CANCER CHEMOPREVENTION (R AGARWAL, K EL BAYOUMY AND S YU, SECTION EDITORS)
The Mevalonate Pathway and Terpenes:
a Diversity of Chemopreventatives
Jeffrey D. Neighbors
Published online: 27 February 2018
Springer International Publishing AG, part of Springer Nature 2018
Purpose of Review The goal of the present review is to give an overview of the most recent papers demonstrating the chemo-
prevention effects of terpenes. We were interested in showing the structural diversity of these compounds and elucidating
overlapping mechanistic factors that may be responsible for chemoprevention by the terpenes in general in these effects.
Recent Findings The studies reviewed point to chemoprevention effects across the broad array of structural classes of the
terpenes, from the very small-molecule monoterpenes (10 carbon atoms) to the tetraterpenes (40 carbon atoms). These com-
pounds have chemopreventative effects in cancers of the colon, bladder, skin, and liver. Some studies demonstrated that natural
product mixtures have more robust effects and that synergy between compounds can be found in these natural products.
Summary Terpenes are the most diverse class of compounds on earth. The complex biology of animals including the develop-
ment of cancers has evolved with these compounds enabling numerous structurally diverse groups of the terpenes to have similar
effects on the development and progression of cancers. Mechanistically, these actions tend to cluster into effects of reactive
oxygen species and mediators of inflammation which are key players in carcinogenesis.
Terpenes (Fig. 1) are the most diverse group of natural prod-
ucts, and with over 80,000 known unique structures, they
make up a large fraction of the cataloged natural products
(http://dnp.chemnetbase.com/). From this incredible
diversity of structures comes a similarly vast array of
important biological activities. This intersection of biological
activity and structure is such that in the realm of cancer drugs
approved for use, around 50% are either natural products or
compounds derived from them including a majority that are
terpenes [2••]. Terpenes as well as other natural products have
also found a role in cancer chemoprevention with leading
roles for carotenoids such as lycopene and β-carotene (both
are tetraterpenes). Along with these household name dietary
component compounds, there are numerous other examples of
natural terpenes which display chemopreventative properties.
In this review, we will look at reports of chemopreventative
terpenoids published from 2014 to late 2017 including the
mechanistic themes which run through these diverse studies.
Terpenoids are essentially ubiquitous in nature .
They are built up from the five carbon isoprenoid precur-
sor isomers, isopentenyl pyrophosphate (IPP), and
dimethylallyl pyrophosphate (DMAPP) into longer linear
molecules. By combining one DMAPP with successive
IPP molecules in a Bhead-to-tail^ fashion, the straight
chain unsaturated trans-polyprenyl compounds with 10,
15, and 20 carbons, geranyl pyrophosphate (GPP),
farnesyl pyrophosphate (FPP), and geranylgeranyl pyro-
phosphate (GGPP) respectively are synthesized [4–6].
The enzymes that carry out these initial condensations
are trans-prenyl transferases which have highly conserved
cationic mechanisms . A distinct GPP synthase is pres-
ent in plants for dedicated monoterpene synthesis ;
however, in animals under normal conditions, GPP is
present in only miniscule amounts indicating that it may
only be Bleaking^ from the FPP synthase enzyme .
Perturbation of the enzymes farnesyl pyrophosphate
This article is part of the Topical Collection on Cancer Chemoprevention
* Jeffrey D. Neighbors
Department of Pharmacology and Medicine, Pennsylvania State
University College of Medicine, The Penn State Cancer Institute, 500
University Drive, Hershey, PA 17033-0850, USA
Current Pharmacology Reports (2018) 4:157–169