Department of Zoology, Suez Canal University, Ismailia, EgyptEgypt
Also available as PDF (figures and tables appear in the PDF).
Historically, natural products played a forceful role in human treatment ailments. Nowadays, natural products include a large part of current pharmaceutical agents, mostly in the field of cancer therapy. The main aim of this review is to provide a comprehensive summary of the most known natural product used as anticancer globally, including various other natural products. Many of these natural product appears to act through an anticancer mechanism. Overall, natural product research is a vigorous tool to discover novel biologically active components with unique mechanisms of action. Given the diversity of nature, it is sensible to indicate that chemical leads can be produced that are able to interact with most therapeutic targets. This review creates a solid foundation for further study these natural products with additional research and study.
Keywords: Anticancer; Natural product; Plant compounds; Marine flora; Microorganisms; Venom
ancer is a serous global health problem responsible for mil-
lions of deaths all over the world. It is responsible for approx-
C
imately 7.6 million deaths worldwide, which is expected to increase
to 13.1 million by 2030.1 Despite the progress in the field of cancer
research, still there is a need to discover and develop anti-cancer
therapeutic agents. Since long it has been recognized that, natural
products represent the richest source of high chemical diversity,
providing the basis for identification of novel scaffold structures
that serves as starting points for rational drug design.1 This can
be one of the reasons that efforts have been directed to discover
promising cancer therapeutic agents from natural sources. Over
the years, many natural product-based drugs have been introduced
in the market.2 According to a recent review, 49% of drugs were
either natural products or their derivatives that are used in cancer
treatment.3 Moreover, between the year 2005 and 2010, nineteen
natural product-based drugs have been approved, among which
seven have been classified as natural product, ten as semi-synthetic
natural product and two as natural product-derived drugs.4 Of
these, five drugs, everolimus, temsirolimus, ixabepilone, trabecte-
din and romidepsin, have been developed in the feild of oncology
from 2007 to 2009.1
cc Copyright 2019 by El-Hak HNG.This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which
allows to copy, redistribute, remix, transform, and reproduce in any medium or format, even commercially, provided the original work is properly cited. Natural products comprise any substance produced by
life organism. Mostly, these substances are of small molecular
weight (<3,000 Daltons) and of considerable structural diversity.
Over 40-years, natural products played a powerful role as estab-
lished cancer chemotherapeutic agents, either in their naturally oc-
curring forms or their synthetically modified forms.5 For example,
antitumor antibiotics from microbes include the anthracyclines
(such as doxorubicin), bleomycin, dactinomycin (actinomycin),
and mitomycin C. In turn, members of four classes of plant-de-
rived compounds are used widely as antitumor agents, namely, the
bisindole (vinca) alkaloids, the camptothecins, the epipodophyl-
lotoxins, and the taxanes.6 In addition, there are several examples
of promising natural product-derived antineoplastic agents cur-
rently in advanced clinical development or recently approved, not
only from microbes (e.g., the epothilones and the enediynes) and
plants (e.g., the combretastatin and homoharringtonine analogs),
but also of marine origin (e.g., the bryostatins, ecteinascidin 743,
kahalalide F).5 Of a total of 155 anticancer agents approved for
use in Western medicine and Japan since the 1940s, 47% were
classified as either natural products (14%) semi-synthetic deriva-
tives of natural products (28%), or otherwise derived from natu-
ral products (5%).5 Among the largest groups of taxonomically
identified classes of organisms that may be studied as sources of
new anticancer drugs are arthropods, higher plants, and marine
invertebrates.7 In addition, natural product researchers have ex-
amined other taxonomic classes of organisms found all over the
world, including algae, bacteria, fungi, and even terrestrial ver-
tebrates.5 Natural product drug discovery for anticancer agents
requires special procedures involved with sample collection, in-
clusive of the development of “benefit-sharing” agreements with
source countries, whether the samples are of marine or terrestrial
origin.8
There is a tendency for natural product chemists to spe-
cialize on the types of organisms they work, such higher plants or
marine fauna, due to the different methods of organism collec-
tion and work-up in the laboratory.5 However, there is increasing
evidence that the same secondary metabolite of significance as
a potential anticancer agent may be produced by more than one
type of organism.9
The plant based drug discovery give rise to the development of
anticancer agents, including plants (paclitaxel, etoposide, campto-
Table 1. List of Important Anticancer Plant Compounds and Its Mechanism of Action
100 μg /ml of catechin rich extract (AQCE) was used against MCF-7 Down regulation of NF-κB and AP-1 expression (cell
(Human breast adenocarcinoma cellline)
Acacia catechu (L.f.) Willd.
1 10-100 μg /mL of 70% methanolic extract (ACME) from
against 7, 12-di methyl benz[a] anthracene induced mammary carcinoma ratio and activating caspase cascade which leads to the cleavage of
in Balb/c mice.
Allamandin,β-amyrin, plumericin, isoplumericin,β sitosterol and ursolic Inhibit cyclin dependent kinases (CDK1) protein regulates cell 2 Allamanda cathartica L.
acid from leaves through molecular docking
200 μmol/L of aloin from leaves was used against HUVECs (human receptor (VEGFR) 2 mediated c-src and JAK2. Phosphorylation
3 Aloe barbadensis Miller. umbilical vein endothelial cells) and SW620 (human colorectal cancer of STAT3 in endothelial cells. Down-regulates activated STAT3
cells)with the dosage of 20 μmol/L
40 μM of ovatodiolide against renal cell carcinoma
500 μg/mL of aqueous extract from whole plants and 30 μM apigenin was
used against 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced
MCF-7 cells (Human breast adenocarcinoma) 4 Anisomeles indica L.
10, 20 and 40 μM of ovatodiolide from whole plant were used against phosphorylation of upstream signal IκB kinase. It also suppresses
MDA-MB-231
Methanol extract from stem bark used against N-nitrosodiethyl amine cellular lesion formation. It decreases lipid peroxidation and
(NDEA) induced hepato carcinogenesis in wister albino
5 Bauhinia racemosa L.
50, 100 and 200 mg/kg of methanolic extract from stem bark against
ehrlich ascites carcinoma (EAC) in swiss albinomice
Ethanol extract from bark and stem were used against HeLa, Dalton’s 6 Bauhinia variegata L.
ascetic lymphoma, leukemia and ovariancancer
100 mg/kg and 25 mg/kg of aqueous extract from flower acts against Arrest in G1 phase down-regulates MAP kinase and SAPK/JNK 7 Butea monosperma L.
Huh7 and HepG2 cells (hepatoma cells)
15 or 30 mg/kg of cajanin stilbene acid was used against
8 Cajanus cajan L.
64 μM of cajanol (5-hydroxy-3-(4-hydroxy-2- methoxyphenyl)-7- phase and apoptosis inhibits expression of Bcl-2 and induction bax
methoxychroman-4-one) from root thecin, vinblastine, vincristine, topotecan, and irinotecan). Beside
this there is various agents identified from fruits and vegetables
can used in anticancer therapy (Table 1) include spices yielding
biologically active components such as curcumin, lycopene, sa-
ponins, isoflavones, cucurbitacins, phytosterols, resveratrol, and
others.10 There are compounds which have been identified and
extracted from terrestrial plants for their anticancer properties
include alvaradoin E (bioactivity-directed fractionation of an ex-
tract of the leaves of alvaradoa haitiensis Urb. (picramniaceae).11
Pancratistatin 3,4-O-cyclic phosphate sodium salt (pancratistatin,
a phenanthridone alkaloid, from the bulbs of the plant Pancratium
littorale Jacq. (Amaryllidaceae)).12 Polyphenolic compounds include
(flavonoids which constitute a large family of plant secondary
metabolites as anthocyanins, flavones, flavonols and chalcones13;
14 15 tannins14; curcumin15; Resveratrol which found in foods including
peanuts and grapes and red wine16 and gallacatechins which pres-
ent in green tea.17 Brassinosteroids are naturally occurring com-
pounds found in plants which have role in hormone signalling
to regulate growth and cell differentiation, stem and root cells
elongation and other roles such as tolerance against disease and
stress.17
differentiation and proliferation). Decreases c-jun expression
heartwood acts Induces cell cycle arrest at subG1 phase by increasing Bax/Bcl2
poly adeno ribose polymerase (PARP)-intrinsic pathway
cycle
Apotosis and anti-angiogenesis: Suppresses activation of VEGF
protein, expression of STAT3-regulated antiapoptotic (Bcl-xL),
proliferative (c-Myc) proteins.
Inhibits β-catenin signaling
Anti-metastasis, anti- migration and anti- invasion: Downregulates
matrix metalloproteinase (MMP)-9 enzymatic activities, mRNA
expression, nuclear factor (NF)-κB subunit p65 and activator
protein (AP)-1 subunit c-Fos proteins expression in nucleus
Cancer cell growth inhibition and proliferation: Prevents
activation of c-Jun N-terminal kinase, p38 mitogen-activated
protein kinase, phosphatidylinositol 3-kinase and Akt
Chemoprevention: It suppresses nodule development or hepato
rats enhances antioxidants levels by reducing the formation of free
radicals.
Before treating drug: Increased level of serum enzymes, bilirubin
and decreased protein and uric acid level. Elevated amount of MDA
(malondialdehyde) decreased level of antioxidants.
Arrest G0/G1 phase
signaling pathways
Induce G2M arrest and apoptosis by activating the MCF-7 mitochondrialpathway
ROS-mediated mitochondria-dependent pathway induces G2/M
expression leads to activation of caspase-9 and caspase-3 cascade,
which is involved in PARPcleavage
1,5 and 10 nM of cardenolides and calotropin from root bark used Phosphorylation and degradation of β-catenin by casein kinase 1α 9 Calotropis gigantea L.
against DLD1, HCT116 and SW480 99
Cardiospermum < 20 μg/ml of n-hexane extract from seeds was used against MCF-7
halicacabum L. (Breast cancer cell line)
Cissus quadrangularis Acetone extract from stem used against A431 (Human skin epidermoid Bax–Bcl2 ratio, release of cytochrome c from mitochondria to 11 21 Linn. carcinoma) cellline
500 mg/kg of isocurcumenol was used for A549 (Lung carcinoma),
KB (nasopharyngeal carcinoma), K562 (leukemic), daltons lymphoma
12 Curcuma zedoaria C. ascitescells
400 μM of α-curcumene from Rhizome acts against SiHa cells (Human Mitochondrial cytochrome c complex with Apaf-1 and pro-form of
ovarian cancer)
30 mg/ml of ethyl acetate soluble fraction of 75% ethanol extract of the
13 Dioscorea bulbifera L. rhizomes was acts against JB6 (Mouse epidermal) cell lines induced by Onco-protein kinase activation and reactive oxygen burst
12-O-tetra de canoylphorbol-13-acetate (TPA)
250, 500 mg/kg of ethanol and 500 mg/kg of aqueous extract from whole
plant used against dalton lymphoma ascites (DLA) cells in male and
14 Drosera indica L. female adult swiss albino mice
250 mcg/ml ethanol and aqueous extract was used against ehrlich ascitic Anti tumour: Lactate dehydrogenase (LDH) leakage and increased
carcinoma (EAC) cell line
25, 50, 100 and 200 μg/ml dichloromethane fraction from whole plant was Apoptosis: Enhanced sub G0 content and micronuclei formation. 15 Elephantopus scaber L.
act against HeLa (cervical), A549 (lung), MCF7 (breast) and Caco2 (colon) Genotoxicity. Inhibited MDR transporters (ABCB1 and ABC G2)
10-30 μM of embelin from fruits used against MCF7
16 Embelia ribes Burm.
Embelin from fruits used for molecular docking (breast cancer cells)
121μg and 250 μg of aqueous extract from leaves was used against Hep2 17 Gymnema sylvestre R.Br (Liver cancer) cells
10 μg/ml of whole plant ethanolic extract acts against MCF-7 (Breast 18 Jatropha gossypifolia L.
cancer cells)
Ethyl p methoxy cinnamate from Rhizome was used against HepG2 cells Apoptotic induction and inhibition of proliferation: Increase subG0 19 Kaempferia galanga L.
(Human hepatocellular liver carcinoma)
500 mg/Kg of chloroform extract and 20 mg/Kg of pinostrobin from 20 Kaempferia rotunda L.
Rhizome acts against T47D (Human breast cancer cell lines)
15 mM of pentacyclic triter penoids-reduced LantadenesA and B used Induction of apoptosis: Suppresses the production of nitrite,TNF-α
against HL-60 cells.
20, 40, 80 mg/kg of Ursolic acid stearoyl glucoside act against Induced Lantana camara L.
21 hepato cellular carcinoma in wistar rats by diethylnitrosamine (DENA).
30 μg/mL of ethanolic extract from Leaves act against MCF-7 (Human
breast cancer cell line)
30 μg/ml-1 of leaves chloroform extract act against Hep2 cells and Caco2
(colon )
Lawsonia inermis L.
180 mg/kg of ethanolic crude extract from root was used against Dalton’s
lymphoma ascites.
40 mg/kg/day of methanolic extract acts against ehrlich ascites carcinoma
(EAC) cells in swiss albino mice
60 μM of mollic acid arabinoside was used against Ca Ski cervical cancer
cells
23 Leea indica Burm.
60 μM of mollic acid xyloside (MAX) from leaves against Ca Ski cervical Decreases the expression of proliferative cell nuclear antigen,
cancer cells
500 and 1000 μg/mL of ethyl acetate fraction was used against Ca Ski Inducing apoptosis: Accumulation of sub-G1 cells, depletion of
cellline
50 μg/ml of ethanolic extract from leaves, bark and seed showed activity
Moringa oleifera L. against MDA-MB-231 and HCT-8 (colorectal)
Moringaceae 50-400 μg/ml of leaf extract against HepG2 (Hepato cellular carcinoma
cells) and A549 non-small cell lung cancer
25 Oroxylum Indicum L. 20 μM of baicalein from stem bark against CT-26 (colon
100 and 400 mg/kg of Ethanolic extract from Whole plant for Ehrlich 26 Oxalis corniculata Linn.
ascites carcinoma (EAC)-induced in swiss albino mice inhibits Wnt signaling.
Anti-proliferative activity
cytoplasm, cleavage of PARP
Immuno modulation, immuno stimulation, effects on humoral
immune response, anti-angioneogenesis activity
caspase-9 activates caspase-3 and caspase-9.
Increases caspase-3 activity and decreases DNA, RNA and protein
content. Cell growth inhibition through antioxidant property
scavenging effect
Reduction in TNF-α and synthesized as pro- TNF-α then released
to extra cellular space by TNF-α converting enzyme.
Inactivation of metastatic signaling: MMPs,VEGF and hnRNP-K
transcriptional attenuation of mortalin and activation of p53
Anti-proliferation: Increases intracellular ROS levels
Pro-apoptotic and anti-adhesive effects: Decreases β1- integrin
expression and phosphorylation of the focal adhesion kinase at
Tyr397
cell population
Suppress c-Myc expression
and iNOS gene expression
It suppresses free radical formation by scavenging the hydroxyl
radicals. Modulates the level of lipid peroxidation and increases the
endogenous antioxidant enzymes level
Bid and bax was increased and Bcl-2 was decreased after drug
treatment. It also modulates cleavage of caspase-8, caspase-9 and
poly (ADP-ribose) polymerase(PARP)
Down regulation of c-myc expression
Enhances the activities of catalase, glutathione peroxidase and
glutathione S transferase and increases vitamin C,E and reduced
glutathione level.
cytotoxicity
Induce mitochondrial mediated apoptosis
increases sub-G1 cells and arrest cells in S and G2/M phases
intracellular glutathione and activation of caspase-3.
Anti-malignant properties: Arrest cell
Anti-proliferation and apoptosis
carcinoma) Inhibit activation of pro-PDGF-A,B and pro-VEGF C
Antitumor and antioxidant activity: Increase intotalprotein,
albumincontent,catalaseand reduced glutathione levels. Decrease in
AST, ALT and ALP contents, liver MDA level
25-100 g/ml of chloroform extract from whole plant was used against Inhibit cell proliferation and induce apoptosis: Activation of c-myc,
NCI-H23 (Human lung adenocarcinoma)
6.25 μg/mL of Physalin F used against T-47D cells (Human breast 27 Physalis minima L.
carcinoma)
25-100 g/ml of chloroform extract from whole plant act against Caov-3
(Human ovarian carcinoma)
28 Polyalthia longifolia Sonn. 50 μg/ml of was chloroform extract from Leaves against HL-60 Induce intrinsic or mitochondrial-dependent apoptotic pathway
30 μg/ml of undulatoside-A, undulatoside-B and tecomin from bark acts Cell cycle arrest at S phase, increase in AnnexinV positive cells. 29 Tecomella undulate D.
against K562 (chronic myeloid leukemia cells)
100 μl of chebulagic acid from fruits showed apoptosis in COLO-205 30 Terminalia chebula R.
cells
100 and 200 mg/kg of palmatine (alkaloid) from stem against
7,12-dimethylbenz(a) anthracene (DMBA) induced skin carcino genesis in Antioxidant and chemo-preventive activity
swiss albino mice.
31 Tinospora cordifolia T.
100 μl of Hexane fraction act against EAT (Ehrlich ascites tumor). activation of caspase-9, which in turn activates caspase-3. It cleaves
Triumfetta rhomboidea 100 and 200 mg/ kg of leaves methanolic extract used against ehrlich
Jacq. (Tiliaceae) ascites carcinoma (EAC) DLA bearing male swiss albino
75 μgml-1 of Glycoprotein from bulbs act against HUVECs and EAT cells translocation of nuclear factor kappa B to the nucleus thus 33 Urginea indica Roxb.
in swiss albino mice
10 μg/mL of chrysoplenetin and chrysosplenol D used against PANC-1
(Human pancreatic cancer) cells, NCI-H522 (lung), OVCAR-3 Vitex negundo L.
34 (ovarian) and PC-3 (prostate) cells.
(Verbenaceae)
4 to 6 μg/mL of vitexin from i) Fruit iii) Seeds used against COC1 Apoptosis by caspase activates poly (ADP ribose) polymerase
(ovarian cancer cells) and MDA-MB-231154
Table 2. Anticancer Compounds from Marine Environment
1 Arenamides A–C
2 Heteronemin Sponge (Hyrtios sp.)
3 6-bromoisatin Whelk (Dicathais orbita)
4 Tyrindoleninone Whelk (Dicathais orbita)
5 Cryptosphaerolide
6 MakaluvamineA sponge (Zyzzya fuliginosa)
7 Ascididemin
8 Lamellarin D
9 Spongistatin 1
10 Streptochlorin Streptomyces sp.
Marine floras include microflora (bacteria, actinobacteria, cyano-
bacteria and fungi, microalgae, macroalgae, and flowering plants
(mangroves and other halophytes) contain a massive number of
natural products and novel chemical structures with unique ac-
tivities that may be useful in finding the potential drugs with ma-
jor efficacy and specificity forhuman treatment19 (Table 2). The
marine organisms produce novel chemicals to withstand extreme
variations in their environment, and the chemicals produced are caspase-3 and p53 gene expression
Chemoprevention / apoptosis: Activation of caspase-3 and c-myc
pathways due to the presence of cyclo hexanone and epoxy
moieties.
Apoptosis and autophagy
Increase in FAS, FADD levels and activation of caspase 8 and 3/7
Inhibition activity of COX and 5-LOX
Apoptosis signals activates caspase-8, its substrate BID protein
releases cytochrome C to bind Apaf-1 which induces auto-
poly-ADP-ribose polymerase, lamins and inhibitor of caspase
activated DNase (ICAD).
Antitumor and antioxidant activity: Decreases the level of lipid
peroxidation and increases glutathione (GSH), superoxide mice.
dismutase (SOD) and catalase level
Antiangiogenic and proapoptotic activity: Inhibition of
decreases the expression of vascular endothelial growth factor
gene
Cytotoxicity and apoptotic morphological changes (DNA
fragmentation, nuclear condensation and membrane blebbing)
(PARP) and cleaved into a COOH-terminal fragment
Actinomycete Human colon carcinoma cell line Cyclohexa-depsipeptides (Salinispora arenicola) (HCT-116)
Sesterterpene Leukemia (K562 cells)
Ovary, granulosa, Choriocarcinoma Indole derivative (OVCAR-3, KGN, Jar)
Ovary, granulosa, Choriocarcinoma Indole derivative (OVCAR-3, KGN, Jar)
Ascomycete fungal strain Human colon carcinoma cell line Sesquiterpenoid CNL-523 (Cryptosphaeria sp.) (HCT-116)
Pyrroloquinoline Colon cancer (HCT-116 cells)
Actinomycete Human colon carcinoma cell line Cyclohexa-depsipeptides (Salinispora arenicola) (HCT-116)
Prosobranch mollusc of the genus Alkaloid Leukemia (Lamellaria)
Sponges (Spirastrella Macrocyclic lactone Leukemia (Jurkat cells) spinispirulifera and Hyrtios erecta)
Methyl pyridine Leukemia (U937 cells)
unique in diversity, structural, and functional features.20 Mostly
invertebrates that include sponges, soft corals, sea fans, sea hares,
nudibranchs, bryozoans, and tunicates are proven to be the po-
tent sources of drugs. It is now believed that microbial flora
present in the invertebrates are responsible for the production of
medicinal compounds. Marine floras are rich in biologically active
and medicinally potent chemicals as polyphenols, polysaccharides
and alkaloids are the most predominant group of compounds
which are applicable for antioxidant and anticancer activities.
Table 3. Some Examples of Bacterial Strains with Bioactivity and the Sources where they were Obtained
Pseudomonas Staphylococcus aureus, Streptococcus Pneumonia, osteitis, arthritis, endocarditis,
bromoutilis pneumoniae, Streptococcus pyogenes localized abscesses
Chromobacteria Escherichia coli, Pseudomona aureginosa, Pneumonia, osteitis, arthritis, endocarditis,
marinum Staphylococcus aureus localized abscesses
Flavobacteria
uliginosum
Bacillus sp. + Anticancer HCT-116 cells
Lactococcus lactis + Anticancer
Staphylococcus
aureoverticillatus
Marinobacter Antibacterial Mycobacteria tuberculosis, Bacillus
drocarbonoclasticus (siderofore) anthracis
Marine bacteria: Produce secondary metabolites which have anti-
cancer agents (e.g., eleutherobin, discodermolide, bryostatins, and
sarcodictyin)23 as in Table 3. Most of marine bacteria produces
toxins which are useful in neurophysiological and neuropharma-
cological studies.24 Only a few marine bacteria can be isolated un-
der laboratory conditions and there is an urgent need to isolate
the bacteria that produce unique and novel natural products.25
Marine actinomycetes: Received very recent attention. Gutingi-
mycin is a highly polar trioxacarcin derivative from streptomyces
species, isolated from sediment of the Laguna de Terminos, Gulf
of Mexico. The same Streptomyces species also yields trioxa-
carcins D-F, in addition to the known trioxacarcins A-C. Among
the antibiotic-producing microbes, marine actinomycetes within
the family micromonosporaceae are very promising. These mi-
crobes revealed to be a promising sources of anticanceragents
that target proteasome function.
Thiocoraline is a novel bioactive depsipeptide isolated
from Micromonospora marine, a microorganism located in the mo-
zambique strait that inhibits ribonucleic acid (RNA) synthesis.28
Marine fungi: Marine fungi are least studied than terrestrial fungi.
Obligate marine fungi are still an unexplored resource, although,
marine facultative fungi, have been studied due to their produc-
tion of new metabolites which are not found in terrestrial fungi.29
Recently more interest has been generated on studying biologi-
cally active metabolites from higher fungi (basidiomycetes), en-
dophytic fungi and filamentous fungi from marine habitats, the
symbiotic lichens on its anticancer activity.30
Marinemacro algae (Cyanobacteria): Marinemicro algae is one
of the potential organisms which can be the richest sources of
potent bioactive compounds including toxins with potential for
pharmaceutical applications.31 More than 50% of the marine
cyanobacteria are potentially exploitable for extracting bioactive
substances which are effective in killing the cancer cells.19 Scyto-
nemin is a protein serine/threonine kinase inhibitor isolated from
the cyanobacterium Stigonema sp. and this compound is a yellow-
green ultraviolet sunscreen pigment, known to be present in the
extracellular sheaths of different genera of aquatic and terrestrial
- Anticancer
- Antibacterial
- Anticancer Sarcoma-180 cells Viral tumor
Colorectal Cancer
Human Colorectal Cancer papilloma virus type 16(HPV-16)
+ Anticancer Tumor cells Tumors
- Tuberculosis, carbuncle (anthraxlike)
blue-green algae.23 Largazole derived from Symploca sp. is a novel
chemical scaffold with fabulous antiproliferative activity.19 Other
compounds, apratoxin A, isolated from a strain of Lyngbya boul-
32 33 loni,32 coibamide A derived from a strain of Leptolyngbya,33 cu-
racin-A, isolated from the organic extracts of curacao collections
of Lyngbya majuscule.34
Marine macro algae (Seaweed): Marinemacro algae many re-
searchers have worked on the antioxidant, antitumor, and immu-
nomodulating activities of seaweeds as edible seaweed like Pal-
maria palmate,35 the alcoholic extract of the red alga Acanthophora
36 37 38 spicifera, the seaweeds Acanthaphora spicifera, Ulva reticulate,
39 40 Gracilaria foliifera,39 the brown seaweed Sargassum thunbergii,40 fu-
coidan from Ascophyllum nodosum,41 stylopoldione from Stypodium
27 19 42 sp., condriamide-A from Chondria sp., caulerpenyne from caul-
erpa sp.,43 two compounds meroterpenes and usneoidone isolated
from Cystophora sp.,44 phloroglucinol and its polymers namely
45 45 eckol (a trimer),45 phlorofucofuroeckol A (a pentamer),45 dieckol and
8,8’-bieckol (hexamers) isolated from the brown alga eisenia bicy-
clis and padina45 owing to their biological properties.
Mangroves and other higher marine plants: Mangroves have long
been used in fisher-folk medicine to treat diseases. Based on tra-
ditional knowledge and preliminary scientific work, sixteen higher
marine plants considered asa source of anticancer drugs19 (Table
4). A sulphur containing alkaloid, 1,2-dithiolane (brugine) isolat-
ed form Bruguiera sexangula, ribose derivative of 2-Benzoxazoline
isolated from Acanthus ilicifolius and tea from the mangrove plant
Ceriops decandra has shown anticancer activity.46
Small organic molecules derived naturally from microorganisms
have provided a number of beneficial cancer chemotherapeutic
drugs.5 Introduce microorganisms into the body leads to the ac-
tivation of various immune mechanisms, which manifests itself
in increasing the number and recruitment of congenital immune
cells, activation of acquired immunity cells, and production of
proinflammatory cytokine.48 It is assumed that the rallied im-
mune system, by intentionally introducing microorganisms into
the oncological patient, is able to at least limit the development
Table 4. List of Anticancer Compounds Isolated from Endophytic Fungi from Mangrove Habitats
1 Excoecaria agallocha 3-hydroxy-5-methoxyben-
2 Rhizophora mucronata Pestalotiopsis sp. Pestalasins A-E HeLa
3 Rhizophora mucronata Pestalotiopsis sp.
4 Not mentioned Secalonic acid D
5 Excoecaria agallocha Pestalotiopsis sp. Phomopsis-H76 B KBv200 Inactiveagainstallthe
6 Kandelia woody tissue
7 Sonneratia apetala Zh6-B1 (unidentified)
8 Xylocarpus granatum XG8D (unidentified) Merulin B
9 Acanthus ilicifolius Pestalotiopsis sp. Penicinoline
Unidentified mangrove PaeciloxocinsA 1
10 Pestalotiopsis sp.
(Taiwan Strait) Paeciloxocins B 65
11 Excoecaria agallocha Penicillium expansum
12 Kandelia candel Fusarium sp.
13 Aegiceras corniculatum Alternaria sp. ZJ9-6B
14 Rhizophora mucronata Irpex hynoides Ethyl acetate extract HEp2 125
15 Rhizophora annamalayan Fusarium oxysporum Taxol
16 Bruguiera gymnorrhiza Rhytidhysteron rufulum RhytidchromonesA MCF7 19.3
Compounds are included in the column“isolatedcompound/s”. NA-Not
Phomopsis sp. 2-(7’-hydroxyoxooctyl)- HEp2 25
ZSU-H76 zeneacetic acid ethyl ester HepG2 30
Cytosporones J-N L5178Y
Not Active up to
10 μg/mL
PestalotiopsoidA PC12
PestalotiopsoneA NA
Pestalotiopsone B NA
Pestalotiopsone C NA
L5178Y
Pestalotiopsone D NA
Pestalotiopsone E NA
Pestalotiopsone F 26.89
Mangrove endophytic HL60 0.38
fungus No. ZSU44 K562 0.43
Phomopsis-H76A KB Allthecompoundsare
Phomopsis-H76 C MCF7 Tested cell lines
Halorosellinia sp. 1-hydroxy-3-methyl KB 3.17
Guignardia sp. anthracene-9,10-dione KBv200 3.21
3R,5R-Sonnerlactone 42.4
KV/MDR
3R,5S-Sonnerlactone 41.6
BT474 4.98
MerulinA
SW620 4.84
BT474 >10
SW620 >10
BT474 1.57
Merulin C
SW620 4.11
95-D 0.57
HepG2 6.5
HeLa >100
KB >100
KBv200 >100
HEp2 >100
HepG2
A549 NR
ExpansolsA
HL-60 15.7
A549 1.9
Expansols B
HL-60 5.4
5-O-methyl-2’-methoxy-3’- HEp2 4
methylalpinumisoflavone HepG2 11
Alterporriol K MDA-MB-435 26.97
Alterporriol L MDA-MB-435 13.11
NT NT
Active; NR-Not Reported; NT-Nottested
of cancer.49 This is a method in which microbes indirectly lead to
cancer regression especially in those in whom other commonly
used treatments have failed.
Bacteria: Bacteria can be applied in various forms for therapeutic
purposes. Apart from the whole, living attenuated cells, we can
use genetically engineered bacteria expressing particularly desir-
able factors.50 Microorganisms are also applied as vectors, which
are carriers of specific chemotherapeutics agents or enzymes use-
ful in thedestruction of cancer cell. This method allows a sig-
nificant reduction of the side effects of treatment that usually
accompany traditional chemotherapy.51 Moreover, there is a thera-
peutic potential to use bacterial secretion, for example, toxins.52
Their presence in the tumor environment could have destruct the
cancer cells. The use of sporangial bacteria, which can survive
under unfavorable environmental conditions, represents another
approach, which has been applied in the experiments with Clos-
tridium novyi. This microorganism prefers anaerobic conditions,
which are found in the tumor.53 Instead of spreading over the
entire organism, the bacteria are directed to the tumor site only,
where they have the optimal conditions for growth.54 This bacte-
rial property allows the patient to be protected against the de-
velopment of serious infections. From the bacteria that used in
cancer therapy (Mycobacterium bovis BCG is a strain of mycobac-
terium bovis developed by Albert Calmett and Camille Guérin as
55 56 a tuberculosis vaccine55; Streptococcus pyogenes OK-43256; Clostridium
57 50 novyi57; Salmonella enterica50; serovar typhimurium which is obligate
anaerobes and facultative anaerobes58; Clostridium histolyticum59;
Magnetococcus marinus MC1 is a gram-negative cocci found in the
Atlantic Ocean near Rhode Island, USA.60
Toxoplasma gondii: Toxoplasma gondii is an obligatory intracellu-
larparasite.61 It is life-threatening to people with impaired immu-
nity or pregnant women, who can suffer abortion or birth malfor-
mation. It turns out that the protozoan and its lysate, toxoplasma
lysate antigen, can be used to treat cancer.60
Plasmodium falciparum: Plasmodium falciparum (Malaria) caused
by Plasmodium sp., is one of the most common parasitic diseases in
the world.62 Plasmodium falciparum is considered to be the most ma-
lignant causative agent of malaria because it aggregates erythro-
cytes and thrombocytes that adhere to the vascular endothelium,
which can lead to the closure of vascular light and thus damage to
vascular walls and even necrosis. However, despite all the negative
features of the parasite, it can be used to treat cancer.63
Mammals and milk: Natural product isolated from mammal
source is poorly studied, throughout screening for the review little
data were available. Ryan et al64 described four bovine meat-de-
rived peptides that inhibit angiotensin-converting enzyme (ACE)
and also exhibit anti-proliferative activity. A number of studies
have reported the anticancer effects of milk protein-derived pep-
tides on various cancer cells as the casein fraction-derived ca-
seinophosphopeptides (CPPs) and lactoferrin is an 80-kDa ironbinding glycoprotein that belongs to the transferrin family.65
Amphibians: Amphibians skin secretions contain a wide range of
biologically active compounds and have garnered attention due
to their potential for drug development.66 Moreover, the Chinese
traditionally administered secretions from frog skin and toad
parotid glands for medicinal purposes since ancient times. Hun-
dreds of those peptides have been identified since the discovery
of the first antimicrobial peptide from amphibian skin. Some of
the naturally occurring amphibian skin peptides and their ana-
logs proven to be cytotoxic to tumor cells only and are promising
anticancer agents for example, Alyteserin-2a, isolated from the
52 67 midwife toad (Alytes obstetricans)67; ascaphin-8 and XT-7 peptides
obtained from the skin secretions of Ascaphus truei and Silurana
tropicalis68; aurein peptides from the green and golden bell frog
(Litoria aureus) and the southern bell frog (Litoria raniformis)69; der-
maseptin B2 and B3,of the dermaseptin family, isolated from the
South American tree frog (Phyllomedusa bicolor)70; dermaseptin L1
and phylloseptin L1, isolated from the lemur leaf frog (Agalychnis
lemur).71
Reptilian: Reptilian peptides derived from crocodiles as the cat-
ionic antimicrobial peptides KT2, RT2 and RP9 from Crocodylus
siamensis leukocyte extract proven to have a great anticancer activ-
72 73 ity.72 He et al73 has reported antitumor peptides T1 and T2 derived
from the enzymatic hydrolysates of the Chinese three-striped box
turtle (Cuora trifasciata).
58 59
Animal venoms: Animal venoms and toxins consist of a complex
mixture of proteins and peptides and are rich with biologically
active peptides with potent anticancer activity.74 Among venom-
ous animals, scorpions, is a source of peptidyl neurotoxins, which
are used as tools to study different ion channels, such as the Na+,
+ + − 75 K , Ca , and Cl ion channels (Table 5). Chlorotoxin (CTX) is
a small neurotoxin of 36 amino acids that was isolated from the
venom Leiurus quinquestriatus scorpion. Initially, CTX was used as
a pharmacological tool to characterize chloride channels. CTX
can target glioma, small cell lung carcinoma, melanoma, neuro-
blastoma and medulloblastoma cells.76
Spider venom contain proteins and peptides including
enzymes (such as proteases, phospholipases, andhyaluronidases),
neurotoxins, and cytolytic peptides.77 A short cationic peptide
latarcin 2a (Ltc2a) isolated from Lachesana tarabaevivenom78 have
anticancer activity.
Venom from bees and wasps is now being studied to
design and develop new therapeutic drugs from their venom.79
Melittin peptide (26 amino acid) isolated from the honey bee Apis
mellifera, is the most studied and famous bee venom-derived pep-
tide. It inhibits different cancer cells in vitro, including leukemic,
lung tumor, astrocytoma, glioma, squamous carcinoma,ovarian
carcinoma, hepatocellular carcinoma, renal cancer cells, prostate
cancer and osteosarcoma.80 Unfortunately this peptide is toxic to
both normal and cancer cells. mastoparan is 14-amino acid cat-
ionic peptide isolated from Vespula lewisii venom that has shown
in vitro anticancer activity.81
Table 5. The Anticancer Mechanisms of Some Venomous Peptides and Indirectly Derived Drug
The proliferationand Sodium (Na+) channels AGAP Ion Channels invasion of cancer cells
The invasion, migration,
Integrins angiogenesis, and
metastasis of cancer cells α β ATN-161
G protein-coupled The metastasis of cancer Gastrin-releasing peptide
receptor cells receptor
Membrane mol- The disruption of cancer glycoproteins, PS and PC, 2 Melittin
ecules cell membrane heparansulfate
Most snake venoms are a mixture of several proteins,
peptides, toxins, enzymes and non-protein components.82 Bioac-
tive peptides from snake venoms have significantly contributed
to the treatment of many humandiseases, and some of them may
selectively target cancer cell membranes, affecting the prolifera-
tion of cancer cells.83 For example, crotamine, a polypeptide of
42 amino acids isolated from South American rattle snake venom;
cathelicidin-BF (BF-30) is a cathelicidin-like polypeptide of 30
amino acids and a natural antibacterial peptide extracted from
the venom of the snake Bungarus fasciatus; purified L-amino acid
oxidases from Bothrops leucurus which is toxic to cancer cell.84
This review aims to boost the use of natural product arising from
their anticancer activities. Natural product proven to have efficacy
asan anticancer activity already. The mechanism of action of many
products has been identified and other still under investigation.
Overall, natural product research is a vigorous tool to discover
novel biologically active components with unique mechanisms of
action. Given the diversity of nature, it is sensible to indicate that
chemical leads can be produced that are able to interact with most
therapeutic targets. As such, new and efficacious drugs can be de-
veloped by way of safety treatment of the cancer diseases and get
rid of it.
131I-TM601 Peptide (36aa) Gliomas Phase III - (131I-CTX) Chloride (Cl) channels:
CLC3 BLZ-100
Peptide (36aa) Gliomas tumor marker forsurgery Phase I (ICG-CTX)
Colon cancer cells, Malignant glioma Peptide (66aa) Preclinical studies cells
Potassium (K+) channels: peptide Ergtoxin Ovarian cancer cells Preclinical studies KV11.1(hERG) (42-62aa)
Transient receptor Solid tumors with potential(TRP) channels: SOR-C13 peptide(13aa) Phase I overexpressing the TRPV6 ion channel TRPV6
1 Glioblastoma with methylated 1 PhaseIII MGMT promoter
Peptidomimetic αvβ3, αvβ5 Cilengitide 2 Glioblastoma with (5aa) 2 PhaseII unmethylated MGMTpromoter
3 NSCLC 3 PhaseII
Peptidomimetic Malignant Glioma Phase II 5 1
Five integrin receptors Bone metastasis in metastatic breast GLPG0187 Peptidomimetic Phase I (αvβ1, αvβ3, αvβ5,vβ6,α5β1) cancer
αvβ3, αvβ5, α5β1 Vicrostatin Peptide(69aa) Ovarian cancer, Gliomas Preclinical studies
BAY86-7548 Peptide (14aa) Prostate cancer imaging Phase II/III
1 MP1 1 Peptide (14aa) 1 Human leukemic Jurkatcells
Sialic acid-rich 2 Human renal cancer, lung cancer, 2 Peptide (26aa) Preclinical studies liver cancer,etc.
3 Mastoparan 3 Peptide (14aa) 3 Pancreatic cancer cells
Phospholipids Hemilipin heterodime HUVECs and HPAECs Preclinical studies
The authors declare that they have no conflicts of interest