# Medicinal Plants and Other Living Organisms with Antitumor Potential against Lung Cancer

Authors: Luara de Sousa Monteiro; Katherine Xavier Bastos; José Maria Barbosa-Filho; Petrônio Filgueiras de Athayde-Filho; Margareth de Fátima Formiga Melo Diniz; Marianna Vieira Sobral
Journal: Evidence-Based Complementary and Alternative Medicine
 (2014)

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## Abstract

Lung cancer is a disease with high morbidity and mortality rates. As a result, it is often associated with a significant amount of suffering and a general decrease in the quality of life. Herbal medicines are recognized as an attractive approach to lung cancer therapy with little side effects and are a major source of new drugs. The aim of this work was to review the medicinal plants and other living organisms with antitumor potential against lung cancer. The assays were conducted with animals and humans, and Lewis lung carcinoma was the most used experimental model. China, Japan, South Korea, and Ethiopia were the countries that most published studies of species with antitumor activity. Of the 38 plants evaluated, 27 demonstrated antitumor activity. In addition, six other living organisms were cited for antitumor activity against lung cancer. Mechanisms of action, combination with chemotherapeutic drugs, and new technologies to increase activity and reduce the toxicity of the treatment are discussed. This review was based on the NAPRALERT databank, Web of Science, and Chemical Abstracts. This work shows that natural products from plants continue to be a rich source of herbal medicines or biologically active compounds against cancer.


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## Body

## 1. Introduction

Cancer is a collection of heterogeneous genetic diseases united by common alterations in multiple cellular signaling pathways [1]. Various hallmarks have been proposed for cancer cells. Evasion of programmed cell death or apoptosis has been recognized as one of the main alterations that dictate malignant growth [2]. Furthermore, other features include self-sufficiency in growth signaling, deregulation of cellular energetics, sustained angiogenesis, evasion of immune detection, and tissue invasion and metastasis [1–3]. In addition, two characteristics of cancer that facilitate acquisition of these hallmarks have been described: genome instability and mutation tumor-promoting inflammation [2]. Coordinated processes such as cell proliferation, differentiation, and apoptosis are modified, producing altered cellular phenotypes with these specific characteristics [1, 2].According to the World Health Organization (WHO), cancer represents noncommunicable diseases responsible for 63% of deaths worldwide, where it is characterized as the second cause of death in western countries [4, 5]. Its incidence is strongly affected by demographic aspects, such as population aging, eating habits, and, in particular, environmental factors such as exposure to ultraviolet rays. The International Agency for Research on Cancer (IARC) estimates that there were 12.7 million new cancer cases in 2008 and that this number is expected to grow to 21.4 million by 2030 [6, 7].Lung cancer is currently the malignant tumor with the highest mortality rate worldwide, often because it is not detected until there has been substantial progression of the illness, which leads to a significant reduction in quality of life of the patient [8]. Different factors are pointed out as possible causes of lung cancer, including active cigarette smoking, exposure to secondhand cigarette smoke (passive smoking), pipe and cigar smoking, exposure to indoor and outdoor air pollution, exposure to radiation, and occupational exposure to agents such as asbestos, nickel, chromium, and arsenic [9]. The most important risk factor is smoking [10] and the incidence rates of lung cancer are generally higher among men than women [11]. Lung cancer is classified into nonsmall cell lung carcinoma (NSCLC), including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, which represents 80% of all lung cancer cases, and the remaining cases are small cell lung carcinoma (SCLC) [11, 12]. Recently, a new classification was published that defined “molecular subtypes” of lung cancer based on specific actionable genetic aberrations [13]. Many strategies have been studied for lung cancer chemoprevention and treatment, including STAT3 pathway inhibition (e.g., curcumin), cell-cycle arrest (e.g., gambogenic acid), hTERT silencing, miRNA modulation, iNOS suppression, chitin inhibition, angiotensin receptor blockade, TGF-β antagonism, VEGFR-2/EGFR inhibition (e.g., vandetanib), and Nrf2 activation [14]. Some strategies have been proven effective in human trials, for example, the use of ceritinib, a new ALK (anaplastic lymphoma kinase gene) inhibitor, in patients with advanced lung cancers harboring genetic alterations in ALK, in a phase 1 study [15]. In addition, the study of tumor-associated biomarkers has grown with the aim of reducing the mortality rate of lung cancer by early diagnosis and prognosis [16]. Another approach that has been studied is the use of the cancer stem cell model, which offers new insights into the limitations of current cancer treatments [17]. New opportunities for targeted therapy are under development based on the discovery of multiple molecular mechanisms underlying the development, progression, and prognosis of lung cancer. Among them, the targeted inhibition of the vascular endothelial growth factor (VEGF) or epidermal growth factor (EGF) signaling pathways has been clinically validated in the treatment of advanced NSCLC [18].Nowadays, surgery, chemotherapy, radiation, hormones, and immunotherapy are the main approaches for the cancer treatment, often supplemented by other complementary and alternative therapies, such as herbal medicines. Although chemotherapy is the method most used, several problems are associated with its use, including limited efficacy, severe toxicity, and multidrug resistance [19].Plants have a long history of use in the treatment of cancer and continue to be a major source of new drugs [20]. Herbal medicines have been recognized as one of the attractive approaches for lung cancer therapy because they have proven to be useful and effective in sensitizing conventional agents, prolonging patient survival time, preventing side effects of chemotherapy, and improving quality of life in lung cancer patients [21]. A recent cohort study with 453 cancer patients revealed that the percentage of patients using herbal medicines in combination with conventional chemotherapy was approximately 77% [22]. In these cases, natural products as complementary therapy for the treatment of lung cancer were used mainly with the aim of reducing toxicity, alleviating cancer-related symptoms, stimulating the immune system, and even having direct anticancer effects [23].Many natural products or synthetic analogs are still widely used clinically, for example, the so-called vinca alkaloids, vinblastine and vincristine, isolated from the Madagascar periwinkle,Catharanthus roseus, paclitaxel (Taxol), obtained from the leaves of variousTaxus species, and the two clinically active agents, etoposide and teniposide, which are semisynthetic derivatives of the natural product epipodophyllotoxin [20]. Other promising agents, natural or synthetic analogs, are in the clinical development phase, including flavopiridol [24] and combretastatin A4 [25]. In addition, many compounds obtained from plants or other living organisms, alone or in combination, are still studied byin vitro models for determining their mechanisms of action against lung cancer cells [26–37].The most common forms of therapeutic use of plants worldwide are teas and herbal infusions. Considering that their use has increased in recent years aiming to reduce the risks of cardiovascular disease and cancers, research is going on to characterize this effect. Recent data showed that different teas and herbal infusions widely consumed in Hong Kong, Macau, Taiwan, Mainland China, and many other places in the world have antiproliferative effects against human lung cancer cells [38]. Many cancer patients take these medicines, but their effects at the cellular level are largely unknown. However, different preclinical and clinical studies have shown the antitumor activity of herbal extracts against lung cancer [39]. The data have shown that induction of apoptosis is the major mechanism of action of these extracts. The majority of the articles show the effect of Chinese herbal extracts. Some of them show that the response of lung tumor cells to these extracts was similar to their response to conventional chemotherapeutic drugs, and that their mechanism of action was associated with apoptosis induction [40]. Some examples of medicinal herbs with antitumor activity against lung cancer cells can be cited.Selaginella tamariscinais a traditional Chinese herb with antimetastatic effectsin vitro andin vivo against lung cancer cells [41].Crocus sativusL. (Saffron) aqueous extract is widely used as a food additive and in traditional medicine for cancer. Its effects against lung cancer cells were investigated, and antilung cancer activity was associated with induction of apoptosis [31]. The bioactive fraction ofToona sinensis leaves inhibited H441 xenograft tumor growth in both therapeutic and preventive experiments. Anin vitro study revealed that the natural product acts by inducing apoptosis [42]. The methanolic fraction ofSesbania grandiflorawas found to exert potent antiproliferative effects especially against human lung cancer cell lines. This effect was related to the induction of apoptosis associated with high levels of reactive oxygen species (ROS) intermediates [43]. A study of the combination of active components ofPrunella revealed that total triterpenes and total phenols had antilung cancer activity and that their combination significantly enhanced the activity. Thus, its efficacy against lung cancer was attributable to multiple components acting at an optimal ratio [44].Descurainia sophiahas been traditionally used in Korean medicine. Recent data from the study of gene expression profile found the antitumor effect of the ethanol extract of the seeds ofD. sophia against lung cancer to be involved with the regulation of metabolism- and signaling-related pathways [45]. Mountain ginseng butanol extract inhibited lung cancer cell growth by inducing apoptosis. Its mechanisms were associated with a reduction in NF-κB activity and increase in p53 activity [46].Substances isolated from various medicinal plants have also been extensively studied for their antilung cancer activity.[
6
]-Gingerol, a pungent ingredient of ginger (Zingiber officinale) showed antiangiogenic activityin vitro andin vivoand reduced the number of lung metastases in mice receiving B16F10 melanoma cells [47]. Embelin, an active component of fruits ofEmbelia ribes, has been demonstrated to possess a broad spectrum of therapeutic properties, including antitumor activity against lung cancer cells. Recent data indicate the crucial role of p38 and JNK pathways in embelin-induced apoptosis [48]. Danshen (Salvia miltiorrhizaBunge) is a traditional medicine that has been used in China to treat various diseases, including cancer. Tanshinone I is a diterpene isolated from this species, which reduced lung adenocarcinoma tumor growth. The studies of its mechanisms showed that the compound inhibits pulmonary tumor formation in an animal model by downregulation of the cell cycle at S and G2/M phases [27]. A carbazole alkaloid isolated fromMurraya koenigiiSpreng, girinimbine, inhibited lung cancer cell growth by inducing both intrinsic and extrinsic pathways of apoptosis [49]. Capilliposide, extracted from a traditional Chinese medicine,Lysimachia capillipes, induced apoptosis in NSCLC cells. Xenograft tumor growth was significantly decreased afterin vivo treatment. Thein vitro data revealed that capilliposide increased the intracellular level of ROS, which activated the mitochondrial apoptotic pathway [50].Scutellaria baicalensis root is used in China as an adjuvant in the chemotherapy of lung cancer. Recently, three compounds were associated with its activity, baicalin, baicalein, and wogonin [51]. Subamolide A, isolated fromCinnamomum subavenium, induced lung cancer cell death by ROS generation, which triggers mitotic catastrophe followed by apoptosis [52]. Terpinen-4-ol, a monoterpene component of the essential oils of several aromatic plants, showed its antitumor effect on NSCLC cells by induction of apoptosis, with involvement of the mitochondrial apoptotic pathway [53]. Davallic acid is the major active compound ofDavallia divaricata, a species traditionally employed in folk medicine for the therapy of lung cancer in Taiwan. Recent data showed that this compound induced oxidative stress and apoptosis in lung cancer cells [54]. Total flavonoids ofDaphne genkwa inhibited tumor growth and metastasis by protecting the viability of host immunocytes and their proliferation potential and selectively inhibiting tumor cell proliferation. In this fraction, daphnodorin B was the predominant constituent [55].In addition, many studies have shown the use of combined therapy of herbal medicines or natural substances with chemotherapeutic drugs to enhance their antitumor effects and/or reduce their toxicity. The combination of Xiao-Ai-Ping, a traditional Chinese medicine, and cisplatin promotes the infiltration and function of CD8+ T cells and thus enhances the growth-inhibitory effects of cisplatin on LLC xenografts [56].Marsdenia tenacissimahas long been used as a remedy to treat cancer in China. Its combination with gefitinib, an orally active tyrosine kinase inhibitor, improved gefitinib efficacy in NSCLC regardless of EGFR status [57, 58]. The combined therapy of plants extracts,Phyllanthus emblica andTerminalia bellerica, with doxorubicin or cisplatin resulted in a synergistic effect and the possibility of reducing the doses of the chemotherapeutic drugs [59]. Fuzheng Fangai pill (FZFA), a traditional Chinese formula, is widely used for cancer treatment. Recent studies showed that FZFA combined with cyclophosphamide (CTX) strongly reduced the growth and metastatic rate of LLC through inhibition of the SOCS/JAK-STAT pathway and inflammatory cytokine responses. In addition, it was observed that the combination had greater activity than CTX alone [60]. Osthole is a natural compound extracted from a number of medicinal plants. The combination of osthole and cisplatin, one of the most active chemotherapeutic agents in lung cancer treatment, resulted in greater efficacy in growth inhibition and apoptosis induction [61]. Meta-analysis of randomized trials showed thatAstragalus-based Chinese herbal medicine may increase the effectiveness of platinum-based chemotherapy when combined with chemotherapy [62]. A clinical study showed that the combination of Chinese drugs and conventional chemotherapy in NSCLC patients can enhance short-term therapeutic efficacy in the treatment of NSCLC and prolong patients’ median survival time, but it did not find any evident impact on median time to progression [63].New technologies are in development to enhance the activity and reduce the toxicity of natural products during the research of new therapies. Liposomes may be a promising delivery system for drugs in cancer treatment, including lung cancer [64]. The development of liposome-based cisplatin drug called Lipoplatin was beneficial in reducing the nephrotoxicity of cisplatin, the drug of choice for the treatment of NSCLC. Lipoplatin is anticipated to complete phase III clinical trial testing in 2013 and 2014 [65]. β-elemene, a sesquiterpene vinyl monomer isolated first fromCurcuma wenyujin (Zingiberaceae) rhizome, is present in Chinese herbs and plants. Different studies with this compound have shown efficient antilung cancer activity including inhibiting angiogenesis, inducing tumor cell apoptosis, enhancing radiosensitivity, and favorable chemotherapeutic effects in combination with other anticancer agents. In addition,  β-elemene has only slight side effects. However, the clinical application of β-elemene was limited by its hydrophobic property, poor stability, and low bioavailability. Phase II clinical trials with β-elemene are in development, and aiming to improve of its pharmacokinetics new delivery systems are being produced, including liposome-based delivery systems of β-elemene. The authors emphasize that β-elemene liposomes will be critical for future clinical applications of β-elemene in lung cancer treatment [66]. Herbal extracts have also been studied using new technologies. The ethanolic extract ofPolygala senega(EEPS) caused apoptosis in lung cancer cell line A549. Its poly-(lactic-co-glycolic) acid (PLGA) nanoparticle-encapsulated form enhanced cellular entry and bioavailability and inhibited the growth of lung cancer cells better than EEPS. The apoptosis of A549 cells was associated with decreased expression of survivin and PCNA mRNA and increased expression of caspase-3 and p53 mRNAs of A549 cells. The authors showed that the formulation of EEPS-loaded PLGA nanoparticles was more effective than EEPS, probably due to more aqueous dispersion after nanoencapsulation, and concluded that the nanoencapsulated ethanolic root extract ofP. senegamay serve as a potential chemopreventive agent against lung cancer [67].In the course of our continuing search for bioactive natural plant products, we have published reviews on crude plant extracts and plant-derived compounds with potential uses [68–77]. Moreover, our group has also reviewed the medicinal and poisonous plants of Northeast Brazil [78], among others [79–84].The search was carried out in the Web of Science, Chemical Abstracts, and NAPRALERT (acronym for the University of Illinois Natural Products ALERT service) databanks. The references found in the searches were later consulted. For details on the mechanism-based bioassays utilized for antitumor activity, the original references should be consulted.


## 2. Results and Discussion

Natural products have been increasingly used worldwide to treat various diseases, including cancer. Herbal medicines and phytochemicals can be potent agents for lung cancer chemoprevention and treatment by regulating multimolecular targets involved in angiogenesis, metastasis, and severe side effects; only provided quality control and reproducibility issues are solved [21]. Compared with the conventional drugs used in cancer treatment, the toxicity of medicinal plants may seem trivial; however, it is a serious public health problem. Several medicinal plants are considered toxic and can cause serious damage to the health of patients. Therefore, the assessment of the toxicity of medicinal plants, as well as their herbal preparations, is essential to determine the applicability of the sample as a pharmacological drug [85].In the current review, we present medicinal plants, distributed in diverse parts of the world, with antitumor activity against differentin vivo lung cancer models (Table 1). The effectiveness of the medicinal plants depended on the type of drug studied and the bioassay model. Thus, it was possible to classify the extracts as active or inactive, and the mechanisms of action studied were discussed.Table 1
Medicinal plants and other organisms with antitumor potential against lung cancer.
Family and botanical name
Origin
Part used
Extract
Model
Mammal tested
Result
Reference
Agavaceae
Yucca aloifolia
USA
Flowers
MeOH extract
Ca-lewis lung
Mouse
Active
[120]
Alariaceae
Undaria pinnatifida
Hawaii
Commercial sample of thallus pacific
Type of extract not stated
Ca-lewis lung
Mouse
Active
[90]
Hawaii
Commercial sample of thallus pacific
H2O-insoluble extract
Ca-lewis lung
Mouse
Active
[90]
Japan
Commercial sample of thallus pacific
H2O Extract
Ca-lewis lung
Mouse
Active
[91]
Japan
Dried thallus pacific
Polysaccharide fraction
Ca-lewis lung
Mouse
Active
[92]
Anacardiaceae
Semecarpus anacardium
India
Dried fruit
CHCl3 extract
Ca-lewis lung
Mouse
Inactive
[121]
Apidae
Apis mellifera
Croatia
Fresh venom
Venom
Decreased number of lung metastases
Mouse
Active
[119]
Apocynaceae
Ervatamia heyneana
India
Leaf
MeOH extract
Ca-lewis lung
Mouse
Inactive
[122]
ARALIACEAE
Eleutherococcus senticosus
USSR
Root
EtOH (16%) extract
Chemical induced tumor
Mouse
Active
[123]
Panax ginseng
South Korea
Dried root
H2O extract
Mice exposed to benzopyrene
Mouse
Active
[86]
South Korea
Dried root
H2O extract
Aflatoxin-induced lung adenoma
Mouse
Active
[124]
South Korea
Dried root
H2O extract
Fluorenyl-induced lung adenoma
Mouse
Inactive
[124]
South Korea
Dried root
H2O extract
DMBA-induced lung adenoma
Mouse
Inactive
[124]
South Korea
Dried root
H2O extract
Urethane-induced lung adenoma
Mouse
Active
[124]
Arecaceae
Calamus rotang
India
Aerial parts
EtOH-H2O (50%) extract
Ca-lewis lung
Mouse
Active
[125]
Asteraceae
Tagetes minuta
Ethiopia
Aerial parts
H2O extract
Ca-lewis lung
Mouse
Active
[126]
Celastraceae
Maytenus serrata
Ethiopia
Fruit
EtOH (95%) extract
Ca-lewis lung
Mouse
Active
[127]
Ethiopia
Stemwood
EtOH (95%) extract
Ca-lewis lung
Mouse
Active
[127]
Ethiopia
Root
EtOH (95%) extract
Ca-lewis lung
Mouse
Active
[127]
Kenya
Root
EtOH (95%) extract
Ca-lewis lung
Mouse
Active
[127]
Kenya
Stemwood
EtOH (95%) extract
Ca-lewis lung
Mouse
Active
[127]
Chlorellaceae
Chlorella vulgaris
Pacific (Japan)
Dried cells
Chromatographic fraction
Ca-lung-3LL
Mouse
Active
[101]
Cladoniaceae
Cladonia leptoclada
New Zealand
Thallus
EtOH-H2O (1 : 1) extract
Ca-lewis lung
Mouse
Active
[95]
Euphorbiaceae
Croton macrostachys
Ethiopia
Fruit
EtOH (95%) extract
Ca-lewis lung
Mouse
Active
[87]
Euphorbia esula
USA
Aerial parts
EtOH (95%) extract
Ca-lewis lung
Mouse
Inactive
[128]
USA
Entire plant
EtOH (95%) extract
Ca-lewis lung
Mouse
Active
[129]
Euphorbia fischeriana
China
Dried entire plant
EtOH (95%) extract
Ca-lewis lung
Mouse
Active
[130]
Euphorbia ingens
South Africa
Fresh stem
EtOH-H2O (1 : 1) extract
Ca-lewis lung
Mouse
Inactive
[131]
Jatropha gossypiifolia
Costa Rica
Root
H2O extract
Ca-Lewis lung
Mouse
Inactive
[132]
Costa Rica
Root
EtOH (95%) extract
Ca-Lewis lung
Mouse
Inactive
[133]
Fabaceae
Cassia garrettiana
Thailand
Dried heartwood
MeOH extract
Ca-lewis lung
Mouse
Active
[88]
Thailand
Dried heartwood
MeOH extract
Ca-lewis lung
Mouse
Active
[89]
Sophora flavescens
China
Dried root
Type of extract not stated
Ca-lewis lung
Mouse
Active
[134]
Sutherlandia frutescens
South Africa
Fresh flowers
EtOH-H2O (1 : 1) extract
Ca-lewis lung
Mouse
Inactive
[131]
Ganodermataceae
Ganoderma lucidum
Taiwan
Dried fruit body
H2O extract
Ca-lewis lung
Mouse
Active
[116]
Taiwan
Dried fruit body
EtOH (95%) extract
Ca-lewis lung
Mouse
Active
[116]
Taiwan
Dried fruit body
H2O extract in combination with adriamycin
Ca-lewis lung
Mouse
Active
[116]
Taiwan
Dried fruit body
H2O extract in combination with cisplatin
Ca-lewis lung
Mouse
Active
[116]
Taiwan
Dried fruit body
H2O extract in combination with fluorouracil
Ca-lewis lung
Mouse
Active
[116]
Taiwan
Dried fruit body
H2O extract in combination with methotrexate
Ca-lewis lung
Mouse
Active
[116]
Taiwan
Dried fruit body
H2O extract in combination with imexon
Ca-lewis lung
Mouse
Active
[116]
Taiwan
Dried fruit body
H2O extract in combination with thioguanine
Ca-lewis lung
Mouse
Active
[116]
Taiwan
Dried mycelium
Hot H2O extract
Ca-lewis lung
Mouse
Active
[135]
South Korea
Myceliu
Hot H2O extract
Ca-lewis lung
Mouse
Active
[136]
Japan
Dried fruit body
H2O extract
Ca-lewis lung
Mouse
Active
[117]
Geraniaceae
Pelargonium graveolens
China
Dried root
Type of extractnot stated
Ca-lewis lung
Mouse
Active
[134]
Hymenochaetaceae
Phellinus linteus
South Korea
Mycelium
Polysaccharide fraction
Cancer cell line NCI-H23
Mouse
Active
[102]
Liliaceae
Allium sativum
Japan
Aged bulb
Aged garlic extract used
Sarcoma-180 and LL/2 lung carcinoma cells
Mouse
Active
[103, 104]
Loranthaceae
Viscum album
Germany
Dried aerial parts
H2O soluble fraction
Ca-lewis lung
Mouse
Inactive
[137]
England
Commercial sample of leaf + stem
Type of extract not stated
Small cell lung
Human adult
Active
[100]
Switzerland
Commercial sample of entire plan
H2O Ext
Ca-lewis lung
Mouse
Active
[96]
Malvaceae
Thespesia populnea
India
Fruit
EtOH-H2O (1 : 1) extract
Ca-lewis lung
Mouse
Active
[125]
Hibiscus syriacus
Taiwan
Dried root bark
Acetone extract
Ca-human lung
Mouse
Inactive
[138]
Melastomataceae
Memecylon umbellatum
India
Leaf
EtOH-H2O (1 : 1) extract
Ca-lewis lung
Mouse
Inactive
[125]
Nyctaginaceae
Mirabilis multiflora
USA
Root
H2O extract
Ca-lewis lung
Mouse
Inactive
[139]
Nyssaceae
Nyssa sylvatica
Not stated
Stem bark
H2O extract
Ca-lewis lung
Mouse
Inactive
[140]
Ochnaceae
Lophira lanceolata
Nigeria
Root bark
EtOH-H2O (1 : 1) extract
Ca-lewis lung
Mouse
Inactive
[141]
Oscillatoriaceae
Oscillatoria acutissimastrain B.1
Hawaii
Freeze-dried organism
Type of extract not stated
Ca-lewis lung
Mouse
Inactive
[142]
Papaveraceae
Chelidonium majus
Austria
Dried entire plant
Alkaloid fraction
Lung cancer
Human adult
Active
[105]
Pectinidae
Patinopecten yessoensis
Pacific (Japan)
Fresh organism
Polysaccharide fraction
Cells human embryonic lung
Mouse
Inactive
[143]
Ranunculaceae
Nigella sativa
India
Seed
EtOH-H2O (50%) extract
Ca-lewis lung
Mouse
Active
[125]
Singapore
Commercial sample of seed
Chromatographic fraction
Ca-lewis lung
Mouse
Active
[106]
Rubiaceae
Morinda citrifolia
Hawaii
Dried fruit juice
EtOH insoluble fraction
Ca-lewis lung
Mouse
Active
[144]
Rhizophoraceae
Bruguiera sexangula
Papua-New Guinea
Stem bark
EtOH (95%) extract
Ca-lewis lung
Mouse
Active
[145]
Schisandraceae
Schisandra propinqua
China
Dried root + stem
Hot H2O extract
Ca-human lung
Human adult
Active
[109]
Simaroubaceae
Brucea javanica
China
Dried part not specified
Type of extract not stated
Lung cancer
Human adult
Active
[93]
China
Seed
Seed oil
Squamous carcinoma and adenocarcinoma
Human adult
Active
[94]
China
Seed
Seed oil
The extract showed a therapeutic effect for lung cancers
Human adult
Active
[146]
China
Seed
Fixed oil
Patients with lung cancer
Human adult
Active
[147]
Solanaceae
Withania somnifera
India
Dried root
EtOH (95%) extract
Lung adenomas
Mouse
Active
[110]
India
Dried entire plant
EtOH (95%) extract
Lung adenomas
Mouse
Active
[148]
Theaceae
Camellia sinensis
China
Dried leaf
Polyphenolic fraction
Lung cancer
Mouse
Active
[149]
China
Green leaf
Tea
Lung cancer
Human adult
Active
[112]
China
Black leaf
Leaves
Reduced tumor multiplicity and volume in nnk treated mice
Mouse
Active
[114]
Tricholomataceae
Hypsizygus marmoreus
Japan
Dried fruit
H2O extract
Ca-lewis lung
Mouse
Active
[115]
Lentinus edodes
Japan
Dried fruit body
H2O extract
Ca-lewis lung
Mouse
Inactive
[150]
Violaceae
Viola odorata
South Africa
Fresh leaf
EtOH-H2O (1 : 1) extract
Ca-lewis lung
Mouse
Inactive
[131]Celastraceae was the most cited family for antitumor activity in lung cancer models, followed by Araliaceae, Euphorbiaceae, and Fabaceae.Maytenus serrata was the only species studied of the family Celastraceae, showing antitumor activity for its fruit, root, and stem wood.Eleutherococcus senticosus andPanax ginseng red type were the evaluated species of the family Araliaceae. Among the four mentioned forP. ginseng red type, one of the studies showed the antitumor activity of this species against lung adenoma induced by different carcinogenic agents. Studies withP. ginseng were carried out with the ethanol-insoluble fraction, obtained from the fractionated water extract. The tumor was induced by a single subcutaneous (s.c.) injection of benzo[α]pyrene (BP), and the treatment withP. ginseng significantly inhibited lung tumor incidence. The investigation of the mechanisms of action showed proliferation of splenocytes and generation of activated killer cellsin vitro, suggesting immunomodulatory effects [86].Euphorbia esula,Euphorbia fischeriana,Euphorbia ingens, andCroton macrostachyswere the most studied Euphorbiaceae species. All of them showed significant antitumor activity against lung cancer models. Crotepoxide, a novel cyclohexane diepoxide obtained fromC. macrostachys and alcoholic extracts of the fruits of this species, inhibited the growth of LLC in mice [87].Among the active species of the family Fabaceae,Sophora flavescens andCassia garrettiana were cited. The methanol extract ofC. garrettiana was found to contain the substances identified as cassigarol A and piceatannol. The extract and isolated substances inhibited tumor growth and metastasis in LLC-bearing mice. In addition, cassigarol A and piceatannol inhibited plasmin activity and the formation of capillary-like networks of human umbilical vein endothelial cells (HUVECs), suggesting that the effects of cassigarol A could be due to the inhibition of plasmin activity and formation of tubes (angiogenesis) from HUVECs [88, 89].Viva-Natural, a natural product extracted from the dietary seaweedUndaria pinnantifida(Alariaceae), demonstrated therapeutic activity and moderate prophylactic activity against LLC in allogeneic mice. This product enhanced the natural cytolytic activity of peritoneal macrophages against KB cells as targets in anin vitro assay. The data therefore suggest that the antitumor effect of Viva-Natural may be indirect through the activation of nonspecific immune systems [90]. The antitumor potential against LLC has been evaluated in comparison with standard synthetic immunomodulators. The effect of Viva-Natural has been found to be superior to that of isoprinosine but inferior to that of MVE-2 (pyran copolymer) [91]. The combination therapy of Viva-Natural and standard anticancer drugs was additively or synergistically effective [90]. Cisplatin, 5-fluorouracil, and vincristine at low doses that were not effective when given alone, manifested antitumor activity when combined with the polysaccharide fraction of Viva-Natural, against implanted LLC (intraperitoneal,i.p.) in syngeneic mice. However, an additional effect on the immune system was not observed when the polysaccharide fraction of Viva-Natural was combined with the anticancer drugs at low doses. Thus, the mechanism of action of the beneficial combination is not yet clear [92].Brucea javanica (Simaroubaceae) showed the anticarcinoma effect against brain metastasis as a complication of lung cancer. The results of this study showed that the median survival duration (15 months in the treatment group versus 10 months in the control group) and the quality of life of the patients in the combination of radiotherapy and intravenous (i.v.) injection of 10%Brucea javanica emulsion was much better than in the radiotherapy alone group (control). The results suggest that theB. javanica emulsion treatment group exhibited a synergistic action with radiotherapy in the treatment of brain metastasis as a complication of lung cancer [93]. Another study with this herbal extract showed that the preoperativei.v. emulsion of 10%B. javanica oil may improve surgical treatment of NSCLC [94].The extract of the lichenCladonia leptoclada showed significant inhibitory activity against LLC in mice. In this study, an active extract was fractionated, and the principal tumor-inhibitory constituent was characterized and identified as l-usnic acid [95].Extracts of mistletoe (commercial sample ofViscum albumleaf and stem) have been used for medicinal purposes for several centuries and are known to contain alkaloids with cytotoxic effectsin vitro andin vivo [96]. The administration of mistletoe induced tumor growth inhibition and reduction of metastases, associated with immunomodulation. The authors reported that although lectins represent a class of active components studied of mistletoe origin, it is not likely that they alone are responsible for all effects of the plant extracts [97, 98]. A randomized phase II study of mistletoe combined with carboplatin-containing regimens was conducted in advanced NSCLC patients. No effects on quality of life or total adverse events were seen. Nevertheless, chemotherapy dose reductions, severe nonhaematological side effects, and hospitalizations were less frequent in patients treated with mistletoe, warranting further investigation as a modifier of chemotherapy-related toxicity [99]. In another study, a patient with SCLS was treated initially with extracts of mistletoe and homoeopathic treatment and appeared to respond. Subsequently, radiotherapy was given and the patient lived for five years and seven months [100]. According to the authors, the acknowledgment of theViscum albumextract as a phytotherapeutic adjuvant may lead to its use together with other treatments in advanced cancer biotherapy [97, 98].Different fractions derived from the unicellular green algaChlorella vulgaris, strain CK22, were tested in relation to antitumor activity against lung cancer. The most active fraction consisted of galactose-rich carbohydrate (56.1%) and protein (36.3%), suggesting that the protein moiety of the glycoprotein is mainly related to the expression of antilung cancer activity [101].A study withPhellinus linteus showed that the polysaccharide fraction inhibited tumor growth in NCI-H23-implanted mice and reduced the frequency of pulmonary metastasis of B16F10 melanoma. Also studied was combination therapy with the polysaccharide fraction and Adriamycin. Although the combination was more effective in inhibiting tumor growth, this effect was not observed on the metastases [102].Garlic (Allium sativum) is a common plant used mainly as a food, and it is a medicinal herb commonly used worldwide. The aged garlic extract (AGE) inhibited the growth of LL/2 lung carcinoma (syngeneic) cells transplanted into mice. AGE stimulated the proliferation of mouse spleen cells and the release of cytokines, increased NK activities, and enhanced phagocytosis by peritoneal macrophages. AGE treatment also stimulated the reactivity of lymphocytes in response to cytokines or mitogens. Therefore, it was observed that the immunostimulant effect was associated with antitumor activity [103, 104].A clinical assay showed that treatment withChelidonium majus (preparation Ukrain) in nine men with histologically proven lung cancer, previously untreated, induced an increase in the proportion of total T-cells and a significant decrease in the percentage of T-suppressor cells. The restoration of cellular immunity was accompanied by an improvement in the clinical course of the disease. This effect was particularly pronounced in patients who responded to further chemotherapy. The authors concluded that Ukrain can be immunologically effective in lung cancer patients and can improve cellular immune response [105].Thein vivoantitumor effect of a fraction of an ethanolic extract ofNigella sativa seeds was studied on LLC-implanted (s.c.) mice. This fraction prolonged the life span of the mice and produced significant tumor inhibition. Alpha-hederin, a triterpene saponin, was obtained from this fraction, which induced significant dose-dependent tumor inhibition, suggesting that the activity is related to the presence of this compound. However, the underlying mechanism(s) of antitumor activity of alpha-hederin remains to be established [106].The stems and roots ofSchisandra propinqua are a major component of the Manshanxiang Complex, a herbal medicine preparation used for the treatment of lung carcinoma in several hospitals of Yunnan Province in China [107]. In addition, the water extract from the stems and roots ofS. propinqua shows activity against LLC in animal tests [108]. The triterpenoid manwuweizic acid, isolated from its alcoholic extract, exhibited significant inhibitory activity against LLC, suggesting that this compound is probably a major anticancer active principle of the plant [108, 109].Review articles about the chemical properties, therapeutic benefits, and toxicity ofWithania somnifera (ashwagandha, WS), one of the most important herbs of Ayurveda (the traditional system of medicine in India), have been published. The antitumor activity was described in differentin vitro andin vivoexperimental models, including urethane-induced lung adenoma in mice. The data showed that the ethanol extract ofW. somniferasignificantly reduced tumor incidence. In addition to providing protection from carcinogenic effects, the treatment also reversed the adverse effects of urethane on total leukocyte count, lymphocyte count, body weight, and mortality [110, 111].Current studies have demonstrated that green tea polyphenols, obtained fromCamellia sinensis, are powerful antioxidants with anticarcinogenic properties. The primary catechins in green tea are epicatechin, epicatechin-3-gallate, epigallocatechin, and epigallocatechin-3-gallate. A clinical study investigated the chemopreventive effects of green tea and coffee among cigarette smokers. The results suggest that green tea polyphenols may have an anitmutagenic effect against smoke-induced mutations in humans by blocking the cigarette-induced increase in sister-chromatid exchange frequency. It has also been shown that cultured human lung cells (A549) pretreated with green tea polyphenols and then exposed to a cigarette smoke solution or H2O2 had a reduced incidence of DNA strand breaks. Pretreatment with green tea polyphenols also reduced the overall toxicity of H2O2 as determined by cell growth after exposure. These results suggest that green tea polyphenols may inhibit DNA damage and other mutations in cells exposed to oxidants and that this effect is associated with anticarcinogenic properties [112]. A recent article published evidence from epidemiologic studies on cancer prevention by green tea. Various epidemiologic studies have examined the association between green tea consumption and lung cancer risk. The inconsistent results of those studies could be partly a result of the potential confounding effect of smoking. The data revealed that the protective effect of green tea consumption on lung cancer risk was confined to nonsmokers [113].The effects of black tea obtained fromC. sinensis were also studied. The administration of black tea polyphenols through the drinking water significantly inhibited 4-(methylnitrosamino)-1-(3-pyridyl)-l-butanone (NNK) and induced early bronchial cell proliferation in the short-term model. In long-term studies, administration of black tea, after a single dose of NNK, inhibited the progression of adenoma to adenocarcinoma. The cell proliferation rate in adenomas was also suppressed by black tea treatment. The authors related that such activities, at the early and late stages of lung tumorigenesis, may be important for the cancer-chemopreventive activities of black tea [114].The antitumor activity ofHypsizigus marmoreus, an edible mushroom, was investigated against syngeneic tumor, LLC.H. marmoreus increased the life span, inhibited the activity of spontaneous tumor metastasis, and decreased the number of metastatic nodules. These effects were observed only afteri.p. administration, but not as much by oral administration, and the data showed increased immune activity by competent cells [115].Among the other living organisms with antitumor activity against lung cancer,Ganoderma luncidum (a medicinal fungus) was the most studied and has been used traditionally for the prevention and treatment of cancers for a long time in traditional Chinese medicine [37]. In this review, there were eleven reports describing the speciesG. lucidum (Ganodermataceae), where eight of them investigated the combination ofG. lucidum extracts with antineoplastic drugs. This study showed that an aqueous extract ofG. lucidum, called “Ling-Zhi or holy mushroom” in traditional Chinese medicine, significantly increased the life span of LLC-implanted syngeneic C57BL/6 mice, when administeredi.p. alone or in combination with cytotoxic antitumor drugs (Adriamycin, fluorouracil, thioguanine, methotrexate, and cisplatin) or a synthetic immunomodulator (Imexon) [116]. In another study, the authors suggested that the antitumor and antimetastatic activities of the triterpenoid fraction ofG. lucidum against LLC-implanted mice may be due to the inhibition of tumor-induced angiogenesis. The compound identified as ganoderic acid F was obtained from the acidic fraction of the triterpenoid fraction of the fruit bodies ofG. lucidum as an active substance that inhibited the angiogenesis [117]. Recent data showed that triterpenes ofG. lucidumhave antilung cancer activityin vitroandin vivovia enhancement of immunomodulation and induction of cell apoptosis [37]. In addition,G. tsugae, another well-cultivated species ofGanoderma, was evaluated against lung cancer cells. The results revealed that the natural product inhibited the viability of H23/0.3 cells (doxorubicin-resistant lung adenocarcinoma)in vitroandin vivoand enhanced the growth-suppressive effect of doxorubicin on H23/0.3 cells. This effect is associated with the downregulation of the PI3K/Akt signaling pathway. The authors suggest thatG. tsugae may be a useful adjuvant therapeutic agent in the treatment of lung cancer [118].To evaluate the effect of the bee venom on the tumor growth and metastasis formation, a transplantable mammary carcinoma (MCA) was used in the syngeneic CBA mouse. The results showed that the bee venom suppressed the tumor growth and prolonged the survival of the animals compared to the controls, afters.c.ori.v. administration. However, the antimetastatic activity was observed only afteri.v. administration, indicating that the antitumor effect of the bee venom could be highly dependent on the route of injection [119].Considering all the countries covered in the present study, China, Japan, South Korea, and Ethiopia were those that published the most studies of species with antitumor activity against lung cancer: ten works from China, eight works from Japan, and four publications from South Korea and Ethiopia each. The most used cell model for the investigation of antitumor activity against lung cancer was LLC. Of the 58 studies that showed this cell line as the experimental model used, 44 showed its sensitivity to the samples tested. Those data indicated that this cell line is the most used model worldwide to evaluate the antitumor activity in lung cancer cells. Other models cited in few studies included NSCLC and adenomas.


## 3. Conclusions

Several countries have studied medicinal plants with antitumor potential, including against lung cancer. Because many species are active in different experimental models, the natural products from plants continue to be a rich source of herbal medicines or biologically active compounds. There is a need for further studies on the standardization or chemical characterization of the extracts used. With respect to pharmacological studies, most of them were performed in mice. However, there were also studies with humans for various species of plants. This review shows that many medicinal herbs have been examined for antilung cancer activity, presenting important results that provide insight into their use for the treatment of cancer. However, despite many studies showing the evaluation of possible mechanisms of action of these compounds, the majority of studies still presented only preliminary screening data and therefore did not describe any mechanism of action. For these studies, they are classified only as “active.” In addition, new research findings have shown extracts as potential phytotherapeutic adjuvants in advanced lung cancer therapy. This could lead to greater safety and benefits for people, contributing to a better access to health care and thereby a better quality of life of patients with lung cancer.



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