[Rich66]

Original curcumin post/discussion by Lani: http://her2support.org/vbulletin/sho...light=Curcumin


Cancer Biol Ther. 2010 Jan 21;9(1). [Epub ahead of print]
Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer.

Bayet-Robert M, Kwiatkowski F, Leheurteur M, Gachon F, Planchat E, Abrial C, Mouret-Reynier MA, Durando X, Barthomeuf C, Chollet P.
Centre Jean Perrin, Division de Recherche Clinique, EA4231, Université d'Auvergne, Centre d'Investigation Clinique, Clermont-Ferrand, France.
Background: Since the improvement of chemotherapy with safe molecules is needed for a better efficacy without supplementary toxicity, we investigated the feasibility and tolerability of the combination of docetaxel and curcumin, a polyphenolic derivative extracted from Curcuma longa root. Results: Fourteen patients were accrued in this open-label phase I trial. At the last dose level of curcumin, 3 dose-limiting toxicities were observed and 2 out of 3 patients at this dose level refused to continue treatment, leading us to define the maximal tolerated dose of curcumin at 8,000 mg/d. Eight patients out of 14 had measurable lesions according to RECIST criteria, with 5 PR and 3 SD. Some improvements as biological and clinical responses were observed in most patients. Patients and methods: Patients with advanced or metastatic breast cancer were eligible. Docetaxel (100 mg/m(2)) was administered as a 1-hour i.v. infusion every 3 weeks on d1 for 6 cycles. Curcumin was orally given from 500 mg/d for 7 consecutive days by cycle (from d-4 to d+2) and escalated until a dose-limiting toxicity should occur. The primary endpoint of this study was to determine the maximal tolerated dose of the combination of dose-escalating curcumin and standard dose of docetaxel chemotherapy in advanced and metastatic breast cancer patients. Secondary objectives included toxicity, safety, vascular endothelial growth factor and tumor markers measurements, and assessment of objective and clinical responses to the combination therapy. Conclusion: The recommended dose of curcumin is 6,000 mg/d for 7 consecutive days every 3 weeks in combination with a standard dose of docetaxel. From the encouraging efficacy results, a comparative phase II trial of this regimen plus docetaxel versus docetaxel alone is ongoing in advanced and metastatic breast cancer patients.

PMID: 19901561 [PubMed - as supplied by publisher]



Breast Cancer Res Treat. 2009 Nov 7. [Epub ahead of print]
Targeting breast stem cells with the cancer preventive compounds curcumin and piperine.
PDF of full text

Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G, Wicha MS.
Division of Hematology/Oncology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, 2150 Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI, USA, mkakaral@umich.edu.
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 muM and completely at 10 muM 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 muM and completely at 10 muM. 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.

PMID: 19898931 [PubMed - as supplied by publisher]

Discussion
The cancer stem cell hypothesis proposes that cancers arise in tissue stem cells through dysregulation of the normally, tightly regulated process of self-renewal or in progenitor cells through acquisition of this capacity [1]. If stem/progenitor cells are targets for transformation, then strategies aimed at limiting these cell populations through inhibition of self-renewal represent rational cancer preventive strategies.
Furthermore, since these interventions are based on the regulation of self-renewal, rather than the induction of toxicity, they have the potential of being less toxic than
compounds such as tamoxifen, which affect the bulk differentiated cell populations [10, 35]. Our data suggest that the dietary polyphenols, curcumin and piperine, may have these characteristics. We demonstrate that these dietary polyphenols affect normal stem/progenitor cells, as documented by decreased mammosphere formation upon serial passage and by decrease in the proportion of cells expressing the stem cell marker ALDH-1A1. In contrast, these compounds had little or no effect on differentiated cells. The relative lack of effect of these compounds on differentiated cells may account for their lack of toxicity in animal models and clinical studies [15, 36].
Cancer preventive agents such as curcumin and other polyphenols have been shown to have pleiotrophic mechanisms of action, including NFjB suppression, Cox2 down regulation, and Wnt and Notch pathway downregulation [34, 37–42]. We demonstrated that curcumin was able to inhibit Wnt signaling in MCF7 cells utilizing a TCF-Lef reporter assay system. These results support work in other systems showing the ability of curcumin to inhibit Wnt signaling [33, 43, 44], a pathway which we have previously demonstrated to play an important role in breast stem cell self-renewal and which is frequently dysregulated during breast carcinogenesis [11, 12, 31].
In addition to curcumin, we demonstrate that the dietary polyphenol piperine also is able to inhibit breast stem cell self-renewal and Wnt signaling. Previous studies have suggested that piperine could enhance curcumin’s effects by enhancing bioavailability through inhibition of curcumin’s efflux via P glycoprotein (ABCB1 or MDR1) efflux pump [45–47] as well as through the downregulation of NFjB
release [48]. Our studies demonstrating that piperine affects mammosphere size and colony formation suggest that piperine may affect progenitor cell proliferation as well as enhance curcumin’s effects on breast stem cell self-renewal.

Conclusions
If systemic bioavailability of curcumin can be improved to allow bioactive concentrations of curcumin and piperine in vivo, then this combination may serve as an effective cancer preventive intervention to limit stem cell self renewal, since these cells and dysregulation of self-renewal pathways may be involved in carcinogenesis. Strategies aimed at reducing stem cell number and inhibiting their self-renewal could be an effective approach in cancer prevention. If this is the case, then assays such as mammospher formation and ALDH expression may serve as biomarkers for cancer prevention studies in clinical trials. Curcumin, even at large doses, has been demonstrated to be non-toxic in clinical trials. Piperine has been shown in a small, phase I clinical trial to enhance the systemic bioavailability of curcumin [25]. However, a more systematic phase I trial with pharmacokinetic, pharmacodynamic, and toxicity endpoints of repeated dosing of these agents in combination is still needed. If proven safe and efficacious, dietary polyphenols could be an acceptable non-toxic longterm cancer risk reduction strategy.

LINK:

Turmeric and black pepper: can they be absorbed when taken orally?
Flickr.com

According to a December 8, 2009 University of Michigan, Ann Arbor, Comprehensive Cancer Center press release, "Spices halt growth of breast stem cells, U-M study finds," curcumin, a substance in turmeric and piperine, derived from black peppers, could play role in preventing breast cancer by stopping the growth of breast tumor cells.
The big question for the average consumer to ask is whether the study worked with breast cancer cells only in a culture such as a test tube or Petri dish, but will the substances derived from those spices work on human breast tumor cells in the body? And will the human digestive juices destroy the spices potency before they enter the rest of the body?
The whole idea or goal is to stop breast tumor cells from developing blood vessels that enables them to grow into cancerous lumps. Can turmeric and pepper work in the human body when taken orally as well as they worked in a culture of cells and spice extracts in the laboratory?

A new study finds that compounds derived from the spices turmeric and pepper could help prevent breast cancer by limiting the growth of stem cells, the small number of cells that fuel a tumor’s growth. Researchers at the University of Michigan Comprehensive Cancer Center have found that when the dietary compounds curcumin, which is derived from the Indian spice turmeric, and piperine, derived from black peppers, were applied to breast cells in culture, they decreased the number of stem cells while having no effect on normal differentiated cells.

“If we can limit the number of stem cells, we can limit the number of cells with potential to form tumors,” says lead author Madhuri Kakarala, M.D., Ph.D., R.D., clinical lecturer in internal medicine at the U-M Medical School and a research investigator at the VA Ann Arbor Healthcare System.

Cancer stem cells are the small number of cells within a tumor that fuel the tumor’s growth. Current chemotherapies do not work against these cells, which is why cancer recurs and spreads. Researchers believe that eliminating the cancer stem cells is key to controlling cancer. In addition, decreasing the number of normal stem cells – unspecialized cells that can give rise to any type of cell in that organ – can decrease the risk of cancer.

In this study, a solution of curcumin and piperine was applied to the cell cultures at the equivalent of about 20 times the potency of what could be consumed through diet. The compounds are available at this potency in a capsule form that could be taken by mouth. (Note: This work has not been tested in patients, and patients are not encouraged to add curcumin or piperine supplements to their diet at this time.)

The researchers applied a series of tests to the cells, looking at markers for breast stem cells and the effects of curcumin and piperine, both alone and combined, on the stem cell levels. They found that piperine enhanced the effects of curcumin, and that the compounds interrupted the self-renewal process that is the hallmark of cancer-initiating stem cells. At the same time, the compounds had no affect on cell differentiation, which is the normal process of cell development.

“This shows that these compounds are not toxic to normal breast tissue,” Kakarala says. “Women at high risk of breast cancer right now can choose to take the drugs tamoxifen or raloxifene for prevention, but most women won’t take these drugs because there is too much toxicity. The concept that dietary compounds can help is attractive, and curcumin and piperine appear to have very low toxicity.”

Curcumin and piperine have been explored by other researchers as a potential cancer treatment. But this paper, published online in the journal Breast Cancer Research and Treatment, is the first to suggest these dietary compounds could prevent cancer by targeting stem cells.

In addition, tamoxifen or raloxifene are designed to affect estrogen, which is a factor in most, but not all breast cancers. In fact, the aggressive tumors that tend to occur more often in women with a family history or genetic susceptibility are typically not affected by estrogen. Because curcumin and piperine limit the self renewal of stem cells, they would impact cancers that are not estrogen sensitive as well as those that are.

Researchers are planning an initial Phase I clinical trial to determine what dose of curcumin or piperine can be tolerated in people. The trial is not expected to begin accruing participants until spring. For further information, look at the breast cancer statistics. This year, 194,280 Americans will be diagnosed with breast cancer, and 40,610 will die from the disease, according to the American Cancer Society.

The funding for this study came from the National Institutes of Health. Curcumin and piperine for this study were donated by Sabinsa Co. Additional authors: Dean Brenner, Hasan Korkaya, Connie Cheng, Karim Tazi, Christophe Ginestier, Suling Liu, Gabriel Dontu and Max Wicha, all from the University of Michigan, Ann Arbor.
To read the study, see: "Targeting breast stem cells with the cancer preventive compounds curcumin and piperine," Breast Cancer Research and Treatment, 2009; DOI: 10.1007/s10549-009-0612-x. Authors: Madhuri Kakarala, Dean E. Brenner, Hasan Korkaya, Connie Cheng, Karim Tazi, Christophe Ginestier, Suling Liu, Gabriela Dontu and Max S. Wicha.
Resources
U-M Cancer AnswerLine, 800-865-1125
U-M Comprehensive Cancer Center
Cancer’s Stem Cell Revolution


Cancer Res. 2009 Feb 1;69(3):1000-8. Epub 2009 Jan 27.
Curcumin disrupts the Mammalian target of rapamycin-raptor complex.

Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S.
Department of Biochemistry and Molecular Biology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Recently, we have shown that curcumin inhibits phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), two downstream effector molecules of the mammalian target of rapamycin complex 1 (mTORC1) in numerous cancer cell lines. This study was designed to elucidate the underlying mechanism. We observed that curcumin inhibited mTORC1 signaling not by inhibition of the upstream kinases, such as insulin-like growth factor 1 receptor (IGF-IR) and phosphoinositide-dependent kinase 1 (PDK1). Further, we found that curcumin inhibited mTORC1 signaling independently of protein phosphatase 2A (PP2A) or AMP-activated protein kinase AMPK-tuberous sclerosis complex (TSC). This is evidenced by the findings that curcumin was able to inhibit phosphorylation of S6K1 and 4E-BP1 in the cells pretreated with PP2A inhibitor (okadaic acid) or AMPK inhibitor (compound C), or in the cells expressing dominant-negative (dn) PP2A, shRNA to PP2A-A subunit, or dn-AMPKalpha. Curcumin did not alter the TSC1/2 interaction. Knockout of TSC2 did not affect curcumin inhibition of mTOR signaling. Finally, we identified that curcumin was able to dissociate raptor from mTOR, leading to inhibition of mTORC1 activity. Therefore, our data indicate that curcumin may represent a new class of mTOR inhibitor.

PMID: 19176385 [PubMed - indexed for MEDLIN


mTOR thread HERE





J Immunol. 2004 May 15;172(10):5940-7.
Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis.


FULL TEXT



Bharti AC, Takada Y, Aggarwal BB.
Cytokine Research Section, Department of Bioimmunotherapy, Unit 143, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Numerous studies have indicated that inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with cancers and other diseases. Gene deletion studies have shown that receptor activator of NF-kappaB ligand (RANKL) is one of the critical mediators of osteoclastogenesis. How RANKL mediates osteoclastogenesis is not fully understood, but an agent that suppresses RANKL signaling has potential to inhibit osteoclastogenesis. In this report, we examine the ability of curcumin (diferuloylmethane), a pigment derived from turmeric, to suppress RANKL signaling and osteoclastogenesis in RAW 264.7 cells, a murine monocytic cell line. Treatment of these cells with RANKL activated NF-kappaB, and preexposure of the cells to curcumin completely suppressed RANKL-induced NF-kappaB activation. Curcumin inhibited the pathway leading from activation of IkappaBalpha kinase and IkappaBalpha phosphorylation to IkappaBalpha degradation. RANKL induced osteoclastogenesis in these monocytic cells, and curcumin inhibited both RANKL- and TNF-induced osteoclastogenesis and pit formation. Curcumin suppressed osteoclastogenesis maximally when added together with RANKL and minimally when it was added 2 days after RANKL. Whether curcumin inhibits RANKL-induced osteoclastogenesis through suppression of NF-kappaB was also confirmed independently, as RANKL failed to activate NF-kappaB in cells stably transfected with a dominant-negative form of IkappaBalpha and concurrently failed to induce osteoclastogenesis. Thus overall these results indicate that RANKL induces osteoclastogenesis through the activation of NF-kappaB, and treatment with curcumin inhibits both the NF-kappaB activation and osteoclastogenesis induced by RANKL.

PMID: 15128775 [PubMed - indexed for MEDLINE]