863831.v2

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Review Article

Medicinal Plants Sources of Anticancer Drugs

Latifa Doudach1,2

, Bouchra Meddah1, Laila Benbacer

3, Layachi Chabraoui

4, My.A.

Faouzi1, Abdelhakim Elomri

2 and, Yahia Cherrah

1

1Mohammed V Souissi University of Rabat, Faculty of Medicine and Pharmacy, Laboratory of

Pharmacology and Toxicology, Research Team pharmacokinetic, Morocco

2University of Rouen, CNRS UMR 6014, C.O.B.R.A, UFR Medicine and Pharmacy, 22

Boulevard Gambetta 76183 Rouen, France

3Biology Unit and Medical Research CNESTEN, PB 1382 RP, 10001 Rabat, Morocco

4Biochemical 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. Tel.:

+212 - 5 37 77 04 21, Fax: +212 5 37 77 37 01

E-mail address: [email protected]

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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.

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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

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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

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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 double-

stranded 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]

.

6

Podophyllotoxin (1) Podophyllotoxin (1)

Teniposid (2)Teniposid (2)

Etoposid (3)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]

. They targeted the subunit of tubulin and

depolymerized microtubules.

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Vinblastine (4)Vinblastine (4)

Vincristine (5)Vincristine (5)

Vinorelbine (6)Vinorelbine (6)

Vindesine(7)Vindesine(7)

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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

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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.

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Camptothecin (8) Camptothecin (8)

N(CH3)2

Topotecan (9)

N(CH3)2

Topotecan (9)

Irinotecan (10)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

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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)Paclitaxel (11)

Docetaxel (12)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

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comparable efficacy and less toxicity: the N-desacetyl-colchicine (14), the N-desacetyl-N-

methyl-colchicine (15), trimethyl-colchicine acid and colchicoside (16).

R1 = COCH3; R2 = Me Colchicine (13)R1 = H; R2 = Me N-desacetyl-colchicine (14)R1 = CH3; R2 = Me N-desacetyl- N-methyl colchicine (15)R1 = COCH3; R2 = Glu Colchicoside (16)

R1 = COCH3; R2 = Me Colchicine (13)R1 = H; R2 = Me N-desacetyl-colchicine (14)R1 = CH3; R2 = Me N-desacetyl- N-methyl colchicine (15)R1 = COCH3; R2 = Glu 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]

.

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Betulinic acid (17) 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) 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

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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) 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) Ellipticine (20)

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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.

Combretastatin A4 (21) Combretastatin A4 (21)

Phenstatin (22) Phenstatin (22)

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

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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) Flavopiridol (23)

Rohitukine (24) 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

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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) Roscovitine (25)

Olomoucine (26) 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,

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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) 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

19

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) 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

20

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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34

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

Docetaxel

Stop of the mitotic metaphase-

anaphase stage: inhibits the

depolymerization of microtubules.

Inhibition of proliferation

promoting cell death Taxus

brevifolia Nutt.

Taxus brevifolia Nutt.

(Taxaceae)

Taxus baccata

(Taxaceae)

Cancer of the ovary,

advanced breast and lung

[79.80]

SK-OV-3

MCF7

A-549

IC50=105 nM

IC50= 89 nM

IC50= 899,9 nM

Daphnoretin Inhibition of DNA synthesis and

protein of cancer cells

Wikstroemia indica

(Thymelaeaceae)

Human hepatoma cells

Hep3B. [81]

AGZY-83-a

Hep2

HepG2

IC50= 8.73

IC50= 9.71

IC50= 31.34

Vincristine

Vinblastine

Vinorelbine

Antimitotic:

Inhibition of tubulin polymerization

by binding to tubulin

Catharanthus roseus

(Nyssaceae)

Testicular cancer,

Hodgkin's disease and

lymphocytic leukemia

U937

HL-60

IC50= 4 nM

IC50=2.6 nM

35

Inhibition of microtubule assembly

Inhibition of tubulin

polymerization.

Inhibition of the formation and

function of microtubules.

Acute lung cancer and solid

tumors [82]

Colchicine antimitotic:

Inhibition of tubulin

polymerization.

Inhibition of the formation and

function of microtubules.

Colchicum autumnale

(Colchicaceae)

Gloriosa superba L.

(Colchicaceae)

Leukemia and solid tumors

[83]

HT29

A549

MCF-7

MES-SA

IC50= 2.8 nM

IC50= 2.0 nM

IC50= 3.0 nM

IC50= 2.1 nM

Flavopiridol Cell Apoptosis

Inhibition of angiogenesis

Stop the cell cycle in G1 Or G2

Amoora rohituka

(Meliaceae)

Dysoxylum

binectariferum

(Meliaceae)

Colorectal, prostate,

ovarian carcinoma and solid

tumors [84,85]

SUDHL4

PC3

HCT116

SKOV3

IC50= 120 nM

IC50= 203 nM

IC50= 0.042 M

IC50=0.265 M

36

Combretastatin A-4

Cell cycle arrest in G2 / M phase

Destruction of specific blood

vessels

Inhibition of formation of new

vessels or anti-angiogenesis

Combretum Caffrum

(Combretaceae)

Colon cancer and leukemia

[86]

HCT-15

L1210

IC50= 18 nM

IC50= 0.007M

Indirubin Stop the cell cycle:

Inhibition of cyclin-dependent

kinase

Angelica Gentiana

Aloe Pill

(Umbelliferae

Lung cancer, breast and

colorectal cancer [87]

LXFL529L

MCF-7

IC50= 9.9 M

IC50=4 M

Camptothecin

Topotecan, Irinotecan

Semisynthetic derivative of

Camptothecin

Cell cycle arrest and cell death:

Altered stability of topoisomerase

I-DNA complex and inhibition of

DNA replication

Camptotheca

acuminata

(Nyssaceae)

Leukemia and cancer of

colon, ovarian, colorectal

and lung [86, 88]

L1210

HT-29

IC50=23 M

IC50=0.046 M

Podophyllotoxin

Etoposid and Teniposid :

Cell cycle arrest and / or apoptosis:

Inhibition of polymerization

Podophyllum peltatum

(Berberidaceae)

Cancer of lung, prostate,

colon breast [86]

NCI H460

DU145

IC50=1.1 M

IC50=0.8 M

37

Semisynthetic derivatives

of Podophyllotoxin

microtubule

Inhibition of topoisomrase II

(double-stranded breaks in DNA,

activation of the kinase ATM, the

intervention of the tumor

suppressor protein

HT29

MCF7

IC50=59 M

IC50=4.3 M

Ellipticine

Inhibition of topoisomerase II

Ochrosia borbonica

(Apocynaceae)

Excavatia coccinea

(Apocynaceae)

Ochrosia elliptica

(Apocynaceae)

Breast cancer, leukemia,

neuroblastoma cells and

glioblastoma [89]

MCF-7

HL-60

IMR-32

U87MG

IC50= 1.25 M

IC50= 0.67 M

IC50= 0.27 M

IC50= 1.48 M

Salvicine

Inhibits the catalytic activity of

topoisomerase II (htopo II) which

causes DNA cleavage

Salvia prionitis Hance

(Lamiaceae)

Breast cancer, leukemia and

malignant tumors [90]

K-562

KB

MCF-7

IC50= 0.87 M

IC50= 2.26 M

IC50= 2.61 M

38

Silvestrol Cell apoptosis:

mitochondrial pathway involved

triggering the extrinsic pathway of

programmed cell death of tumor

cells

Aglaia foveolata

Panell

(Meliaceae)

prostate cancer, breast and

lung cancer and leukemia

[91,92,93]

JeKo-1

697 B-cell

IC50

39

Inhibition of the enzyme involved

in the mechanism of DNA repair,

g/mL

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)