatitis C gene expression through the Akt-SREBP-1 pathway.

(PMID: 20017731) Curucmin has anti-fungal properties against Candida via generation of oxidative stress. Curcumin’s effects were prevented by the addition of anti-oxidants. (Excessive doses used?)

(PMID: 18420184) Glutamate excitotoxicity reduced BDNF and reduced cell viability; pretreatment with curcumin prevented these effects. However, a Trk (BDNF receptor) receptor inhibitor blocked these effects, suggesting that the neuroprotective effects of curcumin are mediated by BDNF/TrkB.

(PMID: 19033880) Curcumin abolished upregulation of BDNF transcription and morphine analgesic tolernance after administration of morphine for six days.

(PMID: 20369229) Curcumin inhibits the effects of streptozotocin-induced dementia through PPAR-gamma activation.

(PMID: 20230279) Curcumin reduces DA cell death consequent to application of MPTP. Importantly, this effect is not due exclusively to anti-inflammatory or anti-oxidant activity; rather, curcumin inhibits phosphorylation of JNK1/2 and c-Jun, leading to increased DA neuron survival.

(PMID: 20209961) “Several animal gastric ulcer models prove that curcumin SDs has anti-gastric ulcer effects by inhibiting gastric acid secretion, reducing gastric juice acidity, inhibiting the activity of pepsin and promoting healing of ulcer.”

(PMID: 20337222) Another study showing curcumin has activity against gastric ulcers.

(PMID: 20170701) Here’s one for ATB: curcumin prevents against genotoxic effects of arsenic and flouride.

(PMID: 20346917) Curcumin enhances retinoic acid-induced superoxide radical generating activity, and thus may be an immune potentiator.

Summary Curcumin potentiates the immune system, prevents against genotoxic effects of flouride and arsenic, prevents and treats gastric ulcers, reduces DA cell death upon administration of DA neurotoxin (and do so through more than just anti-inflammatory pathways), reduces tolerance to morphine, provides neuroprotection against glutamate excitotoxicity, shows anti-fungal properties, shows anti-viral properties, is a vitamin D receptor agonist, and may reduce certain types of hyperalgesia.

 

The Caveats
At this point, curcumin has mostly been shown to have no known toxicity and very few negative effects. Still, there are a handful of studies that are worthy of mention.

(PMID: 20029958) Like many other antioxidants, low doses of curcumin scavange ROS, but higher doses may induce ROS and lead to damage. This was seen in a rat model of myocardial necrosis.

(PMID: 11815407) Curcumin is extensively metabolized in the GI tract. Not necessarily a bad thing, but could lead to variable effects.

(PMID: 20346654) Curcumin has some activity at inhibiting 17beta-HSD3, the enzyme catalyzing the final step of testosterone biosynthesis. It is unclear how substantial this effect is, however it could potentially lead to reduced testosterone levels.

(PMID: 19879924) In vitro, curcumin increases LRRK2 mRNA and protein. LRRK2 is a gene whose expression has been positively assocaited with Parkinson’s disease. This could, in theory, lead to increased risk of Parkinson’s disease, but this is also just a single factor out of many.

(PMID: 20198619) Letter with concerns: curcumin may induce DNA damage in vitro and in vivo and may have carcinogenic activity. Curcumin dissolved in water does not bind to DNA, though in solution with ethanol it does. It is not clear if these effects are due to curcumin, curcumin + ethanol, or ethanol. However, the letter suggests that these counter-results may not be appropriate, and curcumin may actually be genotoxic.

(PMID: 20198612) Paper referenced above showing curcumin dissolved in water does not bind or intercalate with DNA. However, doses were low and ROS generation could still result in DNA damage without binding.

Summary In short, there is a speck of evidence to suggest curcumin could increase Parkinson’s risk and there is some [controversial] evidence that may suggest curcumin could cause genotoxic damage. Moreover, like other ROS scavengers, excessively high doses of curcumin may actually create ROS. It is not clear if these are the same doses as used in the cancer studies.

Other Noteworthy Studies and Reviews
(PMID: 20087857) Curcumin easily crosses the BBB. Moreover, curcumin inhibits glioma-induced angiogenesis, again suggesting efficacy in brain cancer.

(PMID: 20172017) Curcumin appears to activate M1 muscarinic receptors.

(PMID: 20388102) Review suggesting that curcumin, by blocking NF-kappaB, may slow down aging.

(PMID: 20100380) Extensive review.

(PMID: 20205886) Review of curcumin and age-related disease.

Conclusion
Well, that’s a wrap. Obviously an insane amount of information to read, but hopefully the summaries suffice for those with a cursory interest.

The vast majority of studies here were either in vitro or in rats. Only a handful of human studies of curcumin exist and, while these show a great deal of potential, they mostly involve the compound’s effects on cancer. Still, there is a truly extraordinary amount of evidence in favor of curcumin’s effects on numerous physiological systems with very little evidence pointing to side effects. This is quite a remarkable finding for a compound that cannot be patented or sold by pharmaceutical companies.

I’d be interested in hearing any experiences with curcumin and/or discussing its potential. For those of you with “adrenal fatigue” (whatever that means) who have tried numerous other options, curcumin may well be worth a try.

 

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