Curcuminoids for malignancies : type, dosage & combination and more

Curcumin is a well-known dietary polyphenol derived from the rhizomes of turmeric. The anticancer effect of curcumin has been demonstrated in many cell, animal and human studies for decades. And used successfully across the world for millenia, in particular in India. The U.S. National Library of Medicine lists over 3000 studies that pertain to curcumin and cancer. And over 8000 health studies on curcumin alone.

Given curcumin’s synergistic ability to regulate, without known side  toxic effects,  multiple pathways, as opposed to one biochemical pathway most synthetic analogs have, curcuminoids are truly holistic substances. (1) In this perspective, curcumin has been shown to  behave in a multi-faceted manner by targeting the classical hallmarks of cancer like sustained proliferation, evasion of apoptosis, sustained angiogenesis,  avoidance of the immune system, cancer stem cells, insensitivity to growth inhibitors, tissue invasion and metastasis, among others. In this post, we will support some of these claims with compelling evidence via multiple peer reviewed studies, a few of which are listed below.

IMMUNE SYSTEM SURVEILLANCE

One of the emerging hallmarks of cancer is its immuno-surveillance inhibition. Growing tumors adopt several strategies to escape immune surveillance. To mitigate this problem it has been shown that curcumin targets this process and helps restore the immune integrity, thanks to which there is more cellular reconnaissance activity against cancer. (EXHIBIT A).

ANTI-INFLAMMATORY RESPONSE

Curcumin has also been shown to be safe and effective  regarding another one of cancer’s hallmark, chronic inflammation. In this field,  strong evidence from in-vitro and in-vivo research, together with clinical trials conducted over the past few decades, substantiates the potential of curcumin as an  anti-inflammatory agent. (EXHIBIT B)

TARGETING CANCER STEM CELLS

More and more emerging evidence also suggests that the dietary polyhenol curcumin also exerts its anti-cancer activities via targeting cancer stem cells of various origins such as those of colorectal cancer, pancreatic cancer, breast cancer, brain cancer, head and neck cancer.  During the last few years,  compelling research has shown that curcumin can target cancer stem cells (CSCs) via  multiple pathways that ACR Institute teaches in its workshops, including, but not limited to those triggering initiation, growth, drug recurrence, CSC self-renewal and recurrence. (EXHIBIT C & D). 

POTENTIATION WITH PEPERINE

When added to piperine, (2) curcumin, when properly dosed, is potentiated. The two combined under specific conditions have  been shown to inhibit Wnt signaling, mammosphere formation, serial passaging, serial passaging, inter alia, without causing toxicity to differentiated and healthy cells. (EXHIBIT E) ALDH enzymes are also  beneficially impacted. (3) The full mechanism of piperine’s bioavailability-enhancing abilities is unknown, but there is evidence that this molecule can inhibit enzyme metabolism, which can impact the effectiveness of certain medications by increasing the bioavailability of various compounds, including, but not limited to enhancing curcumin bioavailability  by as much as 2000% in humans  (4).  At ACR Institute, we suspect that this is due to the inhibition of glucuronidation by the enzyme UDP-glucuronosyltransferase in the liver and small intestine. (5) Piperine can  also  enhance the pharmacokinetic parameters of resveratrol via inhibiting glucuronidation, thereby slowing its metabolism. (6)  (See ACR Institute’s wine’s anti-cancer effect blog for complementary info). It was also shown that piperine can stimulate pigmentation in the skin, together with the exposure to UVB light. (7), that which is a significant showing given ACR Institute’s research findings of UVBs  anti-cancer role.  Likewise with its “anti-depression like activity” and cognitive-enhancing effects in our mammalian relative, the rat. (8) (See ACR Institute’s neuroscience work on this question). Piperine has also been shown to have anti-inflammatory and anti-arthritic effects in human interleukin-1beta-stimulated fibroblast-like synoviocytes and in rat arthritis models. (9)  Arthritis also being a degenerative, inflammatory and auto-immune disease (like cancer), it therefore makes sense to pay heed to peperine’s cancer control role and all the more so that it has anti-angiogenic activities  (10)

TOPICAL USE FOR SKIN CANCER

For skin cancers, topical formulation was as effective as oral curcumin at suppressing tumor growth in a mouse skin cancer model.  (11) (EXHIBITS F & G)

THE CHALLENGE OF BIOAVAILABILITY

One of the clinical challenges with curcumin is its bioavailability. Research is presently working on the development of formulations of curcumin in the form of nanoparticles, liposomes, micelles, or phospholipid complexes to enhance its bioavailability and efficacy. The low bioavailability of curcumin has recently been  improved through the use of structural analogues or special formulations that use black pepper extracts. (EXHIBIT H).

CONCLUSION

Given tumeric’s lack of toxicity, its affordibility, it’s multi-pathways efficiently, it’s compatibility and potentiation with other holistic and integrative techniques, including, but not limited to peperine, ACR Institute recommends its use with all malignancies. However, given curcumin’s lack of bioavailability, for efficiency, therapeutic dosing, (12) specific nutritional combination and synergistic compounding, including, but not limited to peperine,  are encouraged (Cf ACR Institute’s workshops for the details and See the Institute’s research on curcumin’s peperine bonding companion).

Top: peperine’s chemical structure

PRECISION NOTES

(1). A curcuminoid is a linear diarylheptanoid, with molecules such as curcumin or derivatives of curcumin with different chemical groups that have been formed to increase solubility of curcumins and make them suitable for drug formulation. These compounds are natural phenols and produce a pronounced yellow color.

(2) Piperine, along with its isomer chavicine, is the alkaloid responsible for the pungency of black pepper and long pepper.

(3). Aldehyde dehydrogenases  are a group of enzymes that catalyse the oxidation (dehydrogenation) of aldehydes. An aldehyde is an organic compound containing a formyl group. The formyl group is a functional group, with the structure R-CHO, consisting of a carbonyl center (a carbon double bonded to oxygen) bonded to hydrogen and an R group.  Aldehydes differ from ketones in that the carbonyl is placed at the end of a carbon skeleton rather than between two carbon atoms. Aldehydes are common in organic chemistry. Yokoyama et al. found that decreased enzyme activity of aldehyde dehydrogenase-2, caused by the mutated ALDH2 allele, contributes to a higher chance of esophageal and oropharyngolaryngeal cancers. The metabolized acetaldehyde in the blood, which is six times higher than in individuals without the mutation, has shown to be a carcinogen in lab animals. ALDH2 is associated with increased odds of oropharyngolaryngeal, esophageal, gastric, colon, and lung cancer. Yokoyama A, Muramatsu T, Ohmori T; et al. (August 1998). “Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics”. Carcinogenesis 19 (8): 1383–7.

(4). Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS (May 1998). “Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers”. Planta Med. 64 (4): 353–6

(5) Singh J, Dubey RK, Ata CK l (1986). “Piperine-mediated inhibition of glucuronidation activity in isolated epithelial cells of the guinea-pig small intestine: evidence that piperine lowers the endogeneous UDP-glucuronic acid content”. Pharamcol. Exp. Ther. 236: 488–493.

(6).Johnson, J. J.; Nihal, M; Siddiqui, I. A.; Scarlett, C. O.; Bailey, H. H.; Mukhtar, H; Ahmad, N (2011). “Enhancing the bioavailability of resveratrol by combining it with piperine”. Molecular Nutrition & Food Research 55 (8): 1169–76.

(7). Faas, L.; Venkatasamy, R.; Hider, R. C.; Young, A. R.; Soumyanath, A. (2008). “In vivo evaluation of piperine and synthetic analogues as potential treatments for vitiligo using a sparsely pigmented mouse model”. British Journal of Dermatology 158 (5): 941–50

(8). Wattanathorna, Jintanaporn; Pennapa Chonpathompikunlertb; Supaporn Muchimapuraa; Aroonsri Pripremc; Orathai Tankamnerdthai (September 2008). “Piperine, the potential functional food for mood and cognitive disorders”. Food and Chemical Toxicology 46 (9): 3106–3110

(9). Bang JS, Oh DH, Choi HM, et al. Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models, Arthritis Research & Therapy 2009 Mar 30;11(2):R49.

(10). Doucette CD, Hilchie AL, Liwski R, Hoskin DW. J Nutr Biochem 2013;24:231-239.

(11).  In tumeric topical oinments,  tinctures have been make out of it, dried it, put it in Vaseline, and then had cancer patients can rub it on their cancer three times a day. This application can be useful for  cancers of the mouth, breast, skin, vulva, and elsewhere, even breast cancer whenthe tumor ulcerates  through the skin. In this study, the subjects were all people with recurrent ulcerating tumors that had failed to respond to surgery, radiation, and chemo. These open cancers can stink, itch, and ooze, and there was nothing else medicine had to offer. So they rubbed some turmeric ointment to see what happened. It produced remarkable relief. A reduction in smell was noted in 90% of the cases, even in extensively ulcerated cases of breast cancer, and a reduction in itching in almost all cases as well. Most of the lesions dried up, and in many cases this relief lasted for months and in 10 percent of the cases, tumor shrinkage was noticed.

(12). Among other integrative and conventional medical doctors,  Dr Weil recommends to go easy on pepper because one of its components, safrole, also found in small amounts in star anise, nutmeg, witch hazel, and basil and in large amounts in sassafras, may be carcinogenic. He claims that in  the 1960s, the FDA banned the use of safrole in food in the United States after it was found that injecting large amounts caused liver cancer in lab rats. (Source) http://www.drweil.com/drw/u/QAA400102/Easy-on-the-Black-Pepper.html

Top: Tumeric root from which curcuminoids are extracted (Image licensed via CC3.0Unported)

EXHIBIT A

Div. 2015 Oct 12;10:6.

Curcumin and tumor immune-editing: resurrecting the immune system.

Bose S1, Panda AK1, Mukherjee S1, Sa G1.

Curcumin has long been known to posses medicinal properties and recent scientific studies have shown its efficacy in treating cancer. Curcumin is now considered to be a promising anti-cancer agent and studies continue on its molecular mechanism of action. Curcumin has been shown to act in a multi-faceted manner by targeting the classical hallmarks of cancer like sustained proliferation, evasion of apoptosis, sustained angiogenesis, insensitivity to growth inhibitors, tissue invasion and metastasis etc. However, one of the emerging hallmarks of cancer is the avoidance of immune system by tumors. Growing tumors adopt several strategies to escape immune surveillance and successfully develop in the body. In this review we highlight the recent studies that show that curcumin also targets this process and helps restore the immune activity against cancer. Curcumin mediates several processes like restoration of CD4(+)/CD8(+) T cell populations, reversal of type-2 cytokine bias, reduction of Treg cell population and suppression of T cell apoptosis; all these help to resurrect tumor immune surveillance that leads to tumor regression. Thus interaction of curcumin with the immune system is also an important feature of its multi-faceted modes of action against cancer. Finally, we also point out the drawbacks of and difficulties in curcumin administration and indicate the use of nano-formulations of curcumin for better therapeutic efficacy. (Source)

EXHIBIT B

Curr Opin Clin Nutr Metab Care. 2015 Nov;18(6):605-11.

An update on Curcuma as a functional food in the control of cancer and inflammation.
Schaffer M1, Schaffer PM, Bar-Sela G.

PURPOSE OF REVIEW:

Curcumin, commonly known as turmeric, is a spice that comes from the root Curcuma longa. The present article presents an update of new studies of curcumin activities as tested in anticancer models from 2011 to 2015.

RECENT FINDINGS:

Evidence from in-vitro and in-vivo research, together with clinical trials conducted over the past few decades, substantiates the potential of curcumin as an anticancer and anti-inflammatory agent. The development of formulations of curcumin in the form of nanoparticles, liposomes, micelles, or phospholipid complexes to enhance its bioavailability and efficacy are still in the early stages. Clinical trials with curcumin indicate safety, tolerability, and nontoxicity. However, the efficacy is questionable, based on the small numbers of patients in each study.

SUMMARY:

The laboratory and the clinical studies until 2011 were summarized in a review published in this journal. An update of the new studies and knowledge from 2011 to March 2015 focuses on new ways to overcome its low bioavailability and data from clinical trials. (Source)

EXHIBIT C

Cancer Lett. 2014 May 1;346(2):197-205.

Targeting cancer stem cells by curcumin and clinical applications.

Li Y1, Zhang T2.

Curcumin is a well-known dietary polyphenol derived from the rhizomes of turmeric, an Indian spice. The anticancer effect of curcumin has been demonstrated in many cell and animal studies, and recent research has shown that curcumin can target cancer stem cells (CSCs). CSCs are proposed to be responsible for initiating and maintaining cancer, and contribute to recurrence and drug resistance. A number of studies have suggested that curcumin has the potential to target CSCs through regulation of CSC self-renewal pathways (Wnt/β-catenin, Notch, sonic hedgehog) and specific microRNAs involved in acquisition of epithelial-mesenchymal transition (EMT). The potential impact of curcumin, alone or in combination with other anticancer agents, on CSCs was evaluated as well. Furthermore, the safety and tolerability of curcumin have been well-established by numerous clinical studies. Importantly, the low bioavailability of curcumin has been dramatically improved through the use of structural analogues or special formulations. More clinical trials are underway to investigate the efficacy of this promising agent in cancer chemoprevention and therapy. In this article, we review the effects of curcumin on CSC self-renewal pathways and specific microRNAs, as well as its safety and efficacy in recent human studies. In conclusion, curcumin could be a very promising adjunct to traditional cancer treatments. (Source)

EXHIBIT D

Anticancer Agents Med Chem. 2014;14(6):787-92.

Curcumin: a promising agent targeting cancer stem cells.

Zang S, Liu T, Shi J, Qiao L1.

Cancer stem cells are a subset of cells that are responsible for cancer initiation and relapse. They are generally resistant to the current anticancer agents. Successful anticancer therapy must consist of approaches that can target not only the differentiated cancer cells, but also cancer stem cells. Emerging evidence suggested that the dietary agent curcumin exerted its anti-cancer activities via targeting cancer stem cells of various origins such as those of colorectal cancer, pancreatic cancer, breast cancer, brain cancer, and head and neck cancer. In order to enhance the therapeutic potential of curcumin, this agent has been modified or used in combination with other agents in the experimental therapy for many cancers. In this mini-review, we discussed the effect of curcumin and its derivatives in eliminating cancer stem cells and the possible underlying mechanisms. (Source)

EXHIBIT E

Breast Cancer Res Treat. 2010 Aug;122(3):777-85.

Targeting breast stem cells with the cancer preventive compounds curcumin and piperine.

Kakarala M1, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G, Wicha MS.

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. Mammosphere formation assays may be a quantifiable biomarker to assess cancer preventive agent efficacy and Wnt signaling assessment can be a mechanistic biomarker for use in human clinical trials. (Source)

EXHIBIT F

Journal of Skin Cancer Volume 2012 (2012)

Topical Curcumin-Based Cream Is Equivalent to Dietary Curcumin in a Skin Cancer Model

Kunal Sonavane,1 Jeffrey Phillips,1 Oleksandr Ekshyyan,1,2 Tara Moore-Medlin,1,2 Jennifer Roberts Gill,3 Xiaohua Rong,1,2 Raghunatha Reddy Lakshmaiah,1 Fleurette Abreo,4 Douglas Boudreaux,5 John L. Clifford,3 and Cherie-Ann O. Nathan1,2,6

Skin squamous cell carcinoma (SCC), the most common cancer in the USA, is a growing problem with the use of tanning booths causing sun-damaged skin. Antiproliferative effects of curcumin were demonstrated in an aggressive skin cancer cell line SRB12-p9 ( compared to control). Topical formulation was as effective as oral curcumin at suppressing tumor growth in a mouse skin cancer model. Curcumin at 15 mg administered by oral, topical, or combined formulation significantly reduced tumor growth compared to control (). Inhibition of pAKT, pS6, p-4EBP1, pSTAT3, and pERK1/2 was noted in SRB12-p9 cells post-curcumin treatment compared to control (). Inhibition of pSTAT3 and pERK1/2 was also noted in curcumin-treated groups in vivo. IHC analysis revealed human tumor specimens that expressed significantly more activated pERK () and pS6 () than normal skin samples. This is the first study to compare topical curcumin to oral curcumin. Our data upports the use of curcumin as a chemopreventive for skin SCC where condemned skin is a significant problem. Prevention strategies offer the best hope of future health care costs in a disease that is increasing in incidence due to increased sun exposure. (Source)

EXHIBIT G

Tumori. 1987 Feb 28;73(1):29-31.

Turmeric and curcumin as topical agents in cancer therapy.

Kuttan R, Sudheeran PC, Josph CD.

An ethanol extract of turmeric (“Curcuma longa”) as well as an ointment of curcumin (its active ingredient) were found to produce remarkable symptomatic relief in patients with external cancerous lesions. Reduction in smell were noted in 90% of the cases and reduction in itching in almost all cases. Dry lesions were observed in 70% of the cases, and a small number of patients (10%) had a reduction in lesion size and pain. In many patients the effect continued for several months. An adverse reaction was noticed in only one of the 62 patients evaluated. (Source)

EXHIBIT H

Pharmazie. 2012 Jun;67(6):518-24.
Physiological barriers to the oral delivery of curcumin.
Berginc K1, Trontelj J, Basnet NS, Kristl A.

Curcumin, a principal component from Curcuma longa, with antioxidant and anti-inflammatory activities was proposed as a potential candidate for the preventation and/or treatment of cancer and chronic diseases. However, curcumin could not achieve its expected therapeutic outcome in clinical trials due to its low solubility and poor bioavailability. The actual intestinal physiological barriers limiting curcumin absorption after oral administration have not been fully investigated. To identify the main barriers curtailing its absorption, in vitro permeability of curcumin and flux of its glucuronide were monitored in rat jejunum and Transwell grown Caco-2 cells. Curcumin was more permeable under acidic conditions, but the permeability was substantially below the permeability of highly permeable standards. Its efflux could not be inhibited by specific Pgp and MRP inhibitors. BCRP was found to participate in curcumin transport, but the Organic Anion Transporting Polypeptide (OATP) did not. The permeability of curcumin significantly increased when the structure of mucus was compromised. The inhibitor of curcumin metabolism, piperin, failed to act as a permeability enhancer. Piperin inhibited Pgp and MRP transporters and decreased the amount of glucuronide transported back into the intestine. Inclusion of piperin in curcumin-containing formulations is highly recommended as to inhibit curcumin glucuronidation and to increase the transport of formed glucuronides into the plasma, therefore increasing the probability of glucuronide distribution into target tissue and inter-convertion to curcumin. It would also be beneficial, if curcumin delivery systems could reversibly compromise the mucous integrity to minimize the non-specific binding of curcumin to its constituents. (Source)

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Disclaimer.  This post is education and nothing therein is intended to be medical advise, it should therefore not be construed to diagnose or treat cancer. See the Institute’s private policy and terms of use.