Review Article

Medicinal Plants Sources of Anticancer Drugs

Latifa Doudach1,2, Bouchra Meddah1, Laila Benbacer3, Layachi Chabraoui4, My.A.
Faouzi1, Abdelhakim Elomri2 and, Yahia Cherrah1

Mohammed V Souissi University of Rabat, Faculty of Medicine and Pharmacy, Laboratory of

Pharmacology and Toxicology, Research Team pharmacokinetic, Morocco
2

University of Rouen, CNRS UMR 6014, C.O.B.R.A, UFR Medicine and Pharmacy, 22
Boulevard Gambetta 76183 Rouen, France
3

Biology Unit and Medical Research CNESTEN, PB 1382 RP, 10001 Rabat, Morocco
4

Biochemical laboratory, Ibn Sina Hospital Rabat, Morocco.

*Corresponding authors: Pr. Bouchra Meddah, laboratory of Pharmacology and Toxicology,

Faculty of Medicine and Pharmacy, Mohammed V Souissi University, Rabat, Morocco.
+212 - 5 37 77 04 21, Fax: +212 5 37 77 37 01
E-mail address: bouchra_meddah@yahoo.fr

Tel.:

Abstract
Medicinal plants continue to generate interest in pharmacological research and development of
new anticancer agent. Approximately 64% of drugs used in cancer chemotherapy are from
plants materials with different modes of action. This study proposes to list the natural
compounds having the capacity to inhibit or reduce the development of cancer in order to
identify their mechanisms of action and mode of signalization involved in the process of
carcinogenesis, vinblastine, vincristine, topotecan, irinotecan, etoposide, taxol and paclitaxel
are drugs derived from natural resources used in the treatment of a wide variety of cancers.
Data on safety and efficacy are available for an even few number of plants.
Keywords: Medicinal plants, natural products, drugs, cancer.

1. Introduction
Remedies made from plants constitute a promising avenue for the development of drugs
traditionally improved. Estimations from the World Health Organization (WHO) say that over
80% of the population use traditional medicine in health care needs. In fact about 35000 to
70000 plant species are used for medical purposes in the world

[1]

and over 62% of new

biologically active substances are currently used as anticancer agents made from natural
sources (plants, marine organisms and micro-organizations)

[2]

. Studies of separation and

chemical identification have revealed the pharmacological potential of several medicinal plants
[3,4,5]

. The plants are then a source of natural substances with great potential of application and

whose physicochemical properties seem to be related to their compositions of secondary

metabolites. Different therapeutic effects have been associated with natural compounds and
have allowed the isolation of several phytoactive compounds (polyphenols, terpenods,
alkaloids, glycosides and polysaccharides ...). Several studies have documented the use of
plants in the Ethnotherapy and the treatment of several diseases. The root bark extracts of
Calotropis procera, have been the target in multiple uses in Burkina Faso, have demonstrated
antitumor activity

[6]

. Several studies have reported the use of plants in the treatment of

Ethnotherapy and other diseases. Hartwell has estimated the use of over 3 000 plant species in
the treatment of cancer

[7]

. Several chemotherapy drugs are isolated from medicinal plants,

including the Vinca alkaloids, vinblastine and vincristine, isolated from the plant of
Catharanthus

roseus,

etoposide

and

teniposide,

semisyntheticaly

derivative

from

epipodophyllotoxin isomer of podophyllotoxin (isolated from kind of Podophyllum species),

taxanes isolated from Taxus species, the semisynthetic derivatives of camptothecin: topotecan
and irinotecan, isolated from the plant Camptotheca acuminata

[8,9,10]

. Given the current

worldwide interest aroused by the use of medicinal plants to fight disease and maintain health,
knowledge of these plants is now essential and is even crucial in health sector and

pharmaceutical industry. Nature is a source not only of potential chemotherapeutic agents and
lead compounds that have provided the basis and inspiration for the semisynthesis or total
synthesis of effective new drugs, half of the existing pharmaceuticals today are inspired by
natural products

[11,12]

. The improvement of medicinal plants value can be achieved by

searching newer, more effective and less toxic therapeutic molecules, which will add great
values to the resources that can be later, integrated into the therapeutic arsenal already in use.
This work represents a literature review exposing the interest of the phytoactive isolated from
medicinal plants used as active principles for chemotherapy. The identified active extracts are
standardized, will bear the different preclinical steps, pharmaceutical, analytical, toxicological,
pharmacological and clinical according to current regulations. The finished products will be
subject to authorization on the market (AMM) for its efficacy, safety and pharmaceutical
quality. Therefore, the effectiveness of anticancer activity phytoactifs to is reproducible to the
modern medicine, the doses are standardized contrary to traditional medicine, the active
ingredients from plants in complex mixtures, undefined, cant generate a comparable activity.

2. Medicinal Products Made from Aromatic and Medicinal Plants

Most current cancer therapies involve the modulation of a single target. The high cost of
conventional drugs and the desire to consume unprocessed agricultural products, encouraged
the development of several alternative approaches. The use of natural remedies, made from
plants, remains a very promising way to address health problems, such as cancer and other
associated pathologies. Actually, several drugs derived from natural sources are used in
chemotherapy (Table I), among the large classes of anticancer drugs made from plants

[13]

we

find:
2.1. Podophyllotoxin: Podophyllotoxin (1), isolated from plants of the Berberidaceae family:
Podophyllum peltatum and Podophyllum hexandrum has given birth after a few structural
changes, to three compounds: Teniposid (2), Etoposid (3) and phosphate of etoposid widely
4

used in antitumor therapy [14], it is used against several types of tumors, including lung cancer,
testicular, lymphoma, leukemia, sarcoma and Kaposi... the mechanism of action of
podophyllotoxin is based on the inhibition of tubulin polymerization, which causes the
inhibition of tubulin polymerization and hence microtubule assembly, thus arresting the cell
cycle in metaphase

[15,16]

. The podophyllotoxin derivatives induce apoptosis in proliferating

cells by interacting with the topoisomerase II, homodimeric enzyme controlling the degree of
supercoiling of deoxyribonucleic acid (DNA), the etoposid increases the number of doublestranded cuts on DNA in proliferating cells

[17]

. Alterations in DNA structure are associated

with activation of a protein kinase, ATM (ataxia telangiectasia mutated kinase, which
stimulates the active form of the tumor suppressor protein p53, leading to the cell cycle arrest
(en G2) and / or to apoptosis [18].

Teniposid (2)

Podophyllotoxin (1)

Etoposid (3)

2.2. Vinca alkaloids: The isolation of Vinca: vinblastine (4) and vincristine (5) from the
Madagascar periwinkle, Catharanthus roseus G. Don. (Apocynaceae) has introduced a new era
of using plant material as anticancer agents, these phytoactive are used in combination for the
treatment of cancer, including cancer of leukemia, lymphomas, testicular, breast, lung, and
Kaposi's sarcoma

[19]

. The semi-synthetic analogues are vinorelbine (6) and vindesine (7),

obtained from vindoline and catharanthine, which play beneficial role for the treatment of
breast and lung cancers. Vinblastine and vincristine are the first antimitotic identified drugs
causing a malformation of the mitotic spindle

[20]

depolymerized microtubules.

. They targeted the subunit of tubulin and

Vinblastine (4)

Vincristine (5)

Vinorelbine (6)

Vindesine(7)

Vinblastine and vincristine are commonly used in the treatment of some cancers (testicular
cancer, Hodgkin's disease, acute lymphocytic leukemia). Vinblastine binds to tubulin, the
protein of microtubules of the spindle. It inhibits the assembly of microtubules, resulting in
dissolution of the mitotic spindle and the cell is then is arrested in metaphase. In fact, by
binding to tubulin, vinblastine prevents some of his contacts to settle; thus, the lateral contacts
between protofilaments, which are crucial for the stability of microtubules, cannot be
established. Microtubules are hollow cylinders whose walls are made of polymers (or
profilements) of tubulin, an abundant cellular heterodimeric protein consisting of an subunit
and a subunit. A high concentration of vinblastine, when the loss of microtubular contacts
becomes important, the tubulin assembles in spirals at the expense of the formation of
microtubules. In these spirals, the link between tubulin heterodimers is enhanced by contact
with vinblastine molecules, each molecule of vinblastine interacts with the subunit of a
heterodimer and the subunit of the other forming a antimitotic complex [21].
2.3. Camptothecin: Isolated in the early 1970's from the extract of the bark of the tree
Camptotheca acuminata (Nyssaceae), an ornamental tree from China, the camptothecin (8) is
highly toxic for clinical usage. It belongs to the category of anticancer drugs that inhibit
topoisomerase I, a nuclear enzyme that allows supercoiled DNA to relax, thus, allowing
replication, recombination, transcription and DNA repair

[22]

. The effect of camptothecin is to

stabilize a cleavable complex (ADNtopI) formed at many sites on the double helix. Once
stabilized, the complex stops the replication fork, which, in turn, leads to inhibition of DNA
synthesis and promotion of cell death. Camptothecin is a potent inhibitor of the transcription of
ribosomal and messenger RNA. This inhibition is mainly due to blockage of the elongation by
trapping the cleavage complex Topi / DNA. In studies conducted on dhydrofolate reductase
(DHFR) in Chinese hamster, it appears that camptothecin activates the initiation, but inhibits
the elongation of gene transcription. In human cells, inhibition of transcription by camptothecin
8

is not uniform. While it strongly inhibits the promoter of the endogenous gene c-MYC,
camptothecin has a minimal effect on the episomal gene c-MYC or on the basal transcription of
HSP70 genes and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The inhibition of the
catalytic activity of the Topoisomerase can also prevent transcription by appearance and
accumulation of supercoiled upstream of the transcription complex RNA polymerase.
Topotecan (9) and irinotecan (10) are the synthetic analogues of camptothecin. Topotecan is
used clinically for the treatment of ovarian and small cell lung cancers. Once topoisomerase I
(top I) covalently linked to double-stranded DNA, the binding of topotecan mimics a DNA
base by being inserted at the cleavage site

[23]

. This interaction changes the position of the free

end of the 5'-OH DNA strand cut by banning a subsequent religation. Irinotecan in turn is used
clinically for the treatment of colorectal cancer; the stability of the lactone nucleus of irinotecan
is about 20 times higher than that of camptothecin [24], its action is to prevent the reconstitution
of stranded DNA after cleavage, thereby inhibiting the correct synthesis of DNA. Indeed,
irinotecan binds to the cleavage complex formed by the top I-DNA and inhibits the religation
of DNA fragments.

N(CH3)2

Topotecan (9)

Camptothecin (8)

Irinotecan (10)

2.4. Taxoids: The structure of paclitaxel (11) has been elucidated in 1971 and was introduced in
the clinic (U.S market) in the 1990s

[25,26]

this molecule was isolated from the yew (Taxus

baccata). The Paclitaxel acts by inducing microtubule polymerization and inhibiting their
depolymerization (subunit alpha and beta). This mechanism of action leads to a mitotic arrest in
metaphase-anaphase stage, leading to the inhibition of proliferation and promotion of cell death
[27]

. At low concentrations, cell death occurs after an aberrant mitosis, involving the p53

protein. Once p53 is activated, it acts as a transcription factor that regulates the expression of
many components involved in the pathways of cell cycle regulation. The p21WAF1/CIP1
protein, mostly known for its role as an inhibitor of CDK and kinas proteins, plays also a key
role in the regulation of the cell cycle progression

[28]

. P53 the gatekeeper of the genome,

induces the transcription of the p21WAF1/CIP1 protein that blocks the passage of the cell from
G1 to S phase by inhibiting cyclin D-cdk complex. At high concentrations, there is a mitotic
arrest in G2 / M phase. The accumulation of the mass of microtubules in cells and the induction
10

of apoptosis through mitogen-activated protein kinase (MAP kinase) or protein kinase A are
able to induce bcl2 phosphorylation by inhibiting its anti-apoptotic action

[29.30]

. Paclitaxel is

significantly active against ovarian cancer, advanced breast cancer and lung cancer

[26]

. The

semi-synthetic analogue of paclitaxel is docetaxel (12).

Paclitaxel (11)

Docetaxel (12)

2.5. Colchicine: Colchicine (13), a tricyclic alkaloid isolated in 1820 by PJ Pelletier and JB
Caventou from plants of Gloriosa superba L and Colchicum autumnale, induces cell death by
arresting mitosis in metaphase by inhibiting tubulin polymerization, the formation and function
of microtubules, and by forming combinations with tubulin

[31]

. Three proteins play a key role

in the pharmacokinetics of colchicine: tubulin, its elective target; the cytochrome CYP3A4,
which is involved in its metabolism and ABCB1 protein, which regulates its tissue distribution,
and renal and biliary excretion

[32]

. Colchicine has a direct effect on P-glycoprotein, whose

particularity is to destroy tumor vasculature, causing their necrosis

[33]

. Effective doses of

phytoactive are close to the maximum tolerated dose; it induces strong toxicity and significant
morbidity. Colchicine analogues are obtained by substituting one or more radicals, giving

11

comparable efficacy and less toxicity: the N-desacetyl-colchicine (14), the N-desacetyl-Nmethyl-colchicine (15), trimethyl-colchicine acid and colchicoside (16).

R1 = COCH3; R2 = Me
R1 = H; R2 = Me
R1 = CH3; R2 = Me
R1 = COCH3; R2 = Glu

Colchicine (13)
N-desacetyl-colchicine (14)
N-desacetyl- N-methyl colchicine (15)
Colchicoside (16)

3. Phytoactifs with Anticancer Activity

Natural substances allow the synthesis of selective analogues with increased biological
properties [34,35], many phytoactive isolated from plants are currently in clinical and preclinical
trials.
3.1. Betulinic acid: The betulinic acid (17), which is a pentacyclic triterpene obtained from
many vegetal or synthetic species from betulin, a substance found abundantly in certain species
of birch (Betula papyrifera). It displays anti-tumor activity vis--vis the tumor cell lines and
against other melanocytic tumors ectodermal Such as neuroblastoma, glioma, medulloblastoma
and Ewing sarcoma [36]. The mechanism of action of betulinic acid is mainly manifested by the
induction of apoptosis through proteolytic cleavage of caspases 3 and 8, which is preceded by
the appearance of mitochondrial events and the generation of reactive substances of oxygen,
involving an apoptotic pathway and a mitochondrial phase

[37]

. The betulinic acid has

interesting therapeutic and anticancer activities. It inhibits the enzyme involved in the
mechanism of DNA repair. Thus, the activity of bleomycin (an antitumor agent) that acts by
damaging the DNA of cancer cells is accentuated in the presence of betulinic acid [38].
12

Betulinic acid (17)

3.2. Curcumin: Curcumin or diferuloylmethane (18) isolated from the plant Curcuma longa L.
plays interesting roles in the treatment of cancer; moreover, it has an anti-angiogenic action,
which could explain its chemopreventive effect

[39]

. The anticancer potential of curcumin

results from its ability to stop the proliferation and metastasis of a variety of tumor cells by
inhibiting adhesion molecules and consequently angiogenesis, a cellular process and a crucial
step in the growth and the metastasis of many cancers. This polyphenol inhibit also the activity
of cyclin D1, a proto-oncogene overexpressed in many cancers at higher concentrations.
Curcumin induces apoptosis by blocking the effect of proteins that regulate this process and by
modulating transcription factors. Human clinical trials indicated no dose-limiting toxicity (up to
10 g / day) and a huge anti-cancer potential of curcumin demonstrated in vitro (in italics) on
various tumor cell lines [40].

Curcumin (18)

3.3. Lapachol: The Lapachol (19) is a phytoactive isolated from avellanedae Tabebuia
(Bignoniaceae), tree of South Africa. Highly active against a variety of cancer cells, it blocks
tumor growth at micromolar doses and inhibits invasion and metastasis of cancer cells by
13

altering the protein profiles of invasive cells. The cytotoxicity of this active compound on
hepatocellular carcinoma (HepG2) is significant, and induces apoptosis of these cells by
caspase activation [41.42]. Topoisomerase I and II are the elective targets of this phytoactive, that
effective for the treatment of many types of cancer (breast, prostate and pancreas).

Lapachol (19)

3.4. Ellipticine: Ellipticine (5,11-dimethyl-6H-pyrido (4,3-b) carbazole) (20), an alkaloid

isolated from plants of Ochrosia borbonica, Excavatia coccinea and Ochrosia elliptica from
the family of Apocynaceae, used in cancer chemotherapy for the treatment of a wide variety of
cancers. The main mechanism of action of ellipticine is the inhibition of topoisomerase II.
Ellipticine has the ability to bind to proteins and induce the cytotoxic harmful free radicals to
the body

[43]

; moreover, Ellipticine inhibit the cytochrome P4501A1

[44]

and activate the

transcription of the mutant protein P53. Recently, it has been shown that ellipticine derivatives
can induce stress of the endoplasmic reticulum of cells, and suggest that stress is a contributing
factor to the cytotoxic activity of this class of inhibitors of topoisomerase II. This phytoactive
inhibits cell growth and induces apoptosis of cancer cells of hepatocellular carcinoma (HepG2)
[45]

Ellipticine (20)

14

3.5. Combretastatin A4: Combretastatin A4 (CA4) (21), isolated from the bark of a South
African tree Combretum caffrum, is an antimitotic agent in cancer cells and selectively inhibits
tubulin polymerization of tumor endothelial cells

[46]

. Indeed, disruption of microtubule

cytoskeleton in the CA4 inhibits cell division of endothelial cells in the proliferative phase and
induces apoptosis of this latter. This product induces cell cycle arrest in the growth phase (G2)
or mitosis (M) and acts on the cell proliferation phase and not on the cell quiescent phase

[47]

Combretastatin A4 also acts on the vasculature of solid tumors. It induces the specific
destruction of blood vessels and inhibit the formation of new vessels or anti-angiogenesis

[48]

The phenstatin (22) is an analogue of the CA4 and whose cytotoxic activity is very important.
The CA4 is currently in Phase III of clinical trials as a phosphate product. The combretastatin
A4 phosphate (CA4-P) is an antitubulin agent used for its anti-angiogenic and antivascular
properties.

Phenstatin (22)

Combretastatin A4 (21)

3.6. Flavopiridol: Flavopiridol (23), a semi-synthetic compound derived from the rohitukine
(24), is an alkaloid isolated from the bark of a plant widely used in India, Dysoxylum
binectariferum. Flavopiridol acts by inhibiting the cyclin-dependent kinase (cdk 1, 2 and 4) [49].
Indeed, it binds competitively to the receptors of adenosine triphosphate (ATP), necessary for
the activation of cyclin-dependent kinases (CDKs) and inhibits the phosphorylation of the
amino acid threonine of Cdks (this phosphorylation is required for the activation of Cdks).
Flavopiridol induces apoptosis of several cell lines; furthermore, it reduces the levels of cyclin

15

D1 and inhibit angiogenesis [50,51] through a decrease in the matrix metalloproteinases secretion
leading to the inhibition of c-erbB-2 gene expression. Overexpression of this gene (c-erbB-2) in
breast cancers is correlated with invasion and metastatic progression of these tumors

[52]

through alteration of the stability of ribonucleic acids (mRNAs) encoding the vascular
endothelial growth factor (VEGF), which represent a pathophysiological stimulus for the
induction of angiogenesis in vivo

[53]

. Flavopiridol acts synergistically with several

conventional antitumor drugs. It potentiates the proapoptotic effect of Mitomycin C and

paclitaxel by having a chemopreventive effect of chromosomal abnormalities and genetic
instability induced by paclitaxel [54]. Flavopiridol is currently in Phase I and II of clinical trials,
and it is used for the treatment of a wide variety of cancers, including breast, stomach,
leukemia, lymphomas and solid tumors [55].

Flavopiridol (23)

Rohitukine (24)

3.7. Roscovitine: Roscovitine (25), a synthetic derivative of olomoucine (26), is a natural

product isolated from the plant Raphanus sativus L. Roscovitine initiates the blockage of the
cell cycle in phase G0, G1 and S and in the transition phase G2 / M, leading to the inhibition of
CDK / cyclin complexes, a protein involved in the regulation of cell cycle

[56]

. Roscovitine

inhibits the activity of CDK7, which in turn inhibits the phosphorylation of threonine of CDK1
2 and 4, leading to the prevention of the catalytic activity of the CDK2/cyclineE complex. This
inactivation will lead to a lack of phosphorylation required for the degradation of the natural
inhibitor p27KIP1, whose stability helps in maintaining its role as an inhibitor of CDK2 and
16

CDK4 and thus blocking the cell cycle in G1. Roscovitine is also responsible for stopping cell
division through the deregulation of the activity of CDKs, leading to the blockage of DNA
replication, the formation of the nucleolus, the duplication of centrosome, the fragmentation of
the Golgi apparatus and finally the rupture of the nuclear envelope, thus, leading to cell death,
characterized by caspase activation and cytochrome C release. This product is used to treat
breast and lung cancers. In Europe, roscovitine is in phase II in clinical trials [19, 57].

Roscovitine (25)

Olomoucine (26)

3.8. Daphnoretin: Daphnoretin (27) belongs to the class of bicoumarines, mainly found in
Thymelaeaceae, but also in legumes and Rutaceae

[58]

. Historically, daphnoretin (3.7 '-

dicoumarylester), is the first of bicoumarine Thymelaeaceae, isolated in 1963 from the berries
of Daphne mezereum and leaves of Daphnopsis racemosa [59]. Subsequently, the same group of
researchers isolated the 6-glycoside of daphnoretin called daphnorine of Daphne mezereum [60].
In 1986, Chakrabarti and al. have isolated the Acetyl daphnoretin [61], while qu'ulubelen et al [62]
identified the dimethyl daphnoretine extracted from Daphne gnidioides Szovits ex Meisson.
Several biological activities have been attributed to the Daphnoretin, including antiviral
activity, initiated by the inhibition of the expression of viral antigens (HBsAg) expressed on the
surface of target cells (human hepatoma Hep B Cells), via a mechanism of activation of the
protein kinase C (PKC) pathway

[63]

. It was also shown that Daphnorrtin is also able to

significantly inhibit the growth of cancerous ascites via inhibition of DNA synthesis and
protein of cancer cells

[64]

. An anticancer activity was also attributed to Daphnoretine. Indeed,

17

in several tumor models, the daphnortine appears to inhibit the kinase activity of hEGF
receptors (Human Epidermal Growth Factor receptor). Considering his medical interest, several
studies are now optimizing the extraction methods of Daphnoretin from different natural
resources. Wikstroemia indica (L.) is a model of choice that contains a lot that could serve as a
prototype with important medical and nutritional value

[65]

. These authors confirmed the anti-

cancer effect of Daphnoretin on cancer cell lines of cervical HeLa, the human lung
adenocarcinoma cell A549, cells of neuroendocrine carcinoma (NEC) and tumor cells HE-p2
[65]

Daphnoretin (27)

3.9. Salvicine: The Salvicine (28) is derived from the structurally modified diterpenequinone,
isolated from Salvia prionitis Hance. The salvicine has been widely described for its antitumor
activity in vitro and in vivo

[66.67]

. Using several tumor models, the salvicine showed a broad

spectrum anti MDR (Multi Drug Resistance) and antimetastatic

[68.69]

. Functionally, the

salvicine inhibits the catalytic activity of a human enzyme, topoisomerase II (htopo II) which
causes DNA cleavage. The htopo II is highly expressed in proliferating cells and plays a crucial
role in replication, transcription and organization of chromosomes [70,71,72]. Its depletion leads to
cell death

[71.72]

. Thus, this nuclear enzyme, highly conserved, is an important target for cancer

chemotherapy. Approximately 50% of drugs used in cancer chemotherapy are the htopo II
[73,74,75]

. The salvicine inhibits htopo II by binding to the ATPase domain of the enzyme,

competing with ATP and ADP.Competitive inhibition experiments show that blocking ATP in
a dose-dependent way and competitive to the setting the salvicine the domain of the enzyme
18

ATP-ase, indicating that the salvicine and ATP use the same binding site on 'htopo II. In tumor
cells, the salvicine induced gene-specific DNA damage and triggers cell apoptosis by
modulating the expression of various genes, including-myc, c-fos, c-JNK, c-jun, and mdr1
[76,77,78]

Salvicine (28)

4. Conclusion
The rapid progress made in cell and molecular biology over the last thirty years played a major
role in better understanding the functioning of cancer cells. As a result, more specific
treatments have been developed, and it has become possible to target more precisely the
processes involved in the development, proliferation and survival of tumor cells. A better
understanding of the characteristics of tumor cells has recently led to the development of more
targeted treatments, and therefore generally less toxic. This may include conventional cytotoxic
molecules targeting non-specific molecules expressed on the surface of cancer cells and at less
degree in normal proliferating cells (DNA, enzymes, microtubules...), or of molecules directed
against targets specific to cancer cells (oncogenes). At the present time and given the current
worldwide interest aroused by the use of natural resources, especially medicinal plants used to
fight disease and maintain health, a knowledge of these plants is now essential and has a major
importance in health sector and pharmaceutical industry. In medicine, particularly in the field
of cancer, the use of herbs is increasingly enhanced especially with the excessive use of
synthetic drugs and awareness of their toxicity, which contributed in oncology, leading to a
19

favorable reconsideration of the medicinal practices made from natural herbal. Several research
studies have led to the discovery and development of new active ingredients from natural
molecules (or derivatives) and several of these compounds are used today in clinical practice.
However, apart from the cytotoxic effect of new anticancer agents, only the pre-clinical and
clinical tests that contrasts in their use as new anticancer drugs and thus their integration into
the existing therapeutic armamentarium. In conclusion, the use of naturally occurring
molecules in the treatment of cancer has greatly contributed to the improvement of the
therapeutic efficacy of drugs used today in cancer chemotherapy. Similarly, the
pharmacognosy, which contributed to the improvement of the knowledge of natural medicines,
and to the development of this sector, which offers to the modern medicine great potentials for
progress, based on the discovery and development of new anticancer molecules based on
natural substances.

Conflict of Interest Statement

There is no conflict of interest associated with the authors of this paper, and the fund sponsors
did not cause any inappropriate influence on this work.

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33

Table I: Example of anticancer phytoactives made from herbal and their mechanisms of action
Phytoactives

Mechanism of action

Plant (Family)

Therapeutic use

Cytotoxicity
Lines tested

IC50

Paclitaxel

Stop of the mitotic metaphase-

Taxus brevifolia Nutt.

Cancer of the ovary,

SK-OV-3

IC50=105 nM

Docetaxel

anaphase stage: inhibits the

(Taxaceae)

advanced breast and lung

MCF7

IC50= 89 nM

[79.80]

A-549

IC50= 899,9 nM

depolymerization of microtubules.
Inhibition of proliferation
promoting cell death Taxus

Taxus baccata
(Taxaceae)

brevifolia Nutt.
Daphnoretin

Inhibition of DNA synthesis and

Wikstroemia indica

Human hepatoma cells

AGZY-83-a

IC50= 8.73

protein of cancer cells

(Thymelaeaceae)

Hep3B. [81]

Hep2

IC50= 9.71

HepG2

IC50= 31.34

Testicular cancer,

U937

IC50= 4 nM

HL-60

IC50=2.6 nM

Vincristine

Antimitotic:

Catharanthus roseus

Vinblastine

Inhibition of tubulin polymerization (Nyssaceae)

Hodgkin's disease and

Vinorelbine

by binding to tubulin

lymphocytic leukemia

34

Inhibition of microtubule assembly

Acute lung cancer and solid

Inhibition of tubulin

tumors [82]

polymerization.
Inhibition of the formation and
function of microtubules.
Colchicine

antimitotic:

Colchicum autumnale

Leukemia and solid tumors

HT29

IC50= 2.8 nM

Inhibition of tubulin

(Colchicaceae)

[83]

A549

IC50= 2.0 nM

MCF-7

IC50= 3.0 nM

MES-SA

IC50= 2.1 nM

SUDHL4

IC50= 120 nM

polymerization.

Flavopiridol

Inhibition of the formation and

Gloriosa superba L.

function of microtubules.

(Colchicaceae)

Cell Apoptosis

Amoora rohituka

Colorectal, prostate,

Inhibition of angiogenesis

(Meliaceae)

ovarian carcinoma and solid PC3

IC50= 203 nM

Stop the cell cycle in G1 Or G2

Dysoxylum

tumors [84,85]

HCT116

IC50= 0.042 M

SKOV3

IC50=0.265 M

binectariferum
(Meliaceae)

35

Combretastatin A-4

Cell cycle arrest in G2 / M phase

Combretum Caffrum

Colon cancer and leukemia

HCT-15

IC50= 18 nM

Destruction of specific blood

(Combretaceae)

[86]

L1210

IC50= 0.007M

vessels
Inhibition of formation of new
vessels or anti-angiogenesis
Stop the cell cycle:

Angelica Gentiana

Lung cancer, breast and

LXFL529L

IC50= 9.9 M

Inhibition of cyclin-dependent

Aloe Pill

colorectal cancer [87]

MCF-7

IC50=4 M

kinase

(Umbelliferae

Camptothecin

Cell cycle arrest and cell death:

Camptotheca

Leukemia and cancer of

L1210

IC50=23 M

Topotecan, Irinotecan

Altered stability of topoisomerase

acuminata

colon, ovarian, colorectal

HT-29

IC50=0.046 M

(Nyssaceae)

and lung [86, 88]

NCI H460

IC50=1.1 M

DU145

IC50=0.8 M

Indirubin

Semisynthetic derivative of I-DNA complex and inhibition of

Camptothecin

DNA replication

Podophyllotoxin

Cell cycle arrest and / or apoptosis:

Podophyllum peltatum Cancer of lung, prostate,

Etoposid and Teniposid :

Inhibition of polymerization

(Berberidaceae)

36

colon breast [86]

Semisynthetic derivatives

microtubule

HT29

IC50=59 M

of Podophyllotoxin

Inhibition of topoisomrase II

MCF7

IC50=4.3 M

(double-stranded breaks in DNA,

activation of the kinase ATM, the
intervention of the tumor
suppressor protein
Ellipticine

Inhibition of topoisomerase II

Ochrosia borbonica

Breast cancer, leukemia,

MCF-7

IC50= 1.25 M

(Apocynaceae)

neuroblastoma cells and

HL-60

IC50= 0.67 M

Excavatia coccinea

glioblastoma [89]

IMR-32

IC50= 0.27 M

U87MG

IC50= 1.48 M

(Apocynaceae)
Ochrosia elliptica
(Apocynaceae)
Salvicine

Inhibits the catalytic activity of

Salvia prionitis Hance

Breast cancer, leukemia and K-562

IC50= 0.87 M

topoisomerase II (htopo II) which

(Lamiaceae)

malignant tumors [90]

KB

IC50= 2.26 M

MCF-7

IC50= 2.61 M

causes DNA cleavage

37

Silvestrol

Cell apoptosis:

Aglaia foveolata

prostate cancer, breast and

JeKo-1

mitochondrial pathway involved

Panell

lung cancer and leukemia

697 B-cell

triggering the extrinsic pathway of

(Meliaceae)

[91,92,93]

Apoptosis of cancer cells by

Rhubarb

Breast cancer, colon, ovary,

different routes

(Polygonaceae)

lung, liver and blood [94.95]

Cell apoptosis:

Berberis Amarensis

Caspase-3-dependenteet caspase

(Berberidaceae)

IC50<5 nM

programmed cell death of tumor

cells
Emodin

Berbamine

HCT-116

IC50=21.5 M

Liver cancer and chronic

SMMC7721

IC50=10.9 g/ml

myeloid leukemia [96.97]

K562-r

IC50=11.1
mol/L

activation
Betulinic Acid

Cell apoptosis:

Betula alba

Tumor lines:

181RNOV

IC50= 3.13 M

mitochondrial pathway: generation

(Betulaceae)

Pancreatic cancer and

257RDB

IC50= 2.01 M

of reactive oxygen substances

gastric lymphoma and

HL-60

IC50= 4.5 g/mL

proteolytic cleavage of caspases 3

promyelocytic leukemia

CEM-SS

IC50= 20.5

and 8

[98.99]

WEHI-3B

g/mL

DNA damage

IC50= 10.0

38

g/mL

Inhibition of the enzyme involved

in the mechanism of DNA repair,

SK-OV-3 ovarian adenocarcinoma, MCF7: breast adenocarcinoma, A-549: Carcinoma of the lung, AGZY-83-a:, adenocarcinoma of the lung, HepG2:
hepatocellular carcinoma, U937: histiocytic lymphoma, HL-60, human leukemia cells , HT29 colon Adenocarcinoma, MES-SA: Uterine sarcoma, SUDHL4:
follicular lymphoma cells, PC3: Prostate Adenocarcinoma, HCT116: colon carcinoma, HCT-15: colon Carcinoma, L1210: animal leukemia cells (mouse),
LXFL529L: lung carcinoma, NCI H460: carcinoma of the lung, DU145: prostate cancer, IMR-32: Neuroblastoma, U87MG: Glioblastoma, K-562: CML
leukemia (human), KB: carcinoma of the skin, Jeko-1: acute lymphoblastic leukemia, B-697 cell: acute lymphoblastic leukemia, SMMC7721: human
hepatoma, 181RNOV: Pancreatic carcinoma, 257RDB: Gastric carcinoma, CEM-SS: lymphocytic leukemia (human), WEHI-3B acute promyelocytic leukemia
(human)

39