Cancer Letters

Cancer Letters

Volume 263, Issue 1, 8 May 2008, Pages 1-13
Cancer Letters

Mini-review
Lupeol: Connotations for chemoprevention

https://doi.org/10.1016/j.canlet.2008.01.047Get rights and content

Abstract

The perception of chemoprevention lies still in its infancy. Intervention, to slow down, arrest or reverse the process of carcinogenesis, by the use of either natural or synthetic substances individually or in combination therapy has emerged as a promising and pragmatic medical approach to reduce cancer risk. Pentacyclic lupane-type triterpenes exemplified by lupeol [lup-20(29)-en-3b-ol], are principally found in common fruit plants such as olive, mango, fig, etc. Although, lupeol exhibits an array of biological activities like anti-inflammatory, anti-arthritic, anti-mutagenic and anti-malarial activity both in in vitro and in vivo systems yet, extensive exploration in regard to establish its role as chemopreventive compound is warranted. Interest in developing lupeol based potent anti-neoplastic agents, has led to the discovery of a host of highly active derivatives exhibiting greater potencies and better therapeutic indices. This review asserts on the chemopreventive prospects of lupeol and reveals potential chemoprevention drug targets, central to which are the cell cycle regulatory pathway genes and tries to explain the mechanism operating behind its action.

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)

  • K. Hata et al.

    Anti-leukemia activities of Lup-28-al-20(29)-en-3-one, a lupane triterpene

    Toxicol. Lett.

    (2003)
  • J.M. Fortune et al.

    Topoisomerase II as a target for anticancer drugs: when enzymes stop being nice

    Prog. Nucleic Acid Res. Mol. Biol.

    (2000)
  • S.H. Kaufmann

    Cell death induced by topoisomerase-targeted drugs: ore questions than answers

    Biochim. Biophys. Acta

    (1998)
  • M.T. Yip-Schneider et al.

    Pancreatic tumor cells with mutant K-ras suppress ERK activity by MEK-dependent induction of MAP kinase phosphatase-2

    Biochem. Biophys. Res. Commun.

    (2001)
  • O.W. Brawley et al.

    Prostate cancer prevention trials in the USA

    Eur. J. Cancer

    (2000)
  • H. Takayama et al.

    Fas gene mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of laser captures micro dissected specimens

    Lab. Invest.

    (2001)
  • H. Rezazadeh et al.

    Effect of iron overload on the benzoyl peroxide-mediated tumor promotion in mouse skin

    Cancer Lett.

    (1998)
  • N. Nigam et al.

    Preventive effects of lupeol on DMBA induced DNA alkylation damage in mouse skin

    Food Chem. Toxicol.

    (2007)
  • S.P. Preetha et al.

    Lupeol ameliorates aflatoxin B1-induced peroxidative hepatic damage in rats

    Comp. Biochem. Physiol.

    (2006)
  • M. Rodriguez et al.

    Apoptosis: measurement and technical issues

    J. Mol. Cell. Cardiol.

    (2005)
  • P.R. Dash et al.

    Fas ligand-induced apoptosis is regulated by nitric oxide through the inhibition of fas receptor clustering and the nitrosylation of protein kinase Cε

    Exp. Cell Res.

    (2007)
  • P. Perik et al.

    The dilemma of the strive for apoptosis in oncology

    Crit. Rev. Oncol. Hematol.

    (2005)
  • S. Cowley et al.

    Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells

    Cell

    (1994)
  • A.M. Bode et al.

    Signal transduction pathways: targets for chemoprevention of skin cancer

    Lancet Oncol.

    (2000)
  • B.B. Aggarwal et al.

    Molecular targets of dietary agents for prevention and therapy of cancer

    Biochem. Pharmacol.

    (2006)
  • J.E. Trosko

    The role of stem cells and gap junctions as targets for cancer chemoprevention and chemotherapy

    Biomed. Pharmacother.

    (2005)
  • D.E. Brenner et al.

    Cancer chemoprevention: lessons learned and future directions

    Br. J. Cancer

    (2005)
  • Y.J. Surh

    Cancer chemoprevention with dietary phytochemicals

    Nat. Rev. Cancer

    (2003)
  • B.A. Narayanan

    Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets

    Curr. Cancer Drug Targets

    (2006)
  • M.B. Sporn et al.

    Chemoprevention of Cancer

    Carcinogenesis

    (2000)
  • M. Nagaraj et al.

    Effect of lupeol, a pentacyclic triterpene, on the lipid peroxidation and antioxidant status in rat kidney after chronic cadmium exposure

    J. Appl. Toxicol.

    (2000)
  • M. Laszczyk et al.

    Physical, chemical and pharmacological characterization of a new oleogel-forming triterpene extract from the outer bark of birch (betulae cortex)

    Planta Med.

    (2006)
  • M. Saleem et al.

    Lupeol modulates NF-kappaB and PI3K/Akt pathways and inhibits skin cancer in CD-1 mice

    Oncogene

    (2004)
  • M. Saleem et al.

    Lupeol, a fruit and vegetable based triterpene, induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of Ras signaling pathway

    Carcinogenesis

    (2005)
  • S.K. Roy et al.

    New pentacyclic triterpenes from the roots of Hemidesmus indicus

    Pharmazie

    (2001)
  • P. Jiří

    Biologically active pentacyclic triterpenes and their current medicine

    J. Appl. Biomed.

    (2003)
  • M. Gawrońska-Grzywacz et al.

    Identification and determination of triterpenoids in Hieracium pilosella L

    J. Sep. Sci.

    (2007)
  • S. Imam et al.

    Two triterpenes lupanone and lupeol isolated and identified from Tamarindus indica linn

    Pak. J. Pharm. Sci.

    (2007)
  • G.A. Karikas et al.

    Constituents of the stems of Arbutus unedo

    Planta Med.

    (1987)
  • A. dos Santos Pereira et al.

    Chemical composition of Tipuana tipu, a source for tropical honey bee products

    Z. Naturforsch.

    (2003)
  • H. Zhang et al.

    Oxidosqualene cyclases from cell suspension cultures of Betula platyphylla var. japonica: molecular evolution of oxidosqualene cyclases in higher plants

    Biol. Pharm. Bull.

    (2003)
  • J.B. Nikie´ma et al.

    Effects of antiinflammatory triterpenes isolated from Leptadenia hastata latex on keratinocyte proliferation

    Phytother. Res.

    (2001)
  • Y. Aratanechemuge et al.

    Induction of apoptosis by lupeol isolated from mokumen (Gossampinus malabarica L. Merr) in human promyelotic leukemia HL-60 cells

    Oncol. Rep.

    (2004)
  • T.H. Beveridge et al.

    Phytosterol content in American ginseng seed oil

    J. Agric. Food. Chem.

    (2002)
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