Role of Terpenoids in Cancer

Plant secondary metabolites have proved to be an excellent reservoir of new medical

compounds. Many anti-cancer agents have been isolated from various plant sources like
Catharanthus roseus, Podophyllum species, Taxus brevifolia,Camptotheca acuminate,
Betula alba, Cephalotaxus species, Erythroxylum pervillei, Curcuma longa, Ipomoeca
batatas, Centaurea schischkinii and many others. Scientists are still attempting to
explore the bioavailability of anti-cancerous compounds in unexplored plant species[1].
The chemical constituents of the plant cell that exert biological activities on human and
animal cells fall into two distinct groups, depending on their relative concentration in
the plant body, as well as their major function: primary metabolites, the accumulation
of which satisfies nutritional and structural needs, and secondary metabolites, which
act as hormones, pharmaceuticals and toxins [2].
Plant secondary metabolites as potential anticancer drugs:
Some secondary metabolites are considered as metabolic waste products, for example,
alkaloids may function as nitrogen waste products. However, a significant portion of the
products derived from secondary pathways serve either as protective agents against
various pathogens (e.g. insects, fungi or bacteria) or growth regulatory molecules (e.g.
hormone-like substances that stimulate or inhibit cell division and morphogenesis). Due
to these physiological functions, secondary metabolites are potential anticancer drugs,
since either direct cytotoxicity is effected on cancer cells or the course of tumor
development is modulated, and eventually inhibited. Administration of these
compounds at low concentrations may be lethal for microorganisms and small animals,
such as herbivorous insects, but in larger organisms, including humans, they may
specifically affect the fastest growing tissues such as tumors.
Secondary metabolites are compounds belonging to extremely varied chemical groups,
such as organic acids, aromatic compounds, terpenoids, steroids, flavonoids, alkaloids,
carbonyls, etc.,
Chemical groups of natural products with anticancer properties
Plant-derived natural products with documented anticancer/antitumor properties can
be classified into the following 14 chemical groups namely Aldehydes, Alkaloids ,
Annonaceous acetogenins, Flavonoids, Glycosides, Lignans, Lipids, Lipids
(unsaponified), Nucleic acids, Phenols and derivatives, Polysaccharides, Proteins,
Terpenoids, Unidentified compounds.
Role of terpenoids in cancer prevention
Among these terpene is a naturally occurring hydrocarbon based on combinations of
the isoprene unit. Terpenoids are compounds related to terpenes, which may include
some oxygen functionality or some rearrangement, however the two terms are often
used interchangeably.

Terpenoids are diverse, widely distributed compounds commonly found under groups
such as essential oils, sterols, pigments and alkaloids. They exert significant ecological
functions in plants. Mono- and sesquiterpenoids are found as constituents of steam-
distillable essential oils. Di- and triterpenoids are found in resins. Structure and
properties: They are built up of isoprene or isopentane units linked together in various
ways and with different types of ring closures, degrees of unsaturation and functional
groups. Depending on the number of isoprene molecules in their structure, terpenoids
are basically classified as monoterpenoids (2), sesquiterpenoids (3), diterpenoids
(4)and triterpenoids (6). Sterols share the core structure of lanosterol and other
tetracyclic triterpenoids, but with only two methyl groups at positions 10 and 13 of
their ring system. Steroids occur throughout the plant kingdom as free sterols and their
lipid esters. There exists no general method for isolating terpenoids from plants,
however many of them are non-polar and can be extracted in organic solvents. After
saponification in alcoholic alkali and extraction with ether, most terpenoids will
accumulate into the ether fraction.

Biosynthesis in plant cells: Terpenoids are all derived from mevalonic acid or a closely
related precursor. The pyrophosphate of alcohol farnesol is a key intermediate in
terpenoid biosynthesis, particularly leading to the formation of diterpenoids,
triterpenoids and sterols. Monoterpenoids are derived from geranyl pyrophosphate.
Basis of anticancer/antitumor activity: Terpenoids and sterols often possess alkaloidal
properties, thus being cytotoxic in vivo and in vitro against various cancer types, such as
human prostate cancer, pancreatic cancer, lung cancer and leukemia.

Some plants containing terpenoids and sterols with anticancer properties are
Some of the important anti-cancerous drugs that belongs to terpenoids classification
under clinical trials are
Betulinic acid (3, hydroxy-lup-20(29)-en-28-oic acid), a lupine class type, pentacyclic
triterpene compound is obtained naturally from various plant species. This compound
is obtained in good amounts from the bark of many trees, including white-barked birch
trees (Betula alba). The mechanism of action of betulinic acid is that they trigger the
mitochondrial pathway of apoptosis which causes cancer cell death. Thus this
compound exhibits potent anti-cancer activity in humans[4,5].

Cucurbitacin, a tetracyclic triterpenoid compound is predominantly obtained from the

Cucurbitaceae plants. They possess antiproliferative behavior against various cancer
cell lines. Reports show that Cucurbitacin- I and B selectively inhibit both signal
transducer/Janus Kinase 2 (JAK2) activity and activator of transcription 3 (STAT3)
pathways. STAT3 is activated in many cancer cell types like prostate cancer, breast
cancer and also carcinoma of the head, neck and nasopharynx. Reports show that
inhibition of this oncogenic signaling pathway, STAT3, causes tumor cell growth
inhibition and leads to apoptosis of cancer cells. Polymeric miscelles are used in
delivering this compound because of its water insolubility and non-specific toxicity[6,7].

Salvicine, a diterpenoid quinone is obtained as a derivative of the naturally occurring

lead saprorthoquinone compound. This lead product is isolated from a Chinese
medicinal plant species, Salvia prionitis Hance (Labiatae). Salvicine reported significant
in-vitro and in-vivo activity against malignant tumors by inhibiting the activity of
Topoisomerase II [8].

Triptolide is a traditional Chinese medicine obtained as a puri ied extract from a shrub-
like vine named Tripterygium wilfordii HookF. This diterpenoid triepoxide enhances
the anti-tumor effects of cytotoxic and chemotherapeutic agents and thereby induces
apoptosis of tumor cells. Because of its severe toxicity and water insolubility, new
triptolide derivatives like PG490-88 or F60008 have been synthesized which are water-
soluble and proved to be very safe and effective. PG490-88 (14-succinyl triptolide
sodium salt) is under Phase I clinical trial for treatment of prostate cancer [9].

Ursolic acid Ursolic acid (3-hydroxyurs-12-en-28-oic acid) is a pentacyclic triterpenoid

that occurs in numerous plants and is a constituent of several herbal medicines
marketed in Asia and worldwide for inflammatory conditions (10). Ursolic acids ability
to induce apoptosis in many different cell types is likely to play a major role in its anti-
proliferative activity. Ursolic acid has been shown to decrease the expression of matrix
metalloproteinase-9 (MMP-9) (11) 31. Matrix metalloproteinaseactivities are involved
in the remodeling of the extracellular matrix, part of the tumor micro-environment, and
are thus linked to tumor invasion and increased risk of metastasis (Bjrklund and
Koivunen, 2005). Ursolic acid has been shown to decrease cell viabililty and induce
apoptosis in prostate cancer cells (12).
Polycyclic triterpenoids now offer important new platforms for drug development. The
natural triterpenoid platform provided by the unique stereochemistry of these
particular compounds, and the cyclization of the linear 30-carbon squalene molecule,
have provided an excellent base from which new agents more potent than the parent
squalene could be developed.