Antigenotoxic, antiproliferative and antimetastatic properties of a combination of native medicinal plants from Argentina
Graphical abstract
Introduction
According to the International Agency for Research on Cancer (IARC) statistics, Argentina is the seventh country in South America with high cancer incidence (IARC, 2018). The only common feature among all types of tumors is the uncontrolled cell proliferation, mainly due to mutations that alter cell regulatory mechanisms (Alexandrov and Zhivagui, 2019; Plankar et al., 2011). Therefore, prevention strategies and efficient treatments that, as far as possible, do not alter the life quality of patients becomes crucial. In this sense, there is a growing interest in developing chemotherapeutic or chemopreventive drugs from medicinal herbs used traditionally, or combination of them (Gras et al., 2018). The fundamental purpose underlying this practice is to obtain synergism, to reduce individual component doses in order to achieve lower toxicity, to minimize or delay resistance and to involve several molecular targets simultaneously. Plant mixtures have been playing a crucial role in ‘omic’ techniques to lead to a new generation of plant-derived drugs useful in multicausal pathologies such as cancer, cardiomyopathies, rheumatism, etc. (Wagner and Ulrich-Merzenich, 2009).
Larrea cuneifolia Cav. (Zygophyllaceae), Larrea divaricata Cav. (Zygophyllaceae) and Zuccagnia punctata Cav. (Fabaceae) belong to an important plant community in the Northwest of Argentina known as the “Jarillal” (Carrizo and Grau, 2014). These plant species are among the most useful and popular in traditional healing by local people in arid ecosystems in Argentina (Ladio and Lozada, 2009; Martínez et al., 2004). It was previously stated that they are commonly consumed as infusions or in taking baths (Carabajal et al., 2020b), and that they can be used to heal mycosis, respiratory, musculoskeletal and skin ailments, as well as weakness/tiredness, hypertension, diabetes and tumor treatment (Carabajal et al., 2020b; Davicino et al., 2011; Isla et al., 2016; Moreno et al., 2018). Regarding the latter, the medicinal use of Jarilla leaves to treate tumor formation was reported in ethnopharmacological surveys by Carabajal et al. (2020b), in an indigenous community in northwestern Argentina. Catalá (1938) also reported the application of these plants on “wound ulcers of a malignant nature” in southern Argentina. Moreover, in vivo antitumor capacity of L. divaricata (“Jarilla hembra”) against mammary carcinoma (Anesini et al., 1998) was demonstrated, and antigenotoxic activity of these species was also reported (Carabajal et al., 2017; Zampini et al., 2008). It is well-known that some phenolic compounds from Jarilla shrubs inhibit pathogenic bacteria and fungi, pro-inflammatory enzymes and show antioxidant, antigenotoxic and cytotoxic potential (Blecha et al., 2007; Chieli et al., 2012; Lü et al., 2010; Youngren et al., 2005).
In ancient cultures, mixing medicinal plants led to improve the individual properties of chemical components by increasing their solubility or bioavailability, once they were consumed (Grosso et al., 2015). Diaguita-Calchaqui people indicated that they generally consumed these plants one at a time but in some cases, they mixed them along with other shrubs (Carabajal et al., 2020b). Although no reports describe traditional uses of mixtures of these three Jarilla species, it was previously demonstrated that some such mixtures from Z. punctata/L. divaricata, Z. punctata/L. cuneifolia, and Z. punctata/L. nitida showed a synergistic effect in bi-combinations on antifungal activity against Saccharomyces cerevisiae, Candida albicans, and non-Albicans strains (Butassi et al., 2015; Moreno et al., 2020b). It was also stated that a ternary herbal combination, namely, 50% L. cuneifolia, 25% L. divaricata and 25% Z. punctata, has a synergistic and additive effect on antioxidant activity through several mechanisms of actions, even after passing through the gastro-duodenal tract (Carabajal et al., 2020a). Nevertheless, little is known about the chemotherapeutic potential of Jarilla mixtures against cancer.
Considering the traditional use of Jarilla leaves to treat tumor formation, this work aimed to provide new knowledge on the antigenotoxic potential, as well as the antitumor and anti-metastatic properties of Jarilla species and a ternary combination from them.
Section snippets
Chemicals
HPLC grade acetic acid and methanol were purchased from Merck (Darmstadt, Germany), β-nicotinamide adenine dinucleotide (NADH), nordihydroguaiaretic acid (NDGA), dimethyl sulfoxide (DMSO), L-Histidine, D-Biotin, 4-nitrophenylene-1,2-diamine (4-NPD), 2- aminofluorene (2-AF), penicillin-streptomycin solution and trypsin-EDTA solution, methyl methanesulfonate (MMS), cytochalasin B, oxaliplatin, Cole's hematoxylin/eosin, Aroclor-1254, Hepes solution, Cell Proliferation Kit (XTT-based colorimetric
Phytochemical profiling of ternary mixture infusion
Thirty-three chemical compounds belonging to different phenolic families (tannins, flavonoids, esters and lignans) were identified in HM2 infusion, according to literature and standard fragmentation patterns (Table 1). Most of the compounds belong to Z. punctata components, such as flavonols (compounds 4–6, 13, 24, 33), flavanones (8, 9, 12, 16, 17, 21), hydroxylated and methoxylated chalcones (7, 22, 31, 32), hydrolyzable tannins (1, 3), esters (19, 25, 26) and condensed tannins (catechin
Discussion
Numerous potential chemotherapeutic drugs have been derived from natural sources. Secondary metabolites synthesized by plants did provide several drugs for the treatment of various human diseases and 75% of the modern synthetic drugs have been derived mainly from plants (Newman and Cragg, 2016).
Plant species belonging to “Jarillal” inhabit arid ecosystems in Argentina and are recognized by local people as important plants for its medical, tinctorial, and spiritual uses (Carabajal et al., 2020b
Conclusion
A ternary combination of three Argentine native Jarilla species (HM2), composed by L. cuneifolia (50%), L. divaricata (25%), and Z. punctata (25%) showed anti-cancer effect and the antigenotoxic potential as mechanisms for cancer prevention were revealed. HM2 showed cytotoxic activity on different cell lines derived from human tumors, as well as inhibited tumor growth, and presents an anti-metastatic effect in vivo.
From these results, it could be inferred that the proposed herbal mixture is an
Authors’ contributions
M.P.A.C, H. D-N, I.S–S, A.P.P-G, T.R-E performed the micronucleus assay and antiproliferative in vitro experiments. M.P.A.C and I.C.Z, performed chemical profile analyses and the Ames test. J.P.F designed and performed in vivo experiments. I.C.Z., M.I.I. and D.C.T. designed the experiments and supervised the research. All authors analyzed the data. I.C.Z and M.P.A.C drafted the manuscript. I.C.Z and M.I.I. conceived and initiated the project.
Declaration of competing interest
The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper.
Acknowledgements
The authors are very grateful to the following Argentinian institutions: Universidad Nacional de Tucumán (PIUNT 2018-G637 Project), Agencia Nacional de Promoción Científica y Técnica (ANPCyT PICT2014, 3136 Project, PICT 2017, 4416 Project), and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET- PUE 2018-0011 Project); Brazilian institutions: São Paulo Research Foundation (FAPESP; grant # 2016/24269–7), National Council for Scientific and Technological Development (CNPq) and
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