The therapeutic properties of light have been known for thousands of years, but it was only in the last century that photodynamic therapy (PDT) was developed. At present, PDT is being tested in the clinic for use in oncology--to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin. How does PDT work, and how can it be used to treat cancer and other diseases?

Photodynamic therapy for cancer

In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans.

Therapeutic potential of resveratrol: the in vivo evidence.

The main dietary sources of polyphenols are reviewed, and the daily intake is calculated for a given diet containing some common fruits, vegetables and beverages. Phenolic acids account for about one third of the total intake and flavonoids account for the remaining two thirds. The most abundant flavonoids in the diet are flavanols (catechins plus proanthocyanidins), anthocyanins and their oxidation products. The main polyphenol dietary sources are fruit and beverages (fruit juice, wine, tea, coffee, chocolate and beer) and, to a lesser extent vegetables, dry legumes and cereals. The total intake is approximately 1 g/d. Large uncertainties remain due to the lack of comprehensive data on the content of some of the main polyphenol classes in food. Bioavailability studies in humans are discussed. The maximum concentration in plasma rarely exceeds 1 microM after the consumption of 10-100 mg of a single phenolic compound. However, the total plasma phenol concentration is probably higher due to the presence of metabolites formed in the body's tissues or by the colonic microflora. These metabolites are still largely unknown and not accounted for. Both chemical and biochemical factors that affect the absorption and metabolism of polyphenols are reviewed, with particular emphasis on flavonoid glycosides. A better understanding of these factors is essential to explain the large variations in bioavailability observed among polyphenols and among individuals.

Dietary Intake and Bioavailability of Polyphenols

Chemoprevention refers to the use of agents to inhibit, reverse or retard tumorigenesis. Numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents, but attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals.

Cancer chemoprevention with dietary phytochemicals

Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.

https://science.sciencemag.org/content/sci/275/5297/218.full.pdf

Cancer Chemopreventive Activity of Resveratrol, a Natural Product Derived from Grapes

Resveratrol Inhibits Cyclooxygenase-2 Transcription and Activity in Phorbol Ester-treated Human Mammary Epithelial Cells

Effects of resveratrol on 12-O-tetradecanoylphorbol-13-acetate-induced oxidative events and gene expression in mouse skin.

A composition and method of cancer chemoprevention is disclosed. The composition and method utilize resveratrol as a cancer chemopreventative agent in mammals, including humans.

Cancer chemopreventative composition and method

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a naturally occurring compound shown to inhibit 7,12‐dimethylbenz[a]anthracene-induced preneoplastic lesions in mouse mammary organ culture and 12O-tetradecanoylphorbol-13-acetate-promoted mouse skin tumors. It has been postulated that resveratrol may inhibit tumorigenesis in mouse skin through interference with reactive oxidant pathways, and possibly by modulating the expression of c-fos and TGF-s1. The chemopreventive potential of resveratrol was further examined by investigating its effect on cyclooxygenase (COX) metabolites monitored by HPLC analysis. Resveratrol was found to inhibit the generation of arachidonic acid metabolites catalyzed by both COX-1 and COX-2. In addition, this compound significantly inhibited malignant transformation induced by chemical carcinogens in the mouse C3H10T1/2 cell culture system. These data serve to corroborate the cancer chemopreventive potential of resveratrol.

/pdf/resveratrol-blocks-eicosanoid-production-and-chemically-52qzuvt247.pdf

Mei-Shiang Jang

Papers

Cancer Chemopreventive Activity of Resveratrol, a Natural Product Derived from Grapes

Resveratrol Inhibits Cyclooxygenase-2 Transcription and Activity in Phorbol Ester-treated Human Mammary Epithelial Cells

Effects of resveratrol on 12-O-tetradecanoylphorbol-13-acetate-induced oxidative events and gene expression in mouse skin.

Cancer chemopreventative composition and method

Resveratrol blocks eicosanoid production and chemically- induced cellular transformation: implications for cancer chemoprevention