This blog entry is a companion and sequel to the previous one Neurogenesis, curcumin and longevity.  I focus here on the extensive research related to the anti-cancer properties of curcumin and go further into an issue raised in the last blog entry: does curcumin inhibit the mTOR pathway in humans and, if so, is curcumin a life extending substance due to mTOR in inhibition?

The research literature on curcumin and cancers

The research literature relating to curcumin and cancer is truly vast.  A search in the National Library of medicine database pubmed.org on the terms curcumin and cancer returns 1311 research abstracts of published literature.  Researchers in the field have little to no doubt as to the probable clinical usefulness of curcumin for preventing and treating cancers.  The new (Aug 19 2010) e-publication Curcumin in Cancer Chemoprevention: Molecular Targets, Pharmacokinetics, Bioavailability, and Clinical Trials makes the case very succinctly: “Curcumin (diferuloylmethane), a derivative of turmeric is one of the most commonly used and highly researched phytochemicals. Abundant sources provide interesting insights into the multiple mechanisms by which curcumin may mediate chemotherapy and chemopreventive effects on cancer. The pleiotropic role of this dietary compound includes the inhibition of several cell signaling pathways at multiple levels, such as transcription factors (NF-kappaB and AP-1), enzymes (COX-2, MMPs), cell cycle arrest (cyclin D1), proliferation (EGFR and Akt), survival pathways (beta-catenin and adhesion molecules), and TNF. Curcumin up-regulates caspase family proteins and down-regulates anti-apoptotic genes (Bcl-2 and Bcl-X(L)). In addition, cDNA microarrays analysis adds a new dimension for molecular responses of cancer cells to curcumin at the genomic level. Although, curcumin’s poor absorption and low systemic bioavailability limits the access of adequate concentrations for pharmacological effects in certain tissues, active levels in the gastrointestinal tract have been found in animal and human pharmacokinetic studies. Currently, sufficient data has been shown to advocate phase II and phase III clinical trials of curcumin for a variety of cancer conditions including multiple myeloma, pancreatic, and colon cancer.”

How much is known about the molecular mechanisms through which curcumin prevents or stops cancers?  The answer is the same as the answer to many questions relating to cancers and other critical diseases:  not enough to provide a complete answer, but actually quite a bit.  An excellent summary of the state of knowledge about a year ago is provided in the September 2009 publication Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively? “Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail.”

The above-mentioned paper is worth reading in detail for it summarizes a great deal of the knowledge available only piecewise in hundreds of other publications.  I quote further only highly selectively.  “Curcumin has a diverse range of molecular targets, supporting the concept that it acts upon numerous biochemical and molecular cascades. Curcumin physically binds to as many as 33 different proteins, including thioredoxin reductase, cyclooxygenase-2, (COX2), protein kinase C, 5-lipoxygenase (5-LOX), and tubulin. Various molecular targets modulated by this agent include transcription factors, growth factors and their receptors, cytokines, enzymes, and genes regulating cell proliferation, and apoptosis (6). Curcumin has been shown to inhibit the proliferation and survival of almost all types of tumor cells. Accumulating evidence suggests that the mode of curcumin-induced cell death is mediated both by the activation of cell death pathways and by the inhibition of growth/proliferation pathways (Table I; Refs. 28–173). Many studies indicate the selective role of curcumin towards cancer cells than normal cells (Table II). We could identify more than 40 biomolecules that are involved in cell death induced by curcumin (Fig. 1).  The mechanistic relationship among different signal transduction pathways, whether acting alone or together, leading to apoptosis is described. Because curcumin mediates its effect through multiple cell signaling pathways, the likelihood of developing resistance to it is less.” How these interrelated pathways are activated by curcumin is explained in the publication.

Curcumin and specific cancers

Interestingly, curcumin is active in killing cells of certain deadly cancers for which there are few or no known existing treatments.  One example is glioblastoma.  The August 2010 publication The anti-cancer efficacy of curcumin scrutinized through core signaling pathways in glioblastoma reports “Curcumin exhibits superior cytotoxicity on glioblastoma in a dose- and time-dependent manner in the MTT assay. In the core signaling pathways of glioblastoma, curcumin either significantly influences the p53 pathway by enhancing p53 and p21 and suppressing cdc2 or significantly inhibits the RB pathway by enhancing CDKN2A/p16 and suppressing phosphorylated RB. In the apoptotic pathway, the Bax and caspase 3 are significantly suppressed by curcumin and the Giemsa stain elucidates apoptotic features of DBTRG cells as well. In conclusion, curcumin appears to be an effective anti-glioblastoma drug through inhibition of the two core signaling pathways and promotion of the apoptotic pathway.”  Curcumin apart, there is no known cure for this disease which usually kills humans in less than a year after diagnosis.

Another cancer having cells that are killed by curcumin is Acute lymphoblastic leukemia (ALL), a disease that affects children as well as adults and is sure to be deadly unless treated with a complex and toxic chemotherapy regimen.  The 2008 publication Curcumin inhibits proliferation and induces apoptosis of leukemic cells expressing wild-type or T315I-BCR-ABL and prolongs survival of mice with acute lymphoblastic leukemia reports “Curcumin decreased c-Abl levels in cells expressing the wild, but not the mutant, BCR-ABL oncogene. Curcumin treatment resulted in a statistically significant improved survival in diseased mice along with decreasing white blood and GFP cell counts. — CONCLUSIONS: Curcumin is effective against leukemic cells expressing p210 BCR-ABL and T315I BCR-ABL and holds promise in treating BCR-ABL-induced B-ALL.”

Other publications relating curcumin to leukemias include:

–         (2006) Inhibitory effect of curcumin on MDR1 gene expression in patient leukemic cells. “In summary, curcumin decreased MDR1 mRNA level in patient leukemic cells, especially in high level of MDR1 gene groups. Thus, curcumin treatment may provide a lead for clinical treatment of leukemia patients in the future.”

–         (2006) Curcumin induces apoptosis via inhibition of PI3′-kinase/AKT pathway in acute T cell leukemias. “Taken together, our finding suggest that curcumin suppresses constitutively activated targets of PI3′-kinase (AKT, FOXO and GSK3) in T cells leading to the inhibition of proliferation and induction of caspase-dependent apoptosis.”

–         (2006) Inhibitory effect of curcumin on WT1 gene expression in patient leukemic cells. “In summary, curcumin decreased WT1 mRNA in patient leukemic cells. Thus, curcumin treatment may provide a lead for clinical treatment in leukemic patients in the future.”

–         (2004) Nitric oxide is synthesized in acute leukemia cells after exposure to phenolic antioxidants and initially protects against mitochondrial membrane depolarization.

Curcumin has been tested against a large number of cancer types.  For example, curcumin offers promise for preventing prostate cancer.  The 2010 publication Chemopreventive potential of curcumin in prostate cancer reports “The long latency and high incidence of prostate carcinogenesis provides the opportunity to intervene with chemoprevention in order to prevent or eradicate prostate malignancies. We present here an overview of the chemopreventive potential of curcumin (diferuloylmethane), a well-known natural compound that exhibits therapeutic promise for prostate cancer. In fact, it interferes with prostate cancer proliferation and metastasis development through the down-regulation of androgen receptor and epidermal growth factor receptor, but also through the induction of cell cycle arrest. It regulates the inflammatory response through the inhibition of pro-inflammatory mediators and the NF-kappaB signaling pathway. These results are consistent with this compound’s ability to up-induce pro-apoptotic proteins and to down-regulate the anti-apoptotic counterparts. Alone or in combination with TRAIL-mediated immunotherapy or radiotherapy, curcumin is also reported to be a good inducer of prostate cancer cell death by apoptosis. Curcumin appears thus as a non-toxic alternative for prostate cancer prevention, treatment or co-treatment.”

A search in pubmed.org using the terms “curcumin” and “breast cancer” surfaces 144 research citations.  The blog posts On Cancer stem cells and Update on cancer stem cells suggests the importance of cancer stem cells and the need to target such cells if a cancer therapy is to be effective.  The August 2010 publication Targeting breast stem cells with the cancer preventive compounds curcumin and piperine reports “The cancer stem cell hypothesis asserts that malignancies arise in tissue stem and/or progenitor cells through the dysregulation or acquisition of self-renewal. In order to determine whether the dietary polyphenols, curcumin, and piperine are able to modulate the self-renewal of normal and malignant breast stem cells, we examined the effects of these compounds on mammosphere formation, expression of the breast stem cell marker aldehyde dehydrogenase (ALDH), and Wnt signaling. Mammosphere formation assays were performed after curcumin, piperine, and control treatment in unsorted normal breast epithelial cells and normal stem and early progenitor cells, selected by ALDH positivity. Wnt signaling was examined using a Topflash assay. Both curcumin and piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at 5 microM and completely at 10 microM concentration in normal and malignant breast cells. There was no effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50% at 5 microM and completely at 10 microM. Curcumin and piperine separately, and in combination, inhibit breast stem cell self-renewal but do not cause toxicity to differentiated cells. These compounds could be potential cancer preventive agents.”  Piperine is a compound derived from black pepper commonly added to commercial curcumin supplements to enhance their bioavailability. It is what gives black pepper its zing.

Curcumin analogs and curcumin nanoparticles

Pharmaceutical companies have been investigating the therapeutic values of curcumin analogs as cancer treatments.  Viewed positively, such analogs might be engineered to be more powerful and bioavailable than curcumin itself.  Viewed cynically, drug companies are interested in analogs because there is no money for them to be made from curcumin itself because it is so commonly available, cheap, and not patentable.  One such analog molecule is the subject of the 2010 research report The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity.  “CONCLUSIONS: These data suggest that FLLL32 represents a lead compound that could serve as a platform for further optimization to develop improved STAT3 specific inhibitors for melanoma therapy.”  Other curcumin analogs being explored are PAC and a number of heterocyclic cyclohexanone analogues.   Other approaches drug companies are exploring to add-value to curcumin for treating cancers includes use of curcumin-containing nanoparticles and microparticles(ref)(ref)(ref).  I am not clear how much additional value for patients or ordinary people the analogs or nanoparticle formulations provide beyond that in plain curcumin, if any.  Obviously, since the analogs and nanoparticle formulations are proprietary, they could be very valuable to the pharmaceutical companies that own them if they could be made popular in the medical community.

Hundreds of additional current publications can be found relating curcumin to other specific types of cancer.  Titles of some representative 2010 publications include:

–         Nicotine-induced survival signaling in lung cancer cells is dependent on their p53 status while its down-regulation by curcumin is independent.

–         Apoptosis of human lung cancer cells by curcumin mediated through up-regulation of “growth arrest and DNA damage inducible genes 45 and 153”. 

–         [Curcumin promoted the apoptosis of cisplain-resistant human lung carcinoma cells A549/DDP through down-regulating miR-186*]

–         Curcumin induces apoptosis in human non-small cell lung cancer NCI-H460 cells through ER stress and caspase cascade- and mitochondria-dependent pathways. 

–         Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway.

–         Curcumin enhances dasatinib-induced inhibition of growth and transformation of colon cancer cells.

–         Epigenetic therapy of lymphoma using histone deacetylase inhibitors.

–         Curcumin selectively induces apoptosis in cutaneous T-cell lymphoma cell lines and patients’ PBMCs: potential role for STAT-3 and NF-kappaB signaling. 

–         Systemic administration of polymeric nanoparticle-encapsulated curcumin (NanoCurc) blocks tumor growth and metastases in preclinical models of pancreatic cancer 

–         Development of curcumin as an epigenetic agent.

–         Inhibition of NFkappaB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation. 

–         Chemoprevention strategies for pancreatic cancer.

–         Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers.

–         Reversal of multidrug resistance by curcumin through FA/BRCA pathway in multiple myeloma cell line MOLP-2/R. 

–         Thioredoxin reductase-1 mediates curcumin-induced radiosensitization of squamous carcinoma cells. 

–         Therapeutic efficacy evaluation of curcumin on human oral squamous cell carcinoma xenograft using multimodalities of molecular imaging

–         Colon targeted curcumin delivery using guar gum 

–         Possible action mechanism for curcumin in pre-cancerous lesions based on serum and salivary markers of oxidative stress.

I could go on and list many more relevant 2010 publications.  The simple point is that there is a great deal of current research relating to curcumin as a preventative of or treatment for cancers and a large accumulated body of research knowledge in these areas. 

Clinical trials of curcumin related to cancers

The government database of clinical trials responded to the query “curcumin cancer” with 25 trials.  The list of trials that was retrieved is here.  Looking over the list, I remark that few of the trials head-on address the effectiveness of the substance against a cancer, like the Trial of Curcumin in Advanced Pancreatic Cancer (in the recruiting phase).  Several of the trials look at the effectiveness of curcumin in combination with other substances or drugs, like the trial Phase III Trial of Gemcitabine, Curcumin and Celebrex in Patients With Metastatic Colon Cancer (not yet recruiting), And most of the completed trials are either initial safety/dosage studies or remain not-yet reported in the literature.

More on curcumin, mTOR and life extension

In the past blog entries Longevity genes, mTOR and lifespan, Viva mTOR! Caveat mTOR! and More mTOR links to aging theories and in my treatise, I described how the mTOR pathways appears to be highly conserved across species and how in primitive species as well as mice, inhibition of mTOR signaling is an effective strategy for extending longevity as well as addressing many disease processes.  In my treatise one of the advanced “candidate” aging theories is Increasing mTOR signaling which happens with aging.

I have discussed mTOR in those documents at some length and have speculated on the question of whether human longevity might be extended by somehow chemically inhibiting the mTOR pathway.  mTOR stands for mammalian target of rapamycin and the drug rapamycin inhibits the pathway and can extend the lives of mice.  Rapamycin has certain toxicities however, making it unsuitable for sustained human consumption.  In the most-recent blog post Neurogenesis, curcumin and longevity I reported on how a key researcher of curcumin’s neurological effects thought that curcumin might inhibit the mTOR pathway and I quoted from a research report that indicates that this is indeed the case.

Additional credence to the concept that curcumin inhibits mTOR signaling can be found in other publications.  I came across a relevant passage in the 2009 publication mentioned above Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively? “mTOR regulates Akt activity, a crucial downstream effector in the PI-3K–PTEN pathway, which controls cell proliferation and survival. Targeting this function of mTOR may also have therapeutic potential. For example, curcumin was shown to inhibit the Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase pathway and activate the extracellular-signal-regulated kinases (ERK) 1/2, thereby inducing autophagy (118).”  The reference is to the 2007 publication Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy.  “We previously demonstrated that curcumin induced non-apoptotic autophagic cell death in malignant glioma cells in vitro and in vivo. This compound inhibited the Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase pathway and activated the extracellular signal-regulated kinases 1/2 thereby inducing autophagy.”

A relevant July 2010 publication is Curcumin Extends Life Span, Improves Health Span, and Modulates the Expression of Age-Associated Aging Genes in Drosophila melanogaster.  “Results: We report that curcumin extended the life span of two different strains of D. melanogaster (fruit flies), an effect that was accompanied by protection against oxidative stress, improvement in locomotion, and chemopreventive effects. Life span extension was gender and genotype specific. Curcumin also modulated the expression of several aging-related genes, including mth, thor, InR, and JNK. — Conclusions: The observed positive effects of curcumin on life span and health span in two different D. melanogaster strains demonstrate a potential applicability of curcumin treatment in mammals. The ability of curcumin to mitigate the expression levels of age-associated genes in young flies suggests that the action of curcumin on these genes is a cause, rather than an effect, of its life span–extending effects.”

Going beyond fruit flies, rapamycin fed late in life to genetically heterogeneous mice increases both their median and maximal lifespans, by an average of 14% for females and 9% for males(ref).  If curcumin happens to be doing the same for me by controlling mTOR expression as well as by keeping cancers and neurological deterioration at bay, I would be grateful for the additional 7-8 years due to taking this one supplement alone.  Of course I am also taking a lot of other supplements and pursuing an anti-aging lifestyle program, so the results are likely to be synergistic though far too complex to allow prediction of how long I may live .

Wrapping it up

A group of researchers with Indian-sounding names at the University of Texas were perhaps expressing frustration with Western Medicine when they wrote in the 2008 publication Curcumin and cancer: an “old-age” disease with an “age-old” solution: “Cancer is primarily a disease of old age, and that life style plays a major role in the development of most cancers is now well recognized. While plant-based formulations have been used to treat cancer for centuries, current treatments usually involve poisonous mustard gas, chemotherapy, radiation, and targeted therapies. While traditional plant-derived medicines are safe, what are the active principles in them and how do they mediate their effects against cancer is perhaps best illustrated by curcumin, a derivative of turmeric used for centuries to treat a wide variety of inflammatory conditions. Curcumin is a diferuloylmethane derived from the Indian spice, turmeric (popularly called “curry powder”) that has been shown to interfere with multiple cell signaling pathways, including cell cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF-kappaB, TNF, IL-6, IL-1, COX-2, and 5-LOX). The activity of curcumin reported against leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reflects its ability to affect multiple targets. Thus an “old-age” disease such as cancer requires an “age-old” treatment.”

A funny thing happens to curcumin on its way to the clinic

Wrapping it up, curcumin is non-toxic and without side effects at reasonable doses, inexpensive and easily available.  The complex biomolecular pathways through which it exercises its anti-cancer effects are fairly well understood and being further explored in many laboratories.  It kills multiple types of cancer cells.  Its anti-cancer actions appear to be preventative as well as therapeutic.  Because it operates through many parallel biological channels, cancers cannot readily evolve to neutralize its effects.  It has been used as a traditional medicine for centuries and the countries in which it is heavily consumed have low rates of cancer.  And the research case for basing cancer therapies on curcumin appears to becoming ever-stronger as time progresses.  Perhaps curcumin is even life-extending if regularly taken by humans.

For years, researcher after researcher has declared that cancer therapies can likely be designed based on use of curcumin.  Yet, this substance has not entered mainline clinical practice and probably most oncologists don’t know about it or would not think of prescribing it.  The journals oncologists read may talk about complex, expensive and toxic chemotherapy regimens, but will likely not discuss curcumin which is still regarded by many to be a “folk remedy.” This is the situation despite the vast amounts of solid research on the substance using the most contemporary approaches of molecular biology, genomics and the other “omics.”  One reason for this situation appears to be lack of large-scale clinical trial evidence for curcumin’s anti-cancer efficacy.  This in turn is strongly correlated with the fact that drug companies won’t sponsor clinical trials of plain curcumin because they can’t make any money from selling it. 

Yet, awareness of the potentials of curcumin is slowly expanding.  It took the medical community some 40 years to acknowledge the pluripotent health activities of Vitamin D and embrace its use.   Hopefully, recognition of the health and longevity values of curcumin will happen a lot faster than that.

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FROM TIME TO TIME, THIS BLOG DISCUSSES DISEASE PROCESSES.  THE INTENTION OF THOSE DISCUSSIONS IS TO CONVEY CURRENT RESEARCH FINDINGS AND OPINIONS, NOT TO GIVE MEDICAL ADVICE.  THE INFORMATION IN POSTS IN THIS BLOG IS NOT A SUBSTITUTE FOR A LICENSED PHYSICIAN’S MEDICAL ADVICE. IF ANY ADVICE, OPINIONS, OR INSTRUCTIONS HEREIN CONFLICT WITH THAT OF A TREATING LICENSED PHYSICIAN, DEFER TO THE OPINION OF THE PHYSICIAN. THIS INFORMATION IS INTENDED FOR PEOPLE IN GOOD HEALTH.  IT IS THE READER’S RESPONSIBILITY TO KNOW HIS OR HER MEDICAL HISTORY AND ENSURE THAT ACTIONS OR SUPPLEMENTS HE OR SHE TAKES DO NOT CREATE AN ADVERSE REACTION.