Mini-reviewLupeol: Connotations for chemoprevention
Introduction
Cancer results from a multistage, multi-mechanism carcinogenesis process that involves mutagenic, cell death and epigenetic mechanisms, during the three distinguishable but closely allied stages: initiation, promotion, and progression. Because reducing the initiation phase to a zero level is impossible, the most effective intervention would be at the promotion phase to eliminate premalignant cells before they become malignant [1]. It takes several years for the normal cells to transform into malignant ones. Therefore, concept of delaying or preventing this transformation remains a viable and attainable goal for the future [2]. An offshoot of thinking is to explore the prospects to intrude in the process of cancer development. Foods, diet manipulation strategies, or nutraceuticals may be appropriate to delay or prevent carcinogenesis progression in healthy populations with genetic or epidemiologic evidence of risk for future transformation [2]. It has been anticipated that by these diet manipulation strategies, more than two-thirds of human cancers can be prevented [3]. But, although for prevention of cancer, both the scientific community and general public relies on consumption of fruits and vegetables, their active ingredients (at the molecular level) and their mechanisms of action yet remain inexplicable. Interdisciplinary research endeavors are now solely directed at understanding the molecular mechanisms involved in chemoprevention. Completion of the human genome sequence and the advent of DNA microarrays using cDNAs have also enhanced the detection and identification of hundreds of differentially expressed genes in response to anticancer drugs or chemopreventive agents [4]. Epidemiological and experimental evidences emphasize that specific compounds may positively inhibit carcinogenesis at various sites, including the oral cavity, esophagus, stomach, colon/rectum, lung, breast, and prostate, but at the same time, another compelling body of evidences, together with the data from animal and in vitro studies, strongly supports the relationship between dietary constituents and the risk of cancer development [5]. Vegetables, fruits, dietary fiber, and certain micronutrients apparently seem to be protective against cancer, whereas fat, excessive calories and alcohol seem to increase the cancer risk. Over the past few decades, many chemopreventive agents have been developed empirically and recent advances in the molecular biology of carcinogenesis and drug designing continue to perk up the mechanistic approach in development of such agents. Molecular targeted approaches are designed to retain (or enhance) the preventive effects while reducing the already known toxic effects. Toxicity reduction already is being achieved in clinical trials, as agents working along more precise, or selective, molecular pathways are being developed. Of late, bioactive triterpene, lupeol commonly found in fruits like fig, mango, etc. has attracted interest in context to chemoprevention attributable in large part to its antioxidant [6], apoptosis inducing and antiproliferative [7], anti-mutagenic, anti-inflammatory [8] properties as well as its efficacy in inhibition of in vivo and in vitro cancer growth [9]. The purpose of this review is to briefly highlight the significant, though little, accomplishments made in regard to chemoprevention with lupeol and to present course for future research endeavors.
Section snippets
Distribution, isolation and pharmacokinetics of lupeol
Triterpenes represent a varied class of natural products. Thousands of structures have been reported till date with hundreds of new derivatives discovered each year. Pentacyclic triterpenes are all based on a 30-carbon skeleton comprising five, six-membered rings (ursanes and lanostanes) or four, six-membered rings and one, five-membered ring (lupanes and hopanes). Pentacyclic triterpenes are produced by arrangement of squalene epoxide molecules. These compounds occur commonly and are found in
Anti-inflammatory and anti-carcinogenic effects of lupeol
Not much has been documented on the anti-carcinogenic implications of lupeol although it has been reported to possess anti-mutagenic and anti-inflammatory effects. Inflammation, which orchestrates the tumor-supporting microenvironment, is a critical component of both tumor promotion and tumor progression and is an indispensable participant in the neoplastic process. It has been established that cancer can be promoted and/or exacerbated by inflammation and infections [35]. The hypothesis that
Mechanism of action of lupeol based chemoprevention
Elucidation of critical events associated with carcinogenesis provides an opportunity for bioactive compounds like lupeol and its derivatives to impede cancer development via multi-prong strategy commencing with modulation of a plethora of biomolecules and their cross talk encompassing their signaling pathways, and culminating in induction of apoptosis. Of particular note is that, despite envisaging the properties of lupeol and derivatives pertaining in regard to its chemopreventive potential,
Conclusion and future prospects
It is now evident from the above dialogue that a surfeit of naturally occurring bioactive agents in fruits and vegetables have the knack to interfere with multiple cell-signaling pathways. These agents can be used either in their natural form for prevention in general and perhaps in their pure form for the therapy, where large doses may be desired [87]. Drug-based strategies for chemoprevention may predominantly rely upon targeted therapies with tolerable but defined toxicities for treatment.
References (88)
- et al.
Role of lupeol and lupeol linoleate on lipemic–oxidative stress in experimental hypercholesterolemia
Life Sci.
(2006) - et al.
Effect of three triterpenoids, lupeol, betulin, and betulinic acid on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils
Clin. Chim. Acta
(2002) - et al.
Cytotoxic lupane-type triterpenoids from Acacia mellifera
Photochemistry
(2004) - et al.
Lupeol, a triterpene, inhibits early responses of tumor promotion induced by benzoyl peroxide in murine skin
Pharmacol. Res.
(2001) - et al.
Triterpenoids from Gentiana scabra
Phytochemistry
(2002) - et al.
Anti-inflammatory activity of lupeol and lupeol linoleate in rats
J. Ethnopharmacol.
(2001) - et al.
Hepatoprotective effect of lupeol and lupeol linoleate on tissue antioxidant defence system in cadmium-induced hepatotoxicity in rats
Fitoterapia
(2001) - et al.
Cancer chemopreventive effect of orally administrated lupane-type triterpenoid on ultraviolet light B induced photocarcinogenesis of hairless mouse
Cancer Lett.
(2006) - et al.
Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents
Bioorg. Med. Chem.
(2006) - et al.
Apoptotic activity of betulinic acid derivatives on murine melanoma B16 cell line
Eur. J. Pharmacol.
(2004)