Anticancer Activities of the Quinone-Methide Triterpenes Maytenin and 22-β-hydroxymaytenin Obtained from Cultivated Maytenus ilicifolia Roots Associated with Down-Regulation of miRNA-27a and miR-20a/miR-17-5p

Natural triterpenes exhibit a wide range of biological activities. Since this group of secondary metabolites is structurally diverse, effects may vary due to distinct biochemical interactions within biological systems. In this work, we investigated the anticancer-related activities of the quinone-methide triterpene maytenin and its derivative compound 22-β-hydroxymaytenin, obtained from Maytenus ilicifolia roots cultivated in vitro. Their antiproliferative and pro-apoptotic activities were evaluated in monolayer and three-dimensional cultures of immortalized cell lines. Additionally, we investigated the toxicity of maytenin in SCID mice harboring tumors derived from a squamous cell carcinoma cell line. Both isolated molecules presented pronounced pro-apoptotic activities in four cell lines derived from head and neck squamous cell carcinomas, including a metastasis-derived cell line. The molecules also induced reactive oxygen species (ROS) and down-regulated microRNA-27a and microRNA-20a/miR-17-5p, corroborating with the literature data for triterpenoids. Intraperitoneal administration of maytenin to tumor-bearing mice did not lead to pronounced histopathological changes in kidney tissue, suggesting low nephrotoxicity. The wide-ranging activity of maytenin and 22-β-hydroxymaytenin in head and neck cancer cells indicates that these molecules should be further explored in plant biochemistry and biotechnology for therapeutic applications

Genetic parameters of the populations of <i>Uncaria tomentosa</i> collected in the Amazon region of Brazil.

<p>Genetic parameters of the populations of <i>Uncaria tomentosa</i> collected in the Amazon region of Brazil.</p

Dendrogram, constructed using the unweighted pair group method with arithmetic mean (UPGMA), showing eight populations of <i>Uncaria tomentosa</i> separated into two clusters.

<p>Group I contained UTTA (Tarauacá, Acre), UTFJ (Feijó, Acre) and UTMC (Macapá, Amapá), while group II comprised UTMZ (Mazagão, Amapá), UTML (Mâncio Lima, Acre), UTCS (Cruzeiro do Sul, Acre), UTSA (Santana, Amapá) and UTAF (Afuá, Pará).</p

High performance liquid chromatographic (HPLC) analyses of leaf extracts of three specimens of <i>Uncaria tomentosa</i> populations from the Amazon region of Brazil.

<p>The chromatograms were obtained from specimens collected in: (<b>A</b>) Cruzeiro do Sul, AC, in which peaks labeled <b>a</b> and <b>b</b> correspond to mitraphylline and isomitraphylline, respectively; (<b>B</b>) Afuá, PA, in which the peak labeled <b>b</b> corresponds to isomitraphylline;; (<b>C</b>) Mâncio Lima, AC, in which peaks <b>a</b> and <b>b</b> are absent. Standards (D) mitraphylline and (E) isomitraphylline.</p

Locations, geographical coordinates and altitudes of the populations of <i>Uncaria tomentosa</i> collected in the Amazon region of Brazil.

<p>Locations, geographical coordinates and altitudes of the populations of <i>Uncaria tomentosa</i> collected in the Amazon region of Brazil.</p

Graphical representation of principal coordinates analysis (PCoA) showing individuals (<i>n</i> = 20) belonging to eight populations of <i>Uncaria tomentosa</i> from the Amazon region of Brazil.

<p>Population sampling was carried out in the following locations: UTAF (Afuá, Pará), UTCS (Cruzeiro do Sul, Acre), UTFJ (Feijó, Acre), UTMC (Macapá, Amapá), UTML (Mâncio Lima, Acre), UTMZ (Mazagão, Amapá), UTSA (Santana, Amapá), UTTA (Tarauacá, Acre). PCoA was performed using SRAP markers.</p

Sampling sites of <i>Uncaria tomentosa</i> populations located in the Amazon region of Brazil.

<p>The sites of collection of the eight populations collected found in the states of Acre (AC), Amapá (AP) and Pará (PA) are showed on the map (1–8), 1- Mâncio Lima, AC; 2- Cruzeiro do Sul, AC; 3- Tarauacá, AC 4-Feijó, AC; 5- Mazagão, AP; 6- Santana, AP; 7- Macapá, AP and 8-Afuá, PA. Populations with the largest (1) and smallest (3) genetic variability are evinced by white circles. (Map source: <a href="https://eros.usgs.gov/" target="_blank">https://eros.usgs.gov/</a>).</p

Validation data for mitraphylline.

<p>Validation data for mitraphylline.</p

Bayesian analysis, performed using STRUCTURE software, of eight populations of <i>Uncaria tomentosa</i> from the Amazon region of Brazil showing the tendency to form two clusters.

<p>Group I (predominantly red) contained UTTA (Tarauacá, Acre), UTFJ (Feijó, Acre) and UTMC (Macapá, Amapá), while group II (predominantly green) comprised UTMZ (Mazagão, Amapá), UTML (Mâncio Lima, Acre), UTCS (Cruzeiro do Sul, Acre), UTSA (Santana, Amapá) and UTAF (Afuá, Pará).</p

Genetic variability between and within populations of <i>Uncaria tomentosa</i> collected in the Amazon region of Brazil.

<p>Data estimated by analysis of molecular variance (AMOVA).</p