Curcumin Is Emerging as One of the Most Potent Natural Cancer Treatments

Over the last decade, research into curcumin (Curcuma longa, a constituent of turmeric that gives the curry spice its yellow-orange color) has demonstrated potent chemoprotective and chemopreventive effects, as well as use as an anti-cancer therapy.

Curcumin produces anti-cancer effects through several different channels:

• Inhibits the proliferation of tumor cells
• Decreases inflammation
• Inhibits the transformation of cells from normal to tumor
• Inhibits the synthesis of a protein thought to be instrumental in tumor formation
• Helps your body destroy mutated cancer cells so they cannot spread throughout your body
• Prevents the development of additional blood supply necessary for cancer cell growth (angiogenesis) 

One of the issues with curcumin as a drug is that it is poorly absorbed in its raw form, with some estimates suggesting that only 1-3% of the curcuminoids are absorbed. Importantly, turmeric itself is not an adequate source of curcumin, with only an approximate 3% concentration of curcumin.

Most supplement manufacturers have developed a standardized 95-percent concentration of curcumin, and even with that level of concentration, it takes 2-3 grams of curcumin each day to get therapeutic benefits.

One way to increase absorption is to include black pepper extract (piperine) in the product. Piperine has been shown to inhibit CYP 450 enzymes that are crucial in metabolizing drugs. Research on using piperine with curcumin has demonstrated a 2000% increase in absorption {1}.

[As an aside, piperine may enhance the pharmacokinetic parameters of resveratrol by inhibiting glucuronidation, which slows its metabolism {2}.]

In an interview at Dr. Mercola's site, Dr. William LaValley made the following observation:

I found that a way to change that, to dramatically increase the bioavailability, is actually a very simple process of bringing water to a boil, putting those capsules or some dry powder (I use it by the teaspoon), and boiling it for 10 to 12 minutes. That increases the amount of curcumin dissolved in water from that one-percent amount up to 12 percent or so. That amount is a vast number of curcumin molecules that are now in a bioavailable or absorbable form.

It turns out that curcumin is a fat-loving or lipophilic molecule, which suggests taking curcumin with some sort of oil or fat might improve its absorption and bioavailability. According to Dr. LaValley, incorporating a lipid-based delivery system may promote a seven to eight times higher absorption rate than the 95-percent-concentration of dry powder.

As researchers continue to seek more effective delivery systems, the approaches are becoming much more sophisticated. In a 2014 article from PLoS ONE, researchers are directly targeting the mitochondria as a delivery method {3}.

Mitochondrial-Targeted Curcuminoids: A Strategy to Enhance Bioavailability and Anticancer Efficacy of Curcumin

Abstract


Although the anti-cancer effects of curcumin has been shown in various cancer cell types, in vitro, pre-clinical and clinical studies showed only a limited efficacy, even at high doses. This is presumably due to low bioavailability in both plasma and tissues, particularly due to poor intracellular accumulation. A variety of methods have been developed to achieve the selective targeting of drugs to cells and mitochondrion. We used a novel approach by conjugation of curcumin to lipophilic triphenylphosphonium (TPP) cation to facilitate delivery of curcumin to mitochondria. TPP is selectively taken up by mitochondria driven by the membrane potential by several hundred folds. In this study, three mitocurcuminoids (mitocurcuminoids-1, 2, and 3) were successfully synthesized by tagging TPP to curcumin at different positions. ESI-MS analysis showed significantly higher uptake of the mitocurcuminoids in mitochondria as compared to curcumin in MCF-7 breast cancer cells. All three mitocurcuminoids exhibited significant cytotoxicity to MCF-7, MDA-MB-231, SKNSH, DU-145, and HeLa cancer cells with minimal effect on normal mammary epithelial cells (MCF-10A). The IC₅₀ was much lower for mitocurcuminoids when compared to curcumin. The mitocurcuminoids induced significant ROS generation, a drop in ΔØm, cell-cycle arrest and apoptosis. They inhibited Akt and STAT3 phosphorylation and increased ERK phosphorylation. Mitocurcuminoids also showed upregulation of pro-apoptotic BNIP3 expression. In conclusion, the results of this study indicated that mitocurcuminoids show substantial promise for further development as a potential agent for the treatment of various cancers.

Presented below are some recent studies (all from 2014) on the therapeutic uses of curcumin, primarily as a cancer treatment or chemoprotective.

Citations for the section above

1. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS (1998, May). Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med.; 64 (4): 353–6. doi:10.1055/s-2006-957450. PMID 9619120.

2. 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. doi:10.1002/mnfr.201100117. PMC 3295233. PMID 21714124 

3. Reddy, CA, Somepalli, V, Golakoti, T,  Koteswara, A, Kanugula, R, Karnewar, S, Rajendiran, K, Vasagiri, N, Prabhakar, S, Kuppusamy, P, Kotamraju, P, Kutala, VK. (2014, Mar 12). Mitochondrial-Targeted Curcuminoids: A Strategy to Enhance Bioavailability and Anticancer Efficacy of Curcumin. PLoS ONE; 9(3): e89351. DOI: 10.1371/journal.pone.0089351 

2014 Research on Curcumin Presented in PLoS ONE

For each article I am sharing the citation and the abstract - these are all open access articles.

Citation:  
Seo BR, Min K-j, Cho IJ, Kim SC, Kwon TK. (2014, Apr 17). Curcumin Significantly Enhances Dual PI3K/Akt and mTOR Inhibitor NVP-BEZ235-Induced Apoptosis in Human Renal Carcinoma Caki Cells through Down-Regulation of p53-Dependent Bcl-2 Expression and Inhibition of Mcl-1 Protein Stability. PLoS ONE 9(4): e95588. doi: 10.1371/journal.pone.0095588

AbstractThe PI3K/Akt and mTOR signaling pathways are important for cell survival and growth, and they are highly activated in cancer cells compared with normal cells. Therefore, these signaling pathways are targets for inducing cancer cell death. The dual PI3K/Akt and mTOR inhibitor NVP-BEZ235 completely inhibited both signaling pathways. However, NVP-BEZ235 had no effect on cell death in human renal carcinoma Caki cells. We tested whether combined treatment with natural compounds and NVP-BEZ235 could induce cell death. Among several chemopreventive agents, curcumin, a natural biologically active compound that is extracted from the rhizomes of Curcuma species, markedly induced apoptosis in NVP-BEZ235-treated cells. Co-treatment with curcumin and NVP-BEZ235 led to the down-regulation of Mcl-1 protein expression but not mRNA expression. Ectopic expression of Mcl-1 completely inhibited curcumin plus NVP-NEZ235-induced apoptosis. Furthermore, the down-regulation of Bcl-2 was involved in curcumin plus NVP-BEZ235-induced apoptosis. Curcumin or NVP-BEZ235 alone did not change Bcl-2 mRNA or protein expression, but co-treatment reduced Bcl-2 mRNA and protein expression. Combined treatment with NVP-BEZ235 and curcumin reduced Bcl-2 expression in wild-type p53 HCT116 human colon carcinoma cells but not p53-null HCT116 cells. Moreover, Bcl-2 expression was completely reversed by treatment with pifithrin-α, a p53-specific inhibitor. Ectopic expression of Bcl-2 also inhibited apoptosis in NVP-BE235 plus curcumin-treated cells. In contrast, NVP-BEZ235 combined with curcumin did not have a synergistic effect on normal human skin fibroblasts and normal human mesangial cells. Taken together, combined treatment with NVP-BEZ235 and curcumin induces apoptosis through p53-dependent Bcl-2 mRNA down-regulation at the transcriptional level and Mcl-1 protein down-regulation at the post-transcriptional level.

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Citation:  
Das L, Vinayak M. (2014, Jun 16). Long Term Effect of Curcumin in Regulation of Glycolytic Pathway and Angiogenesis via Modulation of Stress Activated Genes in Prevention of Cancer. PLoS ONE 9(6): e99583. doi: 10.1371/journal.pone.0099583

AbstractOxidative stress, an important factor in modulation of glycolytic pathway and induction of stress activated genes, is further augmented due to reduced antioxidant defense system, which promotes cancer progression via inducing angiogenesis. Curcumin, a naturally occurring chemopreventive phytochemical, is reported to inhibit carcinogenesis in various experimental animal models. However, the underlying mechanism involved in anticarcinogenic action of curcumin due to its long term effect is still to be reported because of its rapid metabolism, although metabolites are accumulated in tissues and remain for a longer time. Therefore, the long term effect of curcumin needs thorough investigation. The present study aimed to analyze the anticarcinogenic action of curcumin in liver, even after withdrawal of treatment in Dalton's lymphoma bearing mice. Oxidative stress observed during lymphoma progression reduced antioxidant enzyme activities, and induced angiogenesis as well as activation of early stress activated genes and glycolytic pathway. Curcumin treatment resulted in activation of antioxidant enzyme super oxide dismutase and down regulation of ROS level as well as activity of ROS producing enzyme NADPH:oxidase, expression of stress activated genes HIF-1α, cMyc and LDH activity towards normal level. Further, it lead to significant inhibition of angiogenesis, observed via MMPs activity, PKCα and VEGF level, as well as by matrigel plug assay. Thus findings of this study conclude that the long term effect of curcumin shows anticarcinogenic potential via induction of antioxidant defense system and inhibition of angiogenesis via down regulation of stress activated genes and glycolytic pathway in liver of lymphoma bearing mice.

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Citation:  
Shakibaei M, Buhrmann C, Kraehe P, Shayan P, Lueders C, et al. (2014, Jan 3). Curcumin Chemosensitizes 5-Fluorouracil Resistant MMR-Deficient Human Colon Cancer Cells in High Density Cultures. PLoS ONE 9(1): e85397. doi: 10.1371/journal.pone.0085397

Abstract 

Objective
Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50–60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells.

Methods
High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays.

Results
Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting.

Conclusion
Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population.

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Citation: 
Meng J, Li Y, Camarillo C, Yao Y, Zhang Y, et al. (2014, Jan 7). The Anti-Tumor Histone Deacetylase Inhibitor SAHA and the Natural Flavonoid Curcumin Exhibit Synergistic Neuroprotection against Amyloid-Beta Toxicity. PLoS ONE 9(1): e85570. doi: 10.1371/journal.pone.0085570

AbstractWith the trend of an increasing aged population worldwide, Alzheimer's disease (AD), an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC) inhibitor, suberoylanilidehydroxamic acid (SAHA), may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ_25–35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.

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Citation:  
Radhakrishnan VM, Kojs P, Young G, Ramalingam R, Jagadish B, et al. (2014, Jan 22). pTyr421 Cortactin Is Overexpressed in Colon Cancer and Is Dephosphorylated by Curcumin: Involvement of Non-Receptor Type 1 Protein Tyrosine Phosphatase (PTPN1). PLoS ONE 9(1): e85796. doi: 10.1371/journal.pone.0085796

AbstractCortactin (CTTN), first identified as a major substrate of the Src tyrosine kinase, actively participates in branching F-actin assembly and in cell motility and invasion. CTTN gene is amplified and its protein is overexpressed in several types of cancer. The phosphorylated form of cortactin (pTyr⁴²¹) is required for cancer cell motility and invasion. In this study, we demonstrate that a majority of the tested primary colorectal tumor specimens show greatly enhanced expression of pTyr⁴²¹-CTTN, but no change at the mRNA level as compared to healthy subjects, thus suggesting post-translational activation rather than gene amplification in these tumors. Curcumin (diferulolylmethane), a natural compound with promising chemopreventive and chemosensitizing effects, reduced the indirect association of cortactin with the plasma membrane protein fraction in colon adenocarcinoma cells as measured by surface biotinylation, mass spectrometry, and Western blotting. Curcumin significantly decreased the pTyr⁴²¹-CTTN in HCT116 cells and SW480 cells, but was ineffective in HT-29 cells. Curcumin physically interacted with PTPN1 tyrosine phosphatases to increase its activity and lead to dephosphorylation of pTyr⁴²¹-CTTN. PTPN1 inhibition eliminated the effects of curcumin on pTyr⁴²¹-CTTN. Transduction with adenovirally-encoded CTTN increased migration of HCT116, SW480, and HT-29. Curcumin decreased migration of HCT116 and SW480 cells which highly express PTPN1, but not of HT-29 cells with significantly reduced endogenous expression of PTPN1. Curcumin significantly reduced the physical interaction of CTTN and pTyr⁴²¹-CTTN with p120 catenin (CTNND1). Collectively, these data suggest that curcumin is an activator of PTPN1 and can reduce cell motility in colon cancer via dephosphorylation of pTyr⁴²¹-CTTN which could be exploited for novel therapeutic approaches in colon cancer therapy based on tumor pTyr⁴²¹-CTTN expression.
  

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Citation:  
Zhu W, Cromie MM, Cai Q, Lv T, Singh K, et al. (2014, Mar 24). Curcumin and Vitamin E Protect against Adverse Effects of Benzo[a]pyrene in Lung Epithelial Cells. PLoS ONE 9(3): e92992. doi: 10.1371/journal.pone.0092992

AbstractBenzo[a]pyrene (BaP), a well-known environmental carcinogen, promotes oxidative stress and DNA damage. Curcumin and vitamin E (VE) have potent antioxidative activity that protects cells from oxidative stress and cellular damage. The objectives of the present study were to investigate the adverse effects of BaP on normal human lung epithelial cells (BEAS-2B), the potential protective effects of curcumin and VE against BaP-induced cellular damage, and the molecular mechanisms of action. MTT assay, flow cytometry, fluorescence microplate assay, HPLC, qRT-PCR, and western blot were performed to analyze cytotoxicity, cell cycle, reactive oxygen species (ROS), BaP diol-epoxidation (BPDE)-DNA adducts, gene expression, and protein expression, respectively. Curcumin or VE prevented cells from BaP-induced cell cycle arrest and growth inhibition, significantly suppressed BaP-induced ROS levels, and decreased BPDE-DNA adducts. While CYP1A1 and 1B1 were induced by BaP, these inductions were not significantly reduced by curcumin or VE. Moreover, the level of activated p53 and PARP-1 were significantly induced by BaP, whereas this induction was markedly reduced after curcumin and VE co-treatment. Survivin was significantly down-regulated by BaP, and curcumin significantly restored survivin expression in BaP-exposed cells. The ratio of Bax/Bcl-2 was also significantly increased in cells exposed to BaP and this increase was reversed by VE co-treatment. Taken together, BaP-induced cytotoxicity occurs through DNA damage, cell cycle arrest, ROS production, modulation of metabolizing enzymes, and the expression/activation of p53, PARP-1, survivin, and Bax/Bcl-2. Curcumin and VE could reverse some of these BaP-mediated alterations and therefore be effective natural compounds against the adverse effects of BaP in lung cells.

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Citation:  
Zheng L, Sun X, Zhu X, Lv F, Zhong Z, et al. (2014, Mar 27). Apoptosis of THP-1 Derived Macrophages Induced by Sonodynamic Therapy Using a New Sonosensitizer Hydroxyl Acetylated Curcumin. PLoS ONE 9(3): e93133. doi: 10.1371/journal.pone.0093133

AbstractCurcumin is extracted from the rhizomes of the traditional Chinese herb Curcuma longa. Our previous study indicated curcumin was able to function as a sonosensitizer. Hydroxyl acylated curcumin was synthesized from curcumin to eliminate the unstable hydroxy perssad in our group. The potential use of Hydroxyl acylated curcumin as a sonosensitizer for sonodynamic therapy (SDT) requires further exploration. This study investigated the sonodynamic effect of Hydroxyl acylated curcumin on THP-1 macrophage. THP-1 macrophages were cultured with Hydroxyl acylated curcumin at a concentration of 5.0 μg/mL for 4 hours and then exposed to pulse ultrasound irradiation (0.5 W/cm² with 1.0 MHz ) for 5 min, 10 min and 15 min. Six hours later, cell viability decreased significantly by CCK-8 assay. After ultrasound irradiation, the ratio of apoptosis and necrosis in SDT group was higher than that in control, Hydroxyl acylated curcumin alone and ultrasound alone. Moreover, the apoptotic rate was higher than necrotic rate with the flow cytometry analysis. Furthermore, Hydroxyl acylated curcumin-SDT induced reactive oxygen species (ROS) generation in THP-1 macrophages immediately after the ultrasound treatment while ROS generation was reduced significantly with the scavenger of singlet oxygen Sodium azide (NaN₃). Hydroxyl acylated curcumin-SDT led to a conspicuous loss of mitochondrial membrane potential (MMP) compared with other groups, while MMP was increased significantly with the scavenger of singlet oxygen Sodium azide (NaN₃), ROS inhibitor N-acetyl cysteine (NAC) and Mitochondrial Permeability Transition Pore (MPTP) inhibitor Cyclosporin A (CsA). The cytochrome C, cleaved-Caspase-9, cleaved-Caspase-3 and cleaved-PARP upregulated after SDT through Western blotting. These findings suggested that Hydroxyl acylated curcumin under low-intensity ultrasound had sonodynamic effect on THP-1 macrophages via generation of intracellular singlet oxygen and mitochondria-caspase signaling pathway, indicating that Hydroxyl acylated curcumin could be used as a novel sonosensitizer in SDT for atherosclerosis.

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Citation: 
Kumar B, Yadav A, Hideg K, Kuppusamy P, Teknos TN, et al. (2014, Mar 27). A Novel Curcumin Analog (H-4073) Enhances the Therapeutic Efficacy of Cisplatin Treatment in Head and Neck Cancer. PLoS ONE 9(3): e93208. doi: 10.1371/journal.pone.0093208

AbstractChemotherapy constitutes the standard modality of treatment for localized head and neck squamous cell carcinomas (HNSCC). However, many patients fail to respond and relapse after this treatments due to the acquisition of chemo-resistance. Therefore, there is an urgent need to develop novel drugs that could reverse the resistant phenotype. Curcumin, the constituent of the spice turmeric has been shown to have anti-inflammatory, anti-oxidant and anti-proliferative properties in several tumor types. However, use of curcumin has been limited due to its poor bio-absorption. Recently, a novel class of curcumin analogs, based on diarylidenylpiperidones (DAP), has been developed by incorporating a piperidone link to the beta-diketone structure and fluoro substitutions on the phenyl groups. In this study, we evaluated the effectiveness of H-4073, a parafluorinated variant of DAP, using both in vitro and in vivo head and neck cancer models. Our results demonstrate that H-4073 is a potent anti-tumor agent and it significantly inhibited cell proliferation in all the HNSCC cell lines tested in a dose-dependent manner. In addition, pretreatment of cisplatin-resistant HNSCC cell lines with H-4073 significantly reversed the chemo-resistance as observed by cell viability assay (MTT), apoptosis assay (Annexin V binding) and cleaved caspase-3 (Western blot). H-4073 mediated its anti-tumor effects by inhibiting JAK/STAT3, FAK, Akt and VEGF signaling pathways that play important roles in cell proliferation, migration, survival and angiogenesis. In the SCID mouse xenograft model, H-4073 significantly enhanced the anti-tumor and anti-angiogenesis effects of cisplatin, with no added systemic toxicity. Interestingly, H-4073 inhibited tumor angiogenesis by blocking VEGF production by tumor cells as well as directly inhibiting endothelial cell function. Taken together, our results suggest that H-4073 is a potent anti-tumor agent and it can be used to overcome chemotherapy resistance in HNSCC.

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Citation: 
Malhotra A, Nair P, Dhawan DK (2014, Apr 4). Study to Evaluate Molecular Mechanics behind Synergistic Chemo-Preventive Effects of Curcumin and Resveratrol during Lung Carcinogenesis. PLoS ONE 9(4): e93820. doi: 10.1371/journal.pone.0093820

Abstract

Background
The combination approach is the future of the war against cancer and the present study evaluated molecular mechanics behind the synergistic effects of curcumin and resveratrol during lung carcinogenesis.

MethodsThe mice were segregated into five groups which included normal control, Benzo[a]pyrene[BP] treated, BP+curcumin treated, BP+resveratrol treated and BP+curcumin+resveratrol treated.

ResultsThe morphological analyses of tumor nodules confirmed lung carcinogenesis in mice after 22 weeks of single intra-peritoneal[i.p] injection of BP at a dose of 100 mg/Kg body weight. The BP treatment resulted in a significant increase in the protein expressions of p53 in the BP treated mice. Also, a significant increase in the protein expression of phosphorylated p53[ser15] confirmed p53 hyper-phosphorylation in BP treated mice. On the other hand, enzyme activities of caspase 3 and caspase 9 were noticed to be significantly decreased following BP treatment. Further, radiorespirometric studies showed a significant increase in the ¹⁴C-glucose turnover as well as ¹⁴C-gulcose uptake in the lung slices of BP treated mice. Moreover, a significant rise in the cell proliferation was confirmed indirectly by enhanced uptake of ³H-thymidine in the lung slices of BP treated mice. Interestingly, combined treatment of curcumin and resveratrol to BP treated animals resulted in a significant decrease in p53 hyper-phosphorylation, ¹⁴C glucose uptakes/turnover and ³H-thymidine uptake in the BP treated mice. However, the enzyme activities of caspase 3 and caspase 9 showed a significant increase upon treatment with curcumin and resveratrol.

ConclusionThe study, therefore, concludes that molecular mechanics behind chemo-preventive synergism involved modulation of p53 hyper-phosphorylation, regulation of caspases and cellular metabolism enzymes.

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Citation: 
Kalinski T, Sel S, Hütten H, Röpke M, Roessner A, et al. (2014, Jun 5). Curcumin Blocks Interleukin-1 Signaling in Chondrosarcoma Cells. PLoS ONE 9(6): e99296. doi: 10.1371/journal.pone.0099296

AbstractInterleukin (IL)-1 signaling plays an important role in inflammatory processes, but also in malignant processes. The essential downstream event in IL-1 signaling is the activation of nuclear factor (NF)-κB, which leads to the expression of several genes that are involved in cell proliferation, invasion, angiogenesis and metastasis, among them VEGF-A. As microenvironment-derived IL-1β is required for invasion and angiogenesis in malignant tumors, also in chondrosarcomas, we investigated IL-1β-induced signal transduction and VEGF-A expression in C3842 and SW1353 chondrosarcoma cells. We additionally performed in vitro angiogenesis assays and NF-κB-related gene expression analyses. Curcumin is a substance which inhibits IL-1 signaling very early by preventing the recruitment of IL-1 receptor associated kinase (IRAK) to the IL-1 receptor. We demonstrate that IL-1 signaling and VEGF-A expression are blocked by Curcumin in chondrosarcoma cells. We further show that Curcumin blocks IL-1β-induced angiogenesis and NF-κB-related gene expression. We suppose that IL-1 blockade is an additional treatment option in chondrosarcoma, either by Curcumin, its derivatives or other IL-1 blocking agents.

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These last two studies are not cancer-related - one looks at pain and the other looks at spinal cord injury.

Citation:  
Zhu X, Li Q, Chang R, Yang D, Song Z, et al. (2014, Mar 6). Curcumin Alleviates Neuropathic Pain by Inhibiting p300/CBP Histone Acetyltransferase Activity-Regulated Expression of BDNF and Cox-2 in a Rat Model. PLoS ONE 9(3): e91303. doi: 10.1371/journal.pone.0091303

AbstractThe management of neuropathic pain is still a major challenge because of its unresponsiveness to most common treatments. Curcumin has been reported to play an active role in the treatment of various neurological disorders, such as neuropathic pain. Curcumin has long been recognized as a p300/CREB-binding protein (CBP) inhibitor of histone acetyltransferase (HAT) activity. However, this mechanism has never been investigated for the treatment of neuropathic pain with curcumin. The aim of the present study was to investigate the anti-nociceptive role of curcumin in the chronic constriction injury (CCI) rat model of neuropathic pain. Furthermore, with this model we investigated the effect of curcumin on P300/CBP HAT activity-regulated release of the pro-nociceptive molecules, brain-derived neurotrophic factor (BDNF) and cyclooxygenase-2 (Cox-2). Treatment with 40 and 60 mg/kg body weight curcumin for 7 consecutive days significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia, whereas 20 mg/kg curcumin showed no significant analgesic effect. Chromatin immunoprecipitation analysis revealed that curcumin dose-dependently reduced the recruitment of p300/CBP and acetyl-Histone H3/acetyl-Histone H4 to the promoter of BDNF and Cox-2 genes. A similar dose-dependent decrease of BDNF and Cox-2 in the spinal cord was also observed after curcumin treatment. These results indicated that curcumin exerted a therapeutic role in neuropathic pain by down-regulating p300/CBP HAT activity-mediated gene expression of BDNF and Cox-2.

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Citation:  
Ormond DR, Shannon C, Oppenheim J, Zeman R, Das K, et al. (2014, Feb 18). Stem Cell Therapy and Curcumin Synergistically Enhance Recovery from Spinal Cord Injury. PLoS ONE 9(2): e88916. doi: 10.1371/journal.pone.0088916

AbstractAcute traumatic spinal cord injury (SCI) is marked by the enhanced production of local cytokines and pro-inflammatory substances that induce gliosis and prevent reinnervation. The transplantation of stem cells is a promising treatment strategy for SCI. In order to facilitate functional recovery, we employed stem cell therapy alone or in combination with curcumin, a naturally-occurring anti-inflammatory component of turmeric (Curcuma longa), which potently inhibits NF-κB. Spinal cord contusion following laminectomy (T9–10) was performed using a weight drop apparatus (10 g over a 12.5 or 25 mm distance, representing moderate or severe SCI, respectively) in Sprague-Dawley rats. Neural stem cells (NSC) were isolated from subventricular zone (SVZ) and transplanted at the site of injury with or without curcumin treatment. Functional recovery was assessed by BBB score and body weight gain measured up to 6 weeks following SCI. At the conclusion of the study, the mass of soleus muscle was correlated with BBB score and body weight. Stem cell therapy improved recovery from moderate SCI, however, it had a limited effect on recovery after severe SCI. Curcumin stimulated NSC proliferation in vitro, and in combination with stem cell therapy, induced profound recovery from severe SCI as evidenced by improved functional locomotor recovery, increased body weight, and soleus muscle mass. These findings demonstrate that curcumin in conjunction with stem cell therapy synergistically improves recovery from severe SCI. Furthermore, our results indicate that the effect of curcumin extends beyond its known anti-inflammatory properties to the regulation of stem cell proliferation.

This is a cool piece of research. Nanocapsules (a water-soluble polymer) and other forms of micro-encapsulation are hot properties in the world of drug delivery systems. The essential advantage to this approach is bypassing the degradation of the target material in the digestive process. Among the substances being researched for this type of delivery system are curcumin, resveratrol, probiotics, and (as this article discusses) luteolin.

Via Wikipedia:

Luteolin has been studied in several preliminary in vitro scientific investigations. Proposed activities include antioxidant activity (ie. scavenging of free radicals), promotion of carbohydrate metabolism, and immune system modulation.^{[citation needed]} Other in vitro studies suggest luteolin has anti-inflammatory activity,^[7][8] and that it acts as a monoamine transporter activator,^[9] a phosphodiesterase inhibitor,^[10] and an interleukin 6 inhibitor.^[7] In vivo studies show luteolin affects xylazine/ketamine-induced anesthesia in mice.^[11] In vitro and in vivo experiments also suggest luteolin may inhibit the development of skin cancer.^[12][13] Importantly, the therapeutic value of the above findings is unclear, and will remain so until further detailed in vivo, toxicity, and clinical studies are performed.

Luteolin has long been thought to have great potential as a chemopreventive substance, but it (like curcumin) suffers considerable breakdown in the gut.

Still, consuming a diet rich is luteolin has measurable anti-inflammatory effects. Luteolin is found in many herbs and plant foods, including carrots, peppers, olive oil, peppermint, rosemary, celery, broccoli, green pepper, parsley, thyme, dandelion, chamomile tea, navel oranges, and oregano, among others.

These new delivery systems can transform therapeutically marginal substances (mostly herbal and food extracts) into highly effective pharmaceutical quality interventions. The research with micro-encapsulated curcumin has shown great promise in prostate cancer.

Anti-inflammatory luteolin concentrated in nanocapsules in the blood inhibits lung-cancer growth

January 9, 2014


Cellular uptake of nanoparticles encapsulating both dye and luteolin (credit: Winship Cancer Institute of Emory University)
Researchers at the Winship Cancer Institute of Emory University have discovered a more effective drug delivery system using nanoparticles that could one day significantly affect cancer prevention.

The study, published in Cancer Prevention Research, involved the use of microscopic amounts of the naturally occurring antioxidant, luteolin, that were encapsulated in a water-soluble polymer. When injected into mice, the nano-luteolin inhibited growth of lung cancer and head and neck cancer cells.

“By using a high concentration of luteolin in the blood, we were better able to inhibit the growth of cancer cells,” says senior study author Dong Moon Shin, MD, professor of hematology and medical oncology at Emory University School of Medicine and associate director of academic development at Winship Cancer Institute.

Luteolin is known for its anti-inflammatory and anti-cancer effects. It is naturally found in green vegetables such as broccoli, celery and artichokes, however, Shin says large quantities would need to be consumed to be effective. By concentrating the compound into a nanoparticle and making it easy to dissolve in water, researchers conclude nano-luteolin has immense potential for future human studies of chemoprevention (to help stop the recurrence of cancer in patients and reduce the risk of cancer in others).

Shin told KurzweilAI several chemotherapeutic agents using nanotechnology have been developed for drug delivery over the last decade. “As a chemopreventive agent, our nanotechnology-driven delivery would be one of those pioneering ones. The new luteolin chemopreventive agent has to still go through many steps, including GMP production, IND filing, conducting phase I, II, and III trials, etc., so it is hard to predict at this moment how long it will take to be commercialized.”

Abstract of Cancer Prevention Research paper

Cancer prevention (chemoprevention) by using naturally occurring dietary agents has gained immense interest because of the broad safety window of these compounds. However, many of these compounds are hydrophobic and poorly soluble in water. They frequently display low bioavailability, poor systemic delivery, and low efficacy. To circumvent this problem, we explored a novel approach toward chemoprevention using nanotechnology to deliver luteolin, a natural compound present in green vegetables. We formulated water-soluble polymer-encapsulated Nano-Luteolin from hydrophobic luteolin, and studied its anticancer activity against lung cancer and head and neck cancer. In vitro studies demonstrated that, like luteolin, Nano-Luteolin inhibited the growth of lung cancer cells (H292 cell line) and squamous cell carcinoma of head and neck (SCCHN) cells (Tu212 cell line). In Tu212 cells, the IC50 value of Nano-Luteolin was 4.13 μmol/L, and that of luteolin was 6.96 μmol/L. In H292 cells, the IC50 of luteolin was 15.56 μmol/L, and Nano-Luteolin was 14.96 μmol/L. In vivo studies using a tumor xenograft mouse model demonstrated that Nano-Luteolin has a significant inhibitory effect on the tumor growth of SCCHN in comparison to luteolin. Our results suggest that nanoparticle delivery of naturally occurring dietary agents like luteolin has many advantages and may have potential application in chemoprevention in clinical settings.

Cancer Prev Res; 7(1); 65–73. ©2013 AACR.

References:

• Debatosh Majumdar et al. (2014). Luteolin Nanoparticle in Chemoprevention: In Vitro and In Vivo Anticancer Activity. Cancer Prevention Research, 7(1); 65–73. DOI: 10.1158/1940-6207.CAPR-13-0230

Related:

• Nano-capsules show potential for more potent chemoprevention

Ursolic Acid for Cancer Prevention and Treatment

There is a new natural substance (well, not really new) that has been getting serious attention from the cancer research world. Ursolic Acid has been around for more than a decade, but it the last few years its prominence as a chemopreventive agent has increased considerably.

Via Wikipedia (follow the links for citation information):

Ursolic acid (sometimes referred to as 3-beta-3-hydroxy-urs-12-ene-28-oic-acid or 3-β-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpene acid capable of inhibiting various cancer cell types by inhibiting the STAT3 activation pathway,[2][3] one of which includes human fibrosarcoma by reducing expression of matrix metalloproteinase-9 via glucocorticoid receptors. It may also decrease proliferation of cancer cells and induce apoptosis.[4] Ursolic acid has also been shown to inhibit JNK expression and IL-2 activation of JURKAT leukemic T Cells leading to the reduction in proliferation and T cell activation.[5] Ursolic acid is present in many plants, including apples, basil, bilberry, cranberries, elder flower, peppermint, rosemary, lavender, oregano, thyme, hawthorn, and prunes. Apple peels contain large quantities of ursolic acid and related compounds.[6]

Ursolic acid can serve as a starting material for synthesis of more potent bioactive derivatives, such as antitumor agents.[7] It has been found to reduce muscle atrophy and to stimulate muscle growth in mice.[8][9] Ursolic acid has potential use as a cardioprotective compound.[10]

Ursolic acid was found to be a weak aromatase inhibitor (IC50 = 32 μM).[11]

Ursolic acid has been shown to increase the amount of muscle and brown fat and decrease white fat obesity and associated conditions when added to diets fed to mice.[12]

If you look for this in health food stores, most of the supplements you'll find are from apple skins or from basil and rosemary. The problem with these supplements is that ursolic acid content is relatively low. For example, NOW Foods Holy Basil Extract (2% standardized) only offers 10 mg per 500 mg capsule; Nature's Way Holy Basil Extract (2.5% standardized) only offers 11.25 mg per 450 mg capsule.

However, in the sports supplement world, this substance has been known for a while as a potential aromatase inhibitor (aromatase converts testosterone to estrogen, especially when T levels are too high) and as a possible "nutrient partitioning" agent (switches metabolism from fat storage to muscle building in the presence of weight training and excess calories). Supplements in this area are dosed much higher: Urso-X contains 600 mg of rosemary leaf per two-capsule dose, being 25% ursolic acid, or 150 mg of ursolic acid per two-capsules; Ursolix is dosed at 225 mg of ursolic acid per 3 capsules (Holy Basil extract, 25% standardized).

Cancer Research

Over the last ten or so years, there has been an increasing amount of research into the use of ursolic acid (or modified pharmaceutical versions of the molecule) in treating and preventing cancer. It turns out that ursoic acid has potent chemopreventive properties.

A study last year (March, 2012) showed that ursolic acid inhibits the initiation and progression of Prostate Cancer by modulating pro-Inflammatory pathways. This puts ursolic acid in the same top tier category as curcumin and resveratrol (the two best researched and validated natural chemopreventive supplements for prostate cancer.

A more recent article (May, 2013) showed that ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis (programmed cell death) in colon cancer cells.

Finally, a study from June, 2012, looked at how ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance, and fatty liver disease in mice fed a high-fat diet with ursolic acid. The results were striking:

[U]rsolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis.

First up, the two cancer articles, then last the article the ergogenic and metabolic effects of ursolic acid. All of these articles are Open Access via PLoS ONE.

Ursolic Acid Inhibits the Initiation, Progression of Prostate Cancer and Prolongs the Survival of TRAMP Mice by Modulating Pro-Inflammatory Pathways

Muthu K. Shanmugam, Tina H. Ong, Alan Prem Kumar, Chang K. Lun, Paul C. Ho, Peter T. H. Wong, Kam M. Hui, Gautam Sethi

Abstract

Prostate cancer is one of the leading causes of cancer death among men worldwide. In this study, using transgenic adenocarcinoma of mouse prostate (TRAMP) mice, the effect of diet enriched with 1% w/w ursolic acid (UA) was investigated to evaluate the stage specific chemopreventive activity against prostate cancer. We found that TRAMP mice fed with UA diet for 8 weeks (weeks 4 to 12) delayed formation of prostate intraepithelial neoplasia (PIN). Similarly, mice fed with UA diet for 6 weeks (weeks 12 to 18) inhibited progression of PIN to adenocarcinoma as determined by hematoxylin and eosin staining. Finally, TRAMP mice fed with UA diet for 12 weeks (weeks 24 to 36) demonstrated markedly reduced tumor growth without any significant effects on total body weight and prolonged overall survival. With respect to the molecular mechanism, we found that UA down-regulated activation of various pro-inflammatory mediators including, NF-κB, STAT3, AKT and IKKα/β phosphorylation in the dorsolateral prostate (DLP) tissues that correlated with the reduction in serum levels of TNF-α and IL-6. In addition, UA significantly down-regulated the expression levels of cyclin D1 and COX-2 but up-regulated the levels of caspase-3 as revealed by immunohistochemical analysis of tumor tissue sections. Finally, UA was detected in serum samples obtained from various mice groups fed with enriched diet in nanogram quantity indicating that it is well absorbed in the GI tract. Overall, our findings provide strong evidence that UA can be an excellent agent for both the prevention and treatment of prostate cancer.

Full Citation: 

Shanmugam MK, Ong TH, Kumar AP, Lun CK, Ho PC, et al. (2012). Ursolic Acid Inhibits the Initiation, Progression of Prostate Cancer and Prolongs the Survival of TRAMP Mice by Modulating Pro-Inflammatory Pathways. PLoS ONE 7(3): e32476. doi:10.1371/journal.pone.0032476

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Ursolic Acid Simultaneously Targets Multiple Signaling Pathways to Suppress Proliferation and Induce Apoptosis in Colon Cancer Cells

Jingshu Wang, Liqun Liu, Huijuan Qiu, Xiaohong Zhang, Wei Guo, Wangbing Chen, Yun Tian, Lingyi Fu, Dingbo Shi, Jianding Chengl, Wenlin Huang, Wuguo Deng

Abstract

Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid distributed in medical herbs, exerts antitumor effects and is emerging as a promising compound for cancer prevention and therapy, but its excise mechanisms of action in colon cancer cells remains largely unknown. Here, we identified the molecular mechanisms by which UA inhibited cell proliferation and induced apoptosis in human colon cancer SW480 and LoVo cells. Treatment with UA led to significant inhibitions in cell viability and clone formation and changes in cell morphology and spreading. UA also suppressed colon cancer cell migration by inhibiting MMP9 and upregulating CDH1 expression. Further studies showed that UA inhibited the phosphorylation of Akt and ERK proteins. Pretreatment with an Akt or ERK-specific inhibitor considerably abrogated the proliferation inhibition by UA. UA also significantly inhibited colon cancer cell COX-2 expression and PGE2 production. Pretreatment with a COX-2 inhibitor (celecoxib) abrogated the UA-induced cell proliferation. Moreover, we found that UA effectively promoted NF-κB and p300 translocation from cell nuclei to cytoplasm, and attenuated the p300-mediated acetylation of NF-κB and CREB2. Pretreatment with a p300 inhibitor (roscovitine) abrogated the UA-induced cell proliferation, which is reversed by p300 overexpression. Furthermore, UA treatment induced colon cancer cell apoptosis, increased the cleavage of PARP, caspase-3 and 9, and trigged the release of cytochrome c from mitochondrial inter-membrane space into cytosol. These results indicate that UA inhibits cell proliferation and induces apoptosis in colon cancer cells through simultaneous modulation of the multiple signaling pathways such as MMP9/CDH1, Akt/ERK, COX-2/PGE2, p300/NF-κB/CREB2, and cytochrome c/caspase pathways.

Full Citation: 

Wang J, Liu L, Qiu H, Zhang X, Guo W, et al. (2013) Ursolic Acid Simultaneously Targets Multiple Signaling Pathways to Suppress Proliferation and Induce Apoptosis in Colon Cancer Cells. PLoS ONE 8(5): e63872. doi:10.1371/journal.pone.0063872

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Ursolic Acid Increases Skeletal Muscle and Brown Fat and Decreases Diet-Induced Obesity, Glucose Intolerance and Fatty Liver Disease 

Steven D. Kunkel, Christopher J. Elmore, Kale S. Bongers, Scott M. Ebert, Daniel K. Fox, Michael C. Dyle, Steven A. Bullard, Christopher M. Adams

Abstract

Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness.

Full Citation: 

Kunkel SD, Elmore CJ, Bongers KS, Ebert SM, Fox DK, et al. (2012) Ursolic Acid Increases Skeletal Muscle and Brown Fat and Decreases Diet-Induced Obesity, Glucose Intolerance and Fatty Liver Disease. PLoS ONE 7(6): e39332. doi:10.1371/journal.pone.0039332