Cancer Letters

Cancer Letters

Volume 269, Issue 2, 8 October 2008, Pages 378-387
Cancer Letters

Mini-review
Multi-targeted prevention and therapy of cancer by proanthocyanidins

https://doi.org/10.1016/j.canlet.2008.03.049Get rights and content

Abstract

In recent years, a considerable emphasis has been focused on the importance of the naturally available botanicals that can be consumed in an individual’s everyday diet and that can also be useful as a chemopreventive or chemotherapeutic agent for certain diseases, including cancers. A wide variety of botanicals, mostly dietary flavonoids or polyphenolic substances, have been reported to possess substantial anti-carcinogenic and antimutagenic activities because of their antioxidant and anti-inflammatory properties. Proanthocyanidins are considered as one of them, and are abundantly available in various parts of the plants, such as fruits, berries, bark and seeds. Their modes of action were evaluated through a number of in vitro and in vivo studies which showed their potential role as anti-carcinogenic agent. We summarize and highlight the latest developments on anti-carcinogenic activities of proanthocyanidins from different sources, specifically from grape seeds, and their molecular targets, such as NF-κB, mitogen-activated protein kinases, PI3K/Akt, caspases, cytokines, angiogenesis and cell cycle regulatory proteins and other check points, etc. Although the bioavailability and metabolism data on proanthocyanidins is still largely unavailable, certain reports indicate that at least monomers and smaller oligomeric procyanidins are absorbed in the gut. The modulation of various molecular targets by proanthocyanidins in vitro and in vivo tumor models suggests their importance, contribution and mechanism of action to the prevention of cancers of different organs.

Introduction

Proanthocyanidins are naturally occurring compounds that are widely found in fruits, vegetables, nuts, seeds, flowers and bark. They are a class of phenolic compounds that take the form of oligomers or polymers of polyhydroxy flavan-3-ol units, such as (+)-catechin and (−)-epicatechin [1]. These compounds are mostly found in pine bark, grape seed and red wines. However, bilberry, cranberry, black currant, green tea, black tea and other plants also contain these flavonoids. The seeds of the grape (Vitis vinifera) are particularly rich source of proanthocyanidins. The grape seed proanthocyanidins (GSPs) are mainly dimers, trimers and highly polymerized oligomers of monomeric catechins [2], [3]. GSPs have been shown to be potent antioxidants and free radical scavengers, being more effective than either ascorbic acid or vitamin E [4], [5]. In addition to have antioxidant activity, GSPs have been shown to have anti-carcinogenic activity in different tumor models [6], [7], [8]. GSPs were subjected to a limited toxicity testing which included acute and subchronic toxicity in rats, and genotoxicity testing, comprising test for induction of gene mutation in bacteria, test for induction of chromosomal aberrations in mammalian cell in vitro, and mouse micronucleus test in vivo, the results of which indicate that these compounds are of a low toxicity and have no genotoxic potential [1]. As there has been considerable interest in the use of botanicals for the prevention of various diseases, phytochemicals might be of interest as protective agents for various cancers. Research on proanthocyanidins is however limited and many questions still remain to be answered. The present review highlights the latest developments and knowledge on the cancer chemopreventive and/or chemotherapeutic effects of proanthocyanidins including molecular targets, in vitro cell culture and in vivo animal studies, clinical trials and bioavailability and metabolism.

Section snippets

Chemistry of proanthocyanidins

Proanthocyanidins are synonymous with condensed tannins, and also known as oligomeric proanthocyanidins, pycno-genols or leukocyanidins, oligomers or polymers of flavan-3-ols and these units are linked mainly through C4→C8 bond, but the C4→C6 linkage also exists (Fig. 1). These linkages are called B-type linkages. An additional ether bond between C2→C7 resulting in doubly linkage of the flavan-3-ol units is called an A-type linkage. The most common types of compounds and linkages are shown in

Molecular targets of proanthocyanidins

The extensive investigations with the proanthocyanidins have identified various molecular targets that can potentially be used for the prevention or treatment of cancers of various organs (Fig. 2). Here, we will summarize the latest developments on chemopreventive and/or chemotherapeutic effects of proanthocyanidins in general and with particular emphasis on grape seed proanthocyanidins (GSPs) which were extensively investigated against the risk of cancers in vitro and in vivo models. Moreover,

Anti-cancer properties of proanthocyanidins: in vitro and in vivo studies

The anti-carcinogenic properties of the proanthocyanidins and its associated molecular mechanisms are illustrated through the following in vitro, in vivo experimental studies and clinical trials.

Present status of clinical trials

At present limited data are available on the clinical trials on proanthocyanidins. Tissue hardness (induration), pain and tenderness are common late adverse effects of curative radiotherapy for early breast cancer. Sixty-six eligible research volunteers with moderate or marked breast induration at a mean 10.8 years since radiotherapy for early breast cancer were randomised to active drug (n = 44) or placebo (n = 22). All patients were given IH636 grape seed proanthocyanidin extract (100 mg) three

Bioavailability and metabolism of proanthocyanidins

The study of bioavailability and metabolism of any medicinal or edible phytochemical is an important part of all investigations. Some studies have been performed to examine the bioavailability and metabolism of proanthocyanidins. One-half of 88 tested foods derived from plants were found to be dietary sources of proanthocyanidins, which suggests that these are among the most abundant polyphenols in our diet [10]. Polymeric proanthocyanidins are not absorbed as such in the gut [54]. The

Conclusion

The in vitro and in vivo experimental data supports the concept that proanthocyanidins, specifically grape seed proanthocyanidins, can act as anti-carcinogenic agents. Potential cancer chemopreventive activities include reduced proliferation, increased apoptosis, cell cycle arrest in tumor cells and the modulation of expression and activity of NF-κB and NF-κB-targeted genes including the invasion and metastasis-specific molecular targets (Fig. 2). The available data from in vitro tests and in

Acknowledgments

The work reported from the author’s laboratory was supported by the funds from National Cancer Institute/NIH (CA104428) and Veterans Affairs Merit Review Award (S.K.K.). The content of this article does not necessarily reflect the views or policies of the funding sources. The authors apologize for not discussing and citing several valuable publications because of the limitations of space and the number of references.

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