Commiphora gileadensis sap extract induces cell cycle-dependent death in immortalized keratinocytes and human dermoid carcinoma cells
- Eitan Winemana,
- Iain Douglasb,
- Vanessa Winemana,
- Ksenia Sharovaa,
- Marcel Jasparsb,
- Shiri Meshnera,
- Zvi Bentwicha,
- Guy Cohena, , ,
- Avi Shtevia
Commiphora gileadensis is an aromatic plant traditionally used in the Middle East as a common remedy for pain and inflammation. Recently, several studies have reported on its anti-proliferative effect in cancer cell lines. Yet, scientific evidence regarding the other properties of C. gileadensis is limited. The aim of the current study was to investigate the cytotoxic action of C. gileadensis sap extracts (CgSE) on human epidermal cells and skin tissues and to ascertain its mode of action. The effects of the extract on cell viability and apoptosis were evaluated on immortalized keratinocytes, human dermal fibroblasts, human dermoid carcinoma cells and on human ex vivo skin cultures. CgSE significantly reduced the viability of both immortalized and transformed epidermal cells by 64% and 68%, respectively. However, normal fibroblasts and human skin organ cultures were protected from this effect. The cytotoxicity was coupled with the induction of capsase-3 and the morphological characteristics of apoptosis. In addition, CgSE-induced apoptosis did not occur in cells in the pre-replicative, G1 phase, but only at later phases involved in DNA replication and cell division. HPLC analysis of CgSE showed only negligible traces of β-caryophyllene, a secondary metabolite previously isolated from C. gileadensis and reported to be cytotoxic. Therefore, additional active compound(s) may be involved in the anti-proliferative phenomenon of the extract. The authors concluded that CgSE contains cytotoxic products which specifically target proliferating cells in a cell cycle-dependent manner, and hence may be relevant for the treatment of skin disorders characterized by hyperproliferation, such as skin cancer and psoriasis.
Source : Journal of Herbal Medicine
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A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention
Andrew C. Chen, M.B., B.S., Andrew J. Martin, Ph.D., Bonita Choy, M.Med., Pablo Fernández-Peñas, Ph.D., Robyn A. Dalziell, Ph.D., Catriona A. McKenzie, M.B., B.S., Richard A. Scolyer, M.D., Haryana M. Dhillon, Ph.D., Janette L. Vardy, M.D., Anne Kricker, Ph.D., Gayathri St. George, M.Sc.Med., Niranthari Chinniah, M.B., B.S., Gary M. Halliday, D.Sc., and Diona L. Damian, Ph.D.
Nonmelanoma skin cancers, such as basal-cell carcinoma and squamous-cell carcinoma, are common cancers that are caused principally by ultraviolet (UV) radiation. Nicotinamide (vitamin B3) has been shown to have protective effects against damage caused by UV radiation and to reduce the rate of new premalignant actinic keratoses.
In this phase 3, double-blind, randomized, controlled trial, we randomly assigned, in a 1:1 ratio, 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years to receive 500 mg of nicotinamide twice daily or placebo for 12 months. Participants were evaluated by dermatologists at 3-month intervals for 18 months. The primary end point was the number of new nonmelanoma skin cancers (i.e., basal-cell carcinomas plus squamous-cell carcinomas) during the 12-month intervention period. Secondary end points included the number of new squamous-cell carcinomas and basal-cell carcinomas and the number of actinic keratoses during the 12-month intervention period, the number of nonmelanoma skin cancers in the 6-month postintervention period, and the safety of nicotinamide.
At 12 months, the rate of new nonmelanoma skin cancers was lower by 23% (95% confidence interval [CI], 4 to 38) in the nicotinamide group than in the placebo group (P=0.02). Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20% [95% CI, −6 to 39] lower rate with nicotinamide, P=0.12) and new squamous-cell carcinomas (30% [95% CI, 0 to 51] lower rate, P=0.05). The number of actinic keratoses was 11% lower in the nicotinamide group than in the placebo group at 3 months (P=0.01), 14% lower at 6 months (P<0.001), 20% lower at 9 months (P<0.001), and 13% lower at 12 months (P=0.001). No noteworthy between-group differences were found with respect to the number or types of adverse events during the 12-month intervention period, and there was no evidence of benefit after nicotinamide was discontinued.
Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients.
Source : New England Journal of Medicine
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Early-Onset Basal Cell Carcinoma and Indoor Tanning: A Population-Based Study
Heather H. Nelson and Steven K. Spencer Diane Gilbert-Diamond, Vicki Sayarath, Rita S. Stephenson, Dorothea Barton, Margaret R. Karagas, M. Scot Zens, Zhigang Li, Therese A. Stukel, Ann E. Perry
OBJECTIVE: Indoor tanning with UV radiation–emitting lamps is common among adolescents and young adults. Rising incidence rates of basal cell carcinoma (BCC) have been reported for the United States and elsewhere, particularly among those diagnosed at younger ages. Recent epidemiologic studies have raised concerns that indoor tanning may be contributing to early occurrence of BCC, and younger people may be especially vulnerable to cancer risk associated with this exposure. Therefore, we sought to address these issues in a population-based case–control study from New Hampshire.
METHODS: Data on indoor tanning were obtained on 657 cases of BCC and 452 controls ≤50 years of age.
RESULTS: Early-onset BCC was related to indoor tanning, with an adjusted odds ratio (OR) of 1.6 (95% confidence interval, 1.3–2.1). The strongest association was observed for first exposure as an adolescent or young adult, with a 10% increase in the OR with each age younger at first exposure (OR per year of age ≤23 = 1.1; 95% confidence interval, 1.0–1.2). Associations were present for each type of device examined (ie, sunlamps, tanning beds, and tanning booths).
CONCLUSIONS: Our findings suggest early exposure to indoor tanning increases the risk of early development of BCC. They also underscore the importance of counseling adolescents and young adults about the risks of indoor tanning and for discouraging parents from consenting minors to this practice.
Source : Journal Pediatrics
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Targeting Multiple Key Signaling Pathways in Melanoma using Leelamine
- Raghavendra Gowda1,
- SubbaRao V Madhanupantula Dr.2,
- Omer F Kuzu3,
- Arati Sharma3, and
- Gavin P Robertson Dr.4,
Melanoma is a highly drug resistant cancer with resistance developing to agents targeting single proteins. To circumvent this problem, a new class of agent inhibiting multiple key pathways important in this disease is being developed to reduce the likelihood of developing resistant disease. The PI3 kinase (PI3K), MAP kinase (MAPK) and STAT3 pathways are constitutively activated in 50-70% of melanomas promoting disease development. To identify a drug simultaneously targeting the PI3K, MAPK and STAT3 cascades, a natural product library was screened to identify leelamine as a potential inhibitor. Leelamine was 4.5-fold more effective at inhibiting cultured melanoma cell survival than normal cells, with average IC50 values of 2 and 9.3 µmol/L, respectively. It inhibited cellular proliferation at a concentration of 2.5 µmol/L by 40-80% and longer exposure increased apoptosis 600% through a mechanism detailed in the article in the current issue of this journal by Kuzu OF et al. Leelamine inhibited the growth of preexisting xenografted melanoma tumors by an average of 60% by targeting the PI3K, MAPK and STAT3 pathways without affecting animal body weight or blood markers of major organ function. The mechanism of action of leelamine is mediated by disruption of cholesterol transport, causing decreased cellular proliferation and, consequently leading to increased tumor cell apoptosis as well as decreased tumor vascularization. Thus, a unique agent and novel mechanism of action has been identified for the treatment of melanoma that acts by inhibiting the activity of three major signaling pathways regulating the development of this disease.
*leelamine, is a natural compound isolated from pine bark, is a diterpene compound and a weak agonist of the cannabinoid CB1 receptor.
Source : Molecular Cancer Therapeutics
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Homeopathic mother tincture of Phytolacca decandra induces apoptosis in skin melanoma cells by activating caspase-mediated signaling via reactive oxygen species elevation
Samrat Ghosh 1 , Kausik Bishayee 1 , Avijit Paul 1 , Avinaba Mukherjee 1 , Sourav Sikdar 1
Debrup Chakraborty 1 , Naoual Boujedaini 2 , Anisur Rahman Khuda-Bukhsh 1
1. Cytogenetics and Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani
741235, West Bengal, India
2.Boiron Laboratories, Lyon 69110, France
Preventive measures against skin melanoma like chemotherapy are useful but suffer from chronic side effects and drug resistance. Ethanolic extract of Phytolacca decandra (PD), used in homeopathy for the treatment of various ailments like chronic rheumatism, regular conjunctivitis, psoriasis, and in some skin diseases was tested for its possible anticancer potential.
Cytotoxicity of the drug was tested by conducting 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide assay on both normal (peripheral blood mononuclear cells) and A375 cells. Fluorescence
microscopic study of 4′,6-diamidino-2-phenylindole dihydrochloride-stained cells
was conducted for DNA fragmentation assay, and changes in cellular morphology, if any, were
also recorded. Lactate dehydrogenase activity assay was done to evaluate the percentages of
apoptosis and necrosis. Reactive oxygen species (ROS) accumulation, if any, and expression
study of apoptotic genes also were evaluated to pin-point the actual events of apoptosis.
Results showed that PD administration caused a remarkable reduction in
proliferation of A375 cells, without showing much cytotoxicity on peripheral blood mononuclear
cells. Generation of ROS and DNA damage, which made the cancer cells prone to apoptosis,
were found to be enhanced in PD-treated cells. These results were duly supported by the
analytical data on expression of different cellular and nuclear proteins, as for example, by down-
regulation of Akt and Bcl-2, up-regulation of p53, Bax and caspase 3, and an increase in number
of cell deaths by apoptosis in A375 cells.
Overall results demonstrate anticancer potentials of PD on A375 cells through activation of caspase-mediated signaling and ROS generation
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Silibinin found in Milk Thistle Protects Against UV Induced Skin cancer
A pair of University of Colorado Cancer Center studies published this month show that the milk thistle extract, silibinin, kills skin cells mutated by UVA radiation and protects against damage by UVB radiation - thus protecting against UV-induced skin cancer and photo-aging."When you have a cell affected by UV radiation, you either want to repair it or kill it so that it cannot go on to cause cancer. We show that silibinin does both," says Rajesh Agarwal, PhD, co-program leader of Cancer Prevention and Control at the CU Cancer Center and professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences.
The first study, published in the journal Photochemistry and Photobiology worked with human skin cells subjected to UVA radiation, which makes up about 95 percent of the sun's radiation that reaches Earth. The Agarwal Lab treated these UVA-affected cells with silibinin. With silibinin, the rate at which these damaged cells died increased dramatically.
"When you take human skin cells - keratinocytes - and treat them with silibinin, nothing happens. It's not toxic. But when you damage these cells with UVA radiation, treatment with silibinin kills the cells," Agarwal says, thus removing the mutated cells that can cause skin cancer and photo-aging.
Specifically, the study shows that pretreatment with silibinin resulted in higher release of reactive oxygen species (ROS) within the UVA-exposed cells, leading to higher rates of cell death.
The second study, published this month by the same authors in the journal Molecular Carcinogenesis shows that instead of beneficially killing cells damaged by UVA radiation, treatment with silibinin protects human skill cells from damage by UVB radiation, which makes up about 5 percent of the sun's radiation reaching Earth.
Again, remember Agarwal's suggestion that the prevention of UV-induced skin cancer can happen in two ways: by protecting against DNA damage or by killing cells with damaged DNA. With UVA, silibinin kills; with UVB, it protects, in this case by increasing cells' expression of the protein interleukin-12, which works to quickly repair damaged cells.
"It has been 20 years of work with this compound, silibinin," Agarwal says. "We first noticed its effectiveness in treating both skin and solid cancers, and we now have a much more complete picture of the mechanisms that allow this compound to work."
Agarwal and colleagues continue to test the effectiveness of silibinin in cancer prevention and treatment in cell lines and mouse models, and are working toward human trials of silibinin-based therapeutics.
Source : Newswise
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Strawberry Extract Protects Against UVA Rays
An experiment has shown that strawberry extract added to skin cell cultures acts as a protector against ultraviolet radiation as well as increasing its viability and reducing damage to DNA. Developed by a team of Italian and Spanish researchers, the study opens the door to the creation of photoprotective cream made from strawberries.
"We have verified the protecting effect of strawberry extract against damage to skins cells caused by UVA rays," as explained by Maurizio Battino, researcher at the Università Politecnica delle Marche in Italy and lead author of the jointly Spanish and Italian study. The results are published in the 'Journal of Agricultural Food Chemistry'.
The team prepared human skin cell cultures (fibroblasts) and added strawberry extract in different concentrations (0.05, 0.25 and 0.5 mg/ml), the only exception being the control extract. Using ultraviolet light, the samples were then exposed to a dose "equivalent to 90 minutes of midday summer sun in the French Riviera."
Data confirm that the strawberry extract, especially at a concentration of 0.5 mg/ml, displays photoprotective properties in those fibroblasts exposed to UVA radiation, it increases cell survival and viability and decreases damage in the DNA when compared with control cells.
"These aspects are of great importance as they provide protection for cell lines subject to conditions that can provoke cancer and other skin-related inflammatory and degenerative illnesses," outlines Battino.
The researcher recognises that this is the "first step in determining the beneficial effects of strawberries in our diet or as a possible compound source for 'food integrators' or cosmetics for instance."
The redness of anthocyanins
But what molecules give strawberries their photoprotective properties? Scientists suspect that it could be the anthocyanins, which are pigments that give leaves, flowers and fruits their red colour. Analyses have confirmed that extracts are rich in such substances.
"These compounds have important anti-inflammatory, antioxidant and anti-tumour properties and are capable of modulating enzymatic processes," explains another of the authors, Sara Tulipani from the University of Barcelona. She adds that "we have not yet found a direct relationship between their presence and photoprotective properties."
"At the moment the results act as the basis for future studies evaluating the 'bioavailability' and 'bioactivity' of anthocyanins in the dermis and epidermis layers of the human skin, whether by adding them to formulations for external use or by ingesting the fruit itself," states Tulipani.
Also made up of researchers from the Universities of Salamanca and Granada, in its previous works the team had already demonstrated that strawberries (Fragaria x ananassa) strengthen the red bloods cells and protect the stomach from the effects of alcohol.
Source : Science Daily
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Pomegranate and berry extracts were shown to protect the skin from the harmful effects of UV exposure
In a new study published in Experimental Dermatology - Pomegranate and berry extracts were shown to protect the skin from the harmful effects of UV exposure
Ellagic acid is a phytochemical, or plant chemical, found in raspberries, strawberries, cranberries, walnuts, pecans, pomegranates, and other plant foods
and Korean scientists involved in the study state that this phytochemical may prevent, in human skin cells, the degradation of collagen, which would slow wrinkle formation and maintain skin structure.
Other studies showed that the phytochemical also prevented thickening of the skin when exposed to UV radiation. Topical application of ellagic acid was associated with a decrease in levels of pro-inflammatory compounds in the skin of the animals, report researchers from the Department of Food and Nutrition at Hallym University in Korea.
Below is the conclusion from the study and to see the full study please press the link below
"In conclusion, the present results demonstrate the photoprotective effects of anti-oxidant ellagic acid on skin wrinkle formation resulting from collagen breakdown through increasing MMP production. The mechanism by which ellagic acid alleviated UV-B-initiated photoageing should be further clarified in terms of cellular signalling components such as mitogen-activated protein kinase and nuclear transcriptional factors. Topical ellagic acid alleviated UV-Binduced dermal roughening and thickening leading to skin wrinkle. In addition, ellagic acid mitigated cutaneous accumulation of inflammatory cytokines and adhesion molecule ICAM-1, and inflammatory infiltrates of macrophages in hairless mice skin. Therefore, topical or dietary interventions
with berries and pomegranate rich in ellagic acid and ellagitannins are promising strategies in curtailing skin wrinkling and cutaneous inflammation associated with chronic UV exposure leading to photoageing.
Source: Experimental Dermatology
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Caffeine May Lower Risk of Common Skin Cancer
Relatively modest caffeine consumption was associated with a significantly lower relative risk of basal cell carcinoma (BCC), data from two large cohort studies showed.
People who consumed more than three cups of coffee a month had a 17% reduction in the relative risk of BCC versus individuals who drank less than one cup per month.
The association pertained to men and women and to sources of caffeine other than coffee.
Investigators found no association between caffeine consumption and squamous-cell carcinoma (SCC) or melanoma, as reported in the July 1 issue of Cancer Research.
"Given that nearly one million new cases [of BCC] are diagnosed each year in the U.S., modification in daily dietary factors with even small protective effects may have great public health impact," Jilali Han, PhD, of Harvard and Brigham and Women's Hospital in Boston, and co-authors wrote in conclusion.
Skin cancers are the most common malignancy among white people in the U.S. White Americans have an estimated 1 in 5 lifetime risk of developing skin cancer.
Laboratory studies have consistently shown that oral and topical caffeine prevents SCC in mice exposed to ultraviolet (UV) light, the authors wrote in their introduction. Other preclinical studies have suggested a potential mechanistic explanation, as topical caffeine has been shown to induce apoptosis in UV-damaged keratinocytes in mice.
Observational data have been less convincing, as studies have shown inconsistent associations between caffeine and skin cancer, including melanoma and nonmelanoma. None of these studies distinguished between caffeinated and decaffeinated coffee or tea, a key piece of evidence that might show whether other components of coffee or tea have anticancer activity.
To address limitations of current information, Han and co-authors reviewed data from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). The NHS included 121,700 women ages 30 to 55 at enrollment in 1976. HPFS enrolled 51,529 men ages 40 to 75 when the study began in 1976.
NHS participants provided information on caffeine intake on several occasions from 1984 to 2006, as did the HPFS participants from 1986 to 2006.
Han and co-authors analyzed data for 112,897 participants from the two studies (72,921 women and 39,976 men). During 24 and 22 years of follow-up in the NHS and HPFS, respectively, 22,786 participants developed BCC, 1,953 developed SCC, and 741 developed melanoma.
Using U.S. Department of Agriculture data, Han and co-authors estimated caffeine content 137 mg per cup of caffeinated coffee, 47 mg per cup of tea, 46 mg per 12-oz container of caffeinated soda, and 7 mg per 1-oz serving of chocolate.
Investigators stratified the study participants into quintiles of daily caffeine consumption, which range from 31 to 604 mg in NHS and 8 to 584 mg in the HPFS. The analysis showed an inverse association between caffeine consumption from all sources combined and the risk of BCC.
Comparison of the highest and lowest quintile of caffeine consumption resulted in a relative risk of 0.82 for BCC in women and 0.87 in men (P<0.0001 for trend in both groups). The relative risk was 0.84 for men and women combined.
Coffee accounted for 78.5% of all caffeine consumption. A separate comparison of skin cancer risk by coffee consumption produced a relative risk of 0.83 for the highest versus lowest quintile (95% CI 0.77 to 0.87). Investigators found a dose-response relationship between caffeine and BCC risk in women (P<0.0001 for trend) and men (P=0.003 for trend).
Caffeine from sources other than coffee tended to have an inverse association with BCC (0.88 in women, 0.93 in men), although the effect did not achieve statistical significance.
The authors noted a number of limitations including the reliance on self-report of BCC without confirmation from histology. Also, they noted that statistical power to calculate any relationship between caffeine and melanoma or SCC was lacking because the number of those cancers in the population was much lower than BCC.
Finally, they said they were "not able to rule out other differences between caffeinated and decaffeinated coffee that could also be etiologically relevant."
Primary source: Cancer Research
Song F, et al "Increased caffeine intake is associated with reduced risk of basal cell carcinoma of the skin" Cancer Res 2012; 72: 3282-3289.
Source : Medpage Today
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