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  • Systematic Review
  • OPEN ACCESS

Activity of Brazilian Cerrado Plants in Tumor Cell Lines: A Systematic Review

  • Gabriela Silva Neubern de Oliveira1,
  • Cassia Senger2 and
  • Rodrigo Cardoso de Oliveira1,* 
 Author information  Cite
Future Integrative Medicine   2024;3(1):50-62

doi: 10.14218/FIM.2023.00042

Abstract

Background and objectives

Medicinal plants have been recognized as a promising alternative treatment against some types of cancer, being rich sources of effective biochemical agents. The aim of this study, therefore, was to gather, through a systematic literature review, articles related to plants from the Brazilian Cerrado biome that have an action on different tumor cells.

Methods

Different keywords were used in the search mechanisms of Pubmed, Scielo, Science Direct, Scopus, and Lilacs databases. Of the studies found, titles that did not reflect the purpose of this review, those that did not provide access to the full text, and those that were published before 2005 were excluded. Articles referring to the activity of Cerrado plants in tumor cells published in the last sixteen years were selected, totaling thirty-nine articles. Registration number of this review: #CRD42020205579.

Results

The extracts from the studied plants demonstrated significant antiproliferative effects against several tumor cell lines. 39 species of plants were identified belonging to the families: Combretaceae, Annonaceae, Celastraceae, Verbenaceae, Solanaceae, Myrtaceae, Rubiaceae, Bignoniaceae, Erythroxylaceae, Sapotaceae, Asteraceae, Elaeocarpaceae, Apocynaceae, Anacardiaceae, Calophyllaceae, Lythraceae, Mimosaceae, and Morseraceae. The extracts were obtained from different parts of the plants and different fractions were used.

Conclusion

It can be concluded that the Cerrado contains a wide variety of plants with antitumor actions, and further studies are needed to discover other species with anticancer potential, in addition to in vivo studies.

Keywords

Cerrado, Medicinal plants, Cancer, Tumor cell

Introduction

Cancer is characterized by uncontrolled cell growth or cell proliferation capable of invading other tissues. There are approximately one hundred types that are named for the tissue, organ, or cell type in which the disease begins. Chemicals, radiation, inadequate diet, infection, environmental factors, and smoking are some of the main risk factors.1 The disease is a relevant problem for public health and the treatment represents an obstacle, as it is often unsuccessful. It is considered the main cause of death in developed countries and the second in developing countries, leading to a considerable increase in health costs and the great need for a better understanding of its mechanisms to control the disease through the development of more effective therapies.2,3

Concerning cancer treatment, medicinal plants represent a promising alternative. These are a source of important bioactive molecules with wide structural diversity that generally demonstrate less toxicity and greater selectivity against tumor cells.4 Furthermore, they have also been shown to decrease the side effects induced by synthetic drugs and increase the survival rate for many patients.5 Moreover, it is recognized that many natural products have a rich chemical diversity, being a source for the identification of new structures and, consequently, for the manufacture of new drugs.6 Currently, the sources of natural products used for developing drugs against cancer include, in addition to plants, marine organisms and microorganisms, being more diversified now than in the past. However, plants remain a promising source of natural products for chemoprevention, as about 25% of currently available therapies derive from plants.7,8

The Cerrado, known as the “Savanna of the Tropical Lands”, is a Brazilian biome that occupies about 20% of the national territory. The vegetation, quite heterogeneous, with taxonomic biodiversity that is even greater than that of the Amazon Forest, occurs especially in the states of Mato Grosso, Goiás, Minas Gerais, São Paulo, and Ceará. The region is considered a global biodiversity hotspot and contains several plant species that are widely used in folk medicine and scientific research. Due to its considerable diversity, there is a growing interest in the Cerrado regarding the discovery of new medicinal plants with bioactive compounds (http://www.mma.gov.br/biomas/Cerrado ).9,10 The species present in the biome are already used by local communities for the treatment of several diseases and research with biological models has already demonstrated the promising potential of several molecules from these species.11 The beneficial action of its plants has already been proven in inflammatory processes against microorganisms and cancer, among other diseases.12

The search for new drugs that exhibit action against various types of tumors is one of the most interesting topics in the field of natural product research.13 In this area, plants are considered very promising, since their derivatives are widely used for cancer control. An example is Catharanthus roseus (Apocynaceae), a plant from which Vinblastine (Velban®) and Vincristine (Oncovin®) were isolated and used in the treatment of various types of tumors.14 Interruption of the cell cycle, induction of apoptosis, and inhibition of angiogenic factors in cancer cells are important effects associated with these plant-based drugs.15 In this sense, the Cerrado stands out, as many compounds with important biological activities have already been obtained from plants in this biome.13

Given the importance of the above subject, this study aimed to gather and discuss, through a systematic literature review, articles related to plants from the Brazilian Cerrado biome that have action on different tumor cells.

Methods

The present systematic review is registered in the PROSPERO database (International Prospective Register of Systematic Reviews) under registration number #CRD42020205579.

Types of study

Articles related to the effects of plants from the Brazilian Cerrado biome on human and animal tumor cells that used plausible control groups for the study (untreated, vehicle, treated vehicle, and standard chemotherapeutics), in vitro, published between 2005 and 2020, in English or Portuguese languages were included. Methods, time, and concentration of extracts/compounds were not considered. The information about the plants gathered in this article includes species, popular name, part of the plant used, type of extract, target cell, probable main active of the extracts, and mode of action.

Search strategy

Our research on the action of Brazilian Cerrado plants on tumor cells was carried out using Pubmed, Science Direct, and Scopus. Date filter (2005–2020), full text, and article type (research articles) were applied. The search included free text and medical subject heading terms: 1) Cerrado plants and Tumor Cell Lines; 2) Medicinal Plants and Cerrado and Tumor Cell Lines; 3) Medicinal Herbs and Cerrado and Tumor Cell Lines; 4) Phytotherapy and Cerrado and Tumor Cell Lines, and 5) Pharmaceutical Plants and Cerrado and Tumor Cell lines. The last survey update was in January/2021 (Fig. 1).

Flowchart of study selection.
Fig. 1  Flowchart of study selection.

Results

A total of 225 scientific articles were selected from the five databases consulted. After excluding duplicate titles, unrelated abstracts, and “not open access” articles, 35 articles remained. After a free search, 4 articles were included, totaling 39 scientific articles. Thirty-nine plant species are cited, along with the popular name, part of the plant used, type of extract, target cell, and reference (Table 1).8,12,16–53 The species are distributed among 33 genera and 20 families. The families include: Combretaceae (Terminalia fagifolia), Annonaceae (Annona coriaceae, Annona crassiflora, Cardiopetalum calophyllum), Celastraceae (Austroplenckia populnea, Salacia crassifolia, Maytenus ilicifolia), Verbenaceae (Lippia salviaefolia), Solanaceae (Solanum lycocarpum), Myrtaceae (Myrcia falax, Myrcia bella, Campomanesia adamantium, Myrcia guianensis, Psidium guineense), Rubiaceae (Palicourea rigidum, Ixora brevifolia), Bignoniaceae (Pyrostegia venusta, Tabebuia avellanedae), Erythroxylaceae (Erythroxylum suberosum, Erythroxylum daphnites and E. subrotundum), Sapotaceae (Pouteria pie, Pouteria ramiflora), Asteraceae (Calea pinnatifida, Chresta sphaerocephala, Eremanthus matogrossensis, Eremanhus seidelii and Lychnophora trichocarpha), Elaeocarpaceae (Sloanea garckeana), Apocynaceae (Calotropis procera), Anacardiaceae (Anacardium humile), Calophyllaceae (Kielmeyera coriacea), Lythraceae (Lafoensia pacari), Mimosaceae (Mimosa caesalpiniifolia), Burseraceae (Protium ovatum), Faba ceae (Senna velutina, Dipteryx alata Vog, Stryphnodendron adstringens and Zornia brasiliensis) and Moraceae (Brosimum gaudichaudii) (Table 1).

Table 1

Description of details about plant species of Brazilian Cerrado, popular name, parts used, type of extract (fraction), tumor cell lines, and references

SpeciesPopular nameUsed part of the plantExtract typeTarget cellReferences
Anacardium humile
Brosimum gaudichaudii
Tabebuia avellanedae		‘Cajuzinho’
‘Inharé’
‘Purple ipê’		Bark (c) and leaves (f)
Bark (c) and leaves (f)
Bark (c) and leaves (f)		EthanolicNCI- H292 (lung) (−)
HEp-2 (larynx) (−)
HT-29 (colon) (−)
HL-60 (promyelocytic leukemia) (−)
MCF-7 (breast) (C, F,+)
NCI- H292 (F, +), HEp-2 (−)
HT-29 (F, +), HL-60 (−)
MCF-7 (C, +)
NCI- H292 (−), HEp-2 (F +)
HT-29 (−), HL-60 (F +)
MCF-7 (−)		16
Annona coriácea‘ Marola’
‘Araticum-liso’		SeedsMethanolicUACC-62 (melanoma), MCF-7 (breast), NCI/ADR/RES (ovary), 786-0 (kidney), NCI-H460 (lung), OVCAR-3 (ovary), HT-29 (colon), K562 (leukemia), UA251 (glioma) (+)17
Annona crassiflora‘Araticum’Seeds and barkPhenolicNCI/ADR/RES (ovary) (+)
U251 (glioma) (+)
MCF-7 (breast) (+)
NCI-H460 (lung) (−)
PC-3 (prostate) (+)
OVCAR-03 (ovary) (+)
HT-29 (colon) (+)
K562 (leukemia) (+)		18
Austroplenckia
Populnea		‘Mangabarana’
‘Marmelo-do-campo’
‘Mangabeira-brava’		FruitPure compounds (proanthocyanidin A and 4′-O-methyl-epigallocatechin)
Three pure extracts (ethanol, ethyl acetate and chloroform)		A549 (lung) (+)
HS578T (breast) (+)
MCF-7 (breast) (+)
A549 (−)
HS578T (−), MCF-7 (−)		19
Calea pinnatifida‘Quebra-tudo’
‘Cipó-cruz’
‘Aruca’		LeavesDichloromethaneUACC-62 (melanoma) (+)
MCF-7 (breast) (+)
786-O (kidney) (+)
NCI-ADR/RES (ovary) (+)
NCI-H460 (lung) (+)
PC-3 (prostate) (+)
OVCAR-3 (ovary) (+)
HT29 (colon) (+)
K-562 (leukemia) (+)		20
Calotropis procera‘Algodão de seda’
‘Leiteiro’
‘Queimadeira’
‘Ciúme’		BarkEthyl acetate, acetone
Hexane, methanolic dichloromethane		B-16/F10 (melanoma - murine) (+)
HCT-8 (human colon) (+)
CEM (human leukemia) (+)
B-16/F10 (−)
HCT-8 (−)
CEM (−)		21
Campomanesia adamantium
Cardiopetalum calophyllum
Protium ovatum		‘Guavira’
‘Imbirinha’
‘Almecega’		Leaves
Leaves
Leaves
Green fruits		Essential oilMCF-7 (breast) (+)
HeLa (cervical) (+)
M059J (glioblastoma) (+)
MCF-7 (+), HeLa (+), M059J (+)
MCF-7 (−), HeLa (−), M059J (+)
MCF-7 (−), HeLa (−), M059J (−)		22
Chresta sphaerocephala‘João-bobo’Leaves
Bark (B)		Hexanic (L)
Hexanic (B)
Methanolic
Ethyl acetate		U251 (glioma) (+), UACC-62 (melanoma) (+)
MCF7 (breast) (−), NCI-ADR/RES (ovary) (+)
786-0 (kidney) (+), NCI-H460 (lung) (+)
OVCAR-3 (ovary) (+), PC-03 (prostate) (+)
HT29 (colon) (+) e K-562 (leukemia) (+)
U251 (−), UACC-62 (+), MCF-7 (+)
NCI-ADR/RES (−), 786-0 (−), NCI-H460 (−)
OVCAR-3 (+), PC-3 (+), HT29 (−), K-562 (+)
Showed no antiproliferative effect
Showed no antiproliferative effect		12
Dipteryx alata Vog.‘Baru’SeedsPhenolicHT29 (colon) (+)23
Eremanthus matogressensis
Eremanthus seidelii		Uninformed
Uninformed		Leaves
Leaves		Isolated compound
isolated compound		T98G (+) e U87MG (+) (glioblastoma)
T98G (−), U87MG (−)		24
Erythroxylum daphnites‘Fruta-de-pomba’LeavesHexanicSCC-9 (oral) (+)25
Erythroxylum daphnites
Erythroxylum suberosum
Erythroxylum subrotundum
Pouteria ramiflora
Pouteria torta		‘Mercurinho’
‘Fruta-de-veado’		Leaves
Leaves
Leaves
Leaves
Leaves		Aqueous
Ethanolic
Hexanic
Aqueous
Ethanolic
Hexanic
Aqueous
Ethanolic
Hexanic
Aqueous
Ethanolic
Hexanic		FaDu (−), SCC-25 (−), SCC-9 (−)
FaDu (−), SCC-25 (−), SCC-9 (−)
FaDu (−), SCC-25 (+), SCC-9 (+)
FaDu (+), SCC-25 (+), SCC-9 (−)
FaDu (+), SCC-25 (−), SCC-9 (−)
FaDu (+), SCC-25 (−), SCC-9 (+)
FaDu (−), SCC-25 (−), SCC-9 (−)
FaDu (+), SCC-25 (−), SCC-9 (−)
FaDu (+), SCC-25 (−), SCC-9 (−)
FaDu (−), SCC-25 (−), SCC-9 (−)
FaDu (−), SCC-25 (−), SCC-9 (−)
FaDu (+), SCC-25 (−), SCC-9 (−)
SCC-25, SCC-9 (tongue)/FaDu (hypopharynx)
FaDu (+), SCC-25 (−), SCC-9 (−)
FaDu (+), SCC-25 (−), SCC-9 (−)
FaDu (−), SCC-25 (−), SCC-9 (−)		26,27
Erythroxylum
suberosum		‘Cabelo-de-negro’LeavesAqueous
Ethanolic
Hexanic		SCC-9 (oral) (+)
FaDu (hypopharynx) (+)
SCC-9 (−), FaDu (+)
SCC-9 (−), FaDu (−)		28
Ixora brevifolia‘Ixora-arborea’TwigsCrude and hydroethanolic extract, hexanicU251 (glioma) (+)
K562 (leukemia) (+)		29
Kielmeyera coriacea‘Pau-santo’Fruits and LeavesEssential oilMDA-MB-231(breast) (+)
DU-145 (prostate) (+)
MDA-MB-231 (−)
DU-145 (−)		30
Kielmeyera coriacea‘Pau-santo’Root barkHexanicHL-60 (leukemia) (+)
HCT-8 (colon) (+)
MDA-MB-435 (breast) (+)
SF-295 (glioblastoma) (+)		31
Kielmeyera coriaceaUninformedLeavesChloroform
Hydroalcoholic
Ethyl acetate
Hexanic
Heptane		B16F10-Nex2 (melanoma murino) (+)
HCT (colon) (+), Siha (cervical) (+)
A2058 (melanoma) (+), SKmel28 (melanoma) (+) and MeWO (melanoma) (+)
B16F10-Nex2 (−)
B16F10-Nex2 (−)
B16F10-Nex2 (−)
B16F10-Nex2 (−)		32
Lafoensia pacari‘Dedaleira’
‘Mangava-brava’		Stem barkMethanolicTRH- 18 (+) (colorectal)33
Lafoensia pacari‘Dedaleira’
‘Mangava-brava’		Stem barkEthanolicH460 Human NSCLC (lung) (+)
A549 (NSCLC, adenocarcinoma) (+)
H2023 (NSCLC, adenocarcinoma) (+)
E9 murina (lung) (+)		34
Lafoensia pacari‘Dedaleira’
‘Mangava-brava’		Stem barkMethanolic and fractionsU-937 (+), Jurkat
Daudi (leukemia) (+)		35
Lippia salviaefoliaUninformedAerial partsAromadendrin
Phloretin		HEK-293 (kidney) (−)
M14 (melanoma) (+)
HEK-293 (+)		36
Lychnophora trichocarpha
Spreng.		‘Arnica
brasileira’		Aerial partsEthanolic
Lychnopholide		30 human tumor cell lines37
Maytenus ilicifolia‘Espinheira santa’Root barkEthanolicHL-60 (leukemia) (+)
K-562 (chronic myelocytic leukemia) (+)
SF-295 (glioblastoma) (+)
HCT- 8 (colon) (+)
MDA/MB-435 (melanoma) (+)		38
Mimosa caesalpiniifolia‘Sabiá’
‘Sansão-do-campo’		LeavesEthanolicMCF-7 (breast) (+)39
Myrcia bella‘Mercurinho’LeavesHydroalcoholicACP02 (gastric) (+)40
Myrcia bella
Myrcia falax
Myrcia guianensis		‘Jacarezinho’
Uninformed
Uninformed		Leaves
Leaves
Leaves		HydroethanolicK562 (+), MCF-7 (+),
786-0 (−), NCI-H460 (−)
PC-3 (−), HT-29 (−)
K562 (+), MCF-7 (−),
786-0 (−), NCI-H460 (−)
PC-3 (−), HT-29 (−)
K562 (leukemia) (+), MCF-7 (breast) (+)
786-0 (kidney) (−), NCI-H460 (lung) (−)
PC-3 (prostate) (−), HT-29 (colon) (−)		27,41
Palicourea rígida‘Douradão’LeavesEthanolic extract (isolated compound)SK-MEL-37 (melanoma) (+)42
Pouteria tortaa‘Guapeva’LeavesHexanic
Ethanolic
Aqueous		OSCC-3 (oral) (+)
MCF-7 (breast) (+)
OSCC-3 (+)
MCF-7 (+)
OSCC-3 (+)
MCF-7 (+)		43
Psidium guineense‘Goiabinha-araçá’
‘Araçá-do-campo’
‘Araçá verdadeiro’
‘Goiabinha selvagem’		LeavesEssential oilOVCAR-3 (ovary) (+)
U251 (glioma) (+), MCF-7 (breast) (+)
NCI-ADR/RES (ovary) (+), 786-0 (kidney) (+)
NCI-H460 (lung) (+), PCO-3 (prostate) (+)
HT-29 (colon) (+), K-562 (leukemia) (+)		44
Pyrostegia venusta‘St. John vine’FlowersHeptane
Hydroalcoholic		B16F10-Nex2 (murine melanoma) (+)
B16F10-Nex2 (−)		45
Salacia crassifolia‘Bacupari-do-Cerrado’
‘Saputá’
‘Seputá’		Stem barkHexanic
Dichloromethane
Ethyl acetate
Hydroalcoholic
Hexanic
Dichloromethane
Ethyl acetate
Hydroalcoholic
Hexanic
Dichloromethane
Ethyl acetate
Hydroalcoholic		MDA-MB-435 (melanoma) (+)
MDA-MB-435 (−)
MDA-MB-435 (−)
MDA-MB-435 (−)
HCT-8 (colon) (+)
HCT-8 (−)
HCT-8 (+)
HCT-8 (−)
SF-295 (central nervous system) (+)
SF-295 (−)
SF-295 (−)
SF-295 (−)		46
Salacia crassifolia‘Bacupari-do-Cerrado’Root woodHexanicColo205 e KM12 (colon) (+)
A498 e U031 (kidney) (+)
HEP3B and SKHEP (liver) (−)
MG63 and MG63.3 (osteosarcoma) (+)		47
Senna velutina‘Fedegosão’LeavesEthanolicJurkat (+) e K562 (+) (leukemia)27,48
Solanum lycocarpum‘Fruit-of-wolf’
‘Lobeira’ or ‘Jurubebão’		FruitGlycoalkaloidHepG2 (liver) (+)
B16F10 (murine melanoma) (+)
HT29 (colon), MCF-7 (breast) (+)
HeLa (cervical) (+), HepG2 (liver) (+)
MO59J, U343 e U251 (glioblastoma) (+)		49
Sloanea garckeanaa‘Urucurana Brava’LeavesMethanolic
Hexanic
Chloroform
Ethyl acetate		UACC-62 (melanoma) (+), NCI-460 (lung) (+)
MCF-7(breast) (+), NCI-ADR (breast) (+)
HT-29 (colon) (+), OVCAR (ovary) (+)
C786-0 (kidney) (+) e PCO-3 (prostate) (+)		50
Stryphnodendron adstringens‘Barbatimão’ or ‘Casca-da-mocidade’Stem barkAqueousB16F10Nex-2 (melanoma) (+)51
Terminalia fagifolia‘Capitão-do-mato’
‘Mirindiba’
‘Pau-de-bicho’		Bark and leavesEthanolicPC3 (prostate) (+)
B16F10 (murine melanoma) (+)		52
Terminalia fagifolia‘Capitão’
‘Capitão -do-Cerrado’
‘Capitão-do-campo’
‘Mirindiba’		Stem barkEthanolic
and fractions		MCF-7 (breast) (+)8
Zornia brasiliensis‘Urinária’
‘Urinana’
‘Carrapicho’		Aerial partsEthanolicHL60 (promyelocytic leukemia) (+)
MCF-7 (breast) (−)
HCC1954 (breast) (−)
T-47D (breast) (−)
4T1 (breast) (−)
HL60 (promyelocytic leukemia) (−)		53

Data set from all relevant studies. aSource: https://www.sibbr.gov.br/ . (+) , effect on tumor cells; (−), null or very low effect.

The major components of the extracts and probable mode of action on tumor cells are presented in Table 2. In general, the major effects of plant compounds are on the modulation of the cellular cycle (proliferation, DNA synthesis, and apoptosis) of tumor cell lines. Some compounds (flavonoids) have free radicals scavenging and antioxidant capacities (Table 2, Fig. 2).16,18–21,24–26,30,31,33,36–46,48–53

Table 2

Description of details of Brazilian Cerrado plant species, major compounds, and probable mode of action

SpeciesCompound and mode of actionReferences
Anacardium humile
Erythroxylum suberosum
Myrcia falax
Sloanea garckeana
Tabebuia avellanedae
Terminalia fagifolia
Zornia brasiliensis		Phenolic compounds - free radical scavenging (A. humile) (T. fagifolia)
Flavonoids - free radical scavenging, prevention of cancer progression, DNA repair and stimulation of the immune system, and an ability to effect the pathway that regulates cell growth and proliferation and tumor formation (T. avellanedae)		16,50,53
Annona crassiflora
Austroplenckia populnea
Brosimum gaudichaudii
Lippia salviaefolia
Myrcia bella
Senna velutina		Flavonoids - antioxidant; free radical scavenging, DNA repair, and immune system stimulation16,18,19,36,40,48
Calea pinnatifidaSesquiterpenes (germacranolides) - potent induction of apoptosis and inhibition of nuclear factor kappa B20
Calotropis proceraCardiotonic glycoside steroids - activation of apoptotic pathways21
Chresta sphaerocephala
Erythroxylum daphnites
Erythroxylum subrotundum
Pouteria ramiflora
Pouteria torta
Salacia crassifólia		Triterpenes - inhibition of tumor growth and cell cycle progression and induction of apoptosis of tumor cells in vitro and in vivo25,43,46
Dipteryx alata
Myrcia spp		Phenolic compounds
Gallic acid (GA) - regulation of several signaling pathways; inhibit proliferation
Gallotannins (GT) - suppression of NFκB activation induced by tumor necrosis factor (TNF-α)
Antioxidants		41,52
Eremanthus matogressensis
Eremanthus seidelii		Sesquiterpene lactones (goyazensolide and lychnofolide) - possible interference in angiogenesis internally and in tumor microenvironment remodeling externally through the ability to degrade proteoglycans24
Erythroxylum suberosum
Mimosa caesalpiniifolia		Catechins - antioxidant26,39
Kielmeyera coriaceaElemen-type sesquiterpenes - inhibition of cell proliferation, stimulation of apoptosis, and induction of cell cycle arrest in the malignant cell30
Kielmeyera coriaceaδ-tocotrienol and dimer - arrest of cell cycle progression/induction of cell apoptosis31
Lafoensia pacariElagitannins - apoptogenic effects
Ellagic acid - regulation of cyclin E (up-regulation), A and B1 (down-regulation) levels, ability to retain cells in the G1/S phase of the cell cycle		33
Lychnophora trichocarphaSesquiterpene lactones - inhibition of enzymes involved in essential biological processes such as DNA and RNA synthesis, protein and purine synthesis, glycolysis, the citric acid cycle, and the mitochondrial electron transport chain.37
Maytenus ilicifoliaPristimerin (triterpenoid) - inhibition of DNA synthesis and ability to trigger apoptosis38
Palicourea rigidaMonoterpenic indole alkaloid called vallesiachotamine - promotion of G0/G1 cell cycle arrest, apoptosis, and necrosis.42
Psidium guineenseSesquiterpenic alcohol - induction of apoptosis44
Pyrostegia venustaAlkanes - induction of cell cycle arrest and apoptosis45
Senna velutinaFlavonoids (epigallocatechin, epicatechin, kaempferol heteroside, rutin) and dimeric and trimeric proanthocyanidin derivatives - induction of leukemic cell death by activating intracellular calcium and caspase-3, ability to decrease mitochondrial membrane potential and interrupt the cell cycle in S and C phases G2.48
Solanum lycocarpum
Ixora brevifolia		Alkaloids - ability to change cell morphology and DNA - irreversible apoptosis, regulation of caspases, regulation of death receptor expression (Example: Tumor necrosis factor receptor I (TNFR-I)).29,49
Stryphnodendron adstringensPhenolic compounds and polyphenols
Gallic acid, gallocatechin, epigallocatechin, dimeric and trimeric proanthocyanidins - antioxidant activity through direct scavenging of free radicals, oxidative hemolysis, inhibition of lipid peroxidation in human erythrocytes, apoptosis-induced cell death through increased levels of intracellular reactive oxygen species (ROS), and induction of mitochondrial membrane potential dysfunction and caspase-3 activation		51

Each compound, found in a specific plant, has a possible mode of action or a target.

Chemical structures of some of the major compounds mentioned in .
Fig. 2  Chemical structures of some of the major compounds mentioned in Table 2.

All plants and their main information (photos, geographic distribution, etc.) can be found on the main platform: http://floradobrasil.jbrj.gov.br .

Discussion

A total of thirty-nine species of medicinal plants from the Brazilian Cerrado biome that have antitumor properties were identified. The species are distributed among 33 genera and 20 families. In most previous studies leaves were used to carry out the tests, and their use as sources of active compounds is a relevant strategy for the sustainable management of endemic species, since it does not compromise the survival of the species.54 In addition to the leaves, stem, trunk bark, root bark, flowers, fruits, seeds, essential oils, and isolated compounds were also used. It must be considered here that different parts of the same plant can synthesize and accumulate different secondary metabolites or different amounts of a certain compound.55

The main compounds responsible for the antitumor potential and for several other pharmacological activities, such as antimicrobial, antioxidant, anti-inflammatory effects against intestinal and respiratory diseases include cardiotonic glycoside steroids (C. procera), phenolic compounds and tannins (A . humile), alkaloids (S. lycocarpum), phenolic acids (A. coriacea), flavonoids - quercetin (A. crassiflora), triterpenes (M. ilicifolia, P. torta, C. sphaerocephala), sesquiterpenes – germacranolides - (C. pinnatifida), flavonoids (E. suberosum, A. populnea, A. coriacea, T. avellanedae, L. salviaefolia, C. procera; E. suberosum; M. caesalpiniifolia, M. bella, M. falax, S. velutina; E. subrotundum, P. ramiflora), spathulenol, germacrene-B and β-caryophyllene oxide (C. adamantium leaves); spathulenol, β-caryophyllene, and β-myrcene (P. ovatum leaves); β-myrcene, α-pinene and limonene (P. ovatum green fruits), spathulenol, viridiflorol, and (Z,E)-farnesol (C. calophyllum leaves), oleic acid and phenolic compounds - gallic acid (D. alata Vog ., S. adstringens), sesquiterpene lactones (L. trichocarpha, E. matogressensis; E. seidelii), triterpenes (E. daphnites), catechins (E. suberosum), lignan syringaresinol and cyclopeptide alkaloids (I. brevifolia), D- germacrene, neo-intermedeol, bicyclogermacrene, Viridiflorol, Globulol, Epi-α-muurolol and δ-cadinene (K. coriacea), δ-tocotrienol and its dimer (K. coriacea), 1-eicosanol, 1-docosanol, and 2- nonadecane (K. coriacea), ellagic acid and others (L. pacari), isomers of galoyl glucose (M. guianensis), monoterpene indole alkaloid (P. rigida), sesquiterpene alcohol spathulenol (P. guineense), alkane (P. venusta)), triterpenes, quinonamethides (S. crassifolia), phenolic compounds (S. garckeana, S. adstringens; T. fagifolia; Z. brasilienses), polyphenols (S. adstringens) and zornioside (Z. brasilienses).

Of all the compounds with antitumor properties presented above, flavonoids appear most frequently. The anticancer action of flavonoids occurs through their effect on the scavenging of free radicals, DNA repair, and stimulation of the immune system.8 In general, the compounds present different modes of action: 1) Arrest of cell cycle progression/induction (triterpenes, gallic acid, element-type sesquiterpenes, δ-tocotrienol and dimer, ellagic acid, monoterpenic indole alkaloid, alkanes)20,25,31,33,41,42,45; 2) Inducer apoptosis (sesquiterpenes, cardiotonic glycoside steroids, Triterpenes, δ-tocotrienol and dimer, elagitannins, pristimerin, alkanes, alkaloids)20,21,25,31,33,38,42,45; 3) Inhibition of nuclear factor kappa B (sesquiterpenes, gallotannins)20,52; 4) Inhibition of DNA synthesis (sesquiterpene lactones, pristimerin),37,38 and 5) DNA repair (flavonoids).16Table 2 presents the major component of the species and the probable mode of action in inhibiting tumor cells. It is noteworthy that plant extracts have thousands of active compounds; here we have gathered just a few of the compounds that were identified in the research.

Cancer cell lines used in previous research include breast, brain, colon, lung, blood, skin, liver, kidney, prostate, ovary, mouth, larynx, and stomach cells, the majority of which are of human origin. According to Caneschi et al.19 and as mentioned by Liu et al.,56 some cell types, such as lung and breast, are more frequently used because they are widely studied in research involving analysis. cytotoxic and because they can be easily used for comparison with different compounds. Regarding the nature of the study, the research used in vitro assays, or more specifically, cell culture. This is an accepted substitute for animal models as its application reduces the number of animal experiments, which is a relevant characteristic of this method.57 Furthermore, these methods are inside the 3Rs principles: replacement, reduction, and refinement, providing stimulation for alternative research, reduction of the use of animals, and an ethical framework for researchers.58,59

Regarding the type of extract, we can verify that ethanolic, methanolic, phenolic, hexane, aqueous, chloroform, hydroalcoholic, hydroethanolic, heptanoic, glycoalkaloid, ethyl acetate, and acetone extracts were used depending on the solvent used to prepare the extract as different solvents produce higher or lower extractive yields and show differences in polarity and, consequently, in the class of compounds extracted from the extract; ethanolic and aqueous extracts, for example, which are the most polar, are rich in polyphenols.28Table 1 shows the types of extracts and details that were discussed in this review, which include species, common name, plant part used, and target cell. In front of each cell line, a positive or negative sign was placed; the sign (+) means that the extract inhibited the tumor cell (regardless of the method) and the sign (−) indicates a null or very low effect. Differences are seen according to the solvent used and this fact is due to the compounds that are extracted according to the solvent, as discussed above.

Conclusion

In view of the data, we conclude that the Brazilian Cerrado biome contains a wide variety of species with antitumor properties and more detailed research is needed to isolate bioactive secondary metabolites with cytotoxic properties. The evaluation of the chemical structure of these compounds is capable of enabling more extensive biological evaluations; thus, additional studies with the fractionated extracts and isolated compounds should be carried out to determine the complete antitumor therapeutic potential of these plants and, also, as future studies, in vivo assays. Moreover, further studies are needed to discover other Cerrado species with antitumor potential.

Declarations

Acknowledgement

We would like to thank to Bauru School of Dentistry and the University of São Paulo.

Data sharing statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Funding

We would like to thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for its financial support (#308897/2021-8). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) Finance Code – 001.

Conflict of interest

The authors declare no conflict of interests.

Authors’ contributions

Study concept and design (GSNO, RCO), acquisition of data (GSNO, CS), analysis and interpretation of data (GSNO), drafting of the manuscript (GSNO, CS), critical revision of the manuscript for important intellectual content (GSNO, CS, RCO). All authors have made a significant contribution to this study and have approved the final manuscript.

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Activity of Brazilian Cerrado Plants in Tumor Cell Lines: A Systematic Review

Gabriela Silva Neubern de Oliveira, Cassia Senger, Rodrigo Cardoso de Oliveira
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