Efeito Antitumoral Do Extrato Metanólico Do Látex De Synadenium Grantii Hook f. (Euphorbiaceae) Em Tumor De Ehrlich Sólido

Abstract

Mammary tumors are frequent in both women and female dogs, representing the most common neoplasms in these species. Among the similarities between mammary tumors in the two species are spontaneous development, tumor progression, biological behavior, and the expression of certain receptors. Thus, the female dog serves as a natural model for this disease. Furthermore, some tumors pose therapeutic challenges, necessitating new therapies when the goal is to improve patient prognosis. In this context, various chemotherapeutic drugs originate from botanical compounds, and the Brazilian Cerrado presents a diversity of plants with potential for the identification of new drugs. Synadenium grantii HOOK F. (Euphorbiaceae), a botanical species used in ethnomedicine in the Central-western and southern regions of Brazil, is empirically used in treating a range of diseases, including cancer. Therefore, this study aimed to evaluate the antiproliferative potential of the methanolic extract of S. grantii latex, administered intraperitoneally, in mice bearing Ehrlich solid tumors (EST), as well as its effects on the tumor microenvironment and the performance of treated animals. Additionally, phorbol esters in the botanical specimen were investigated. Initially, samples of the latex from a specimen of Synadenium grantii were collected in the municipality of Nerópolis, Goiás, Brazil. The latex was diluted in bidistilled water, subjected to lyophilization, and used to prepare the methanolic extract. Subsequently, experimental induction of TES was performed on the dorsum of adult female mice, which were treated with four weekly intraperitoneal applications of methanolic latex extract from S. grantii (MLE) at doses of 5, 15, and 25 mg/kg. Three control groups were utilized, including vehicle control, negative control, and carboplatin. After 7, 14, 21, and 35 days, animals were euthanized, and tumor fragments were collected for histological and immunohistochemical (anti-Ki67 and anti-CD31) evaluations. Phytochemical analysis was performed on the MEL sample using high-performance liquid chromatography coupled with high-resolution mass spectrometry (HPLC-HRMS). Furthermore, the survival rate and weight gain of the animals were determined. The phytochemical analysis identified a phorbol compound (phorbol-12,13,20-triacetate), and the 25 mg/kg dose of S. grantii MEL resulted in a reduced survival rate and weight gain in the animals. Conversely, the 15 mg/kg dose demonstrated safety for intraperitoneal use, reflecting a decrease in mitotic figure counts and neoplastic cell proliferation rates after three consecutive administrations. Additionally, the 15 and 25 mg/kg doses of S. grantii MEL induced structural modifications in the EST microenvironment in mice. The use of the bioproduct also resulted in increased microvascular density and a reduction in the amount of type I and III collagen fibers in intra- and peritumoral regions, significant at 14 and 21 days. It was concluded that S. grantii MEL constitutes a promising source of compounds with antitumor activity. Therefore, it is concluded that the methanolic latex extract of Synadenium grantii represents a promising source of compounds with antitumor activity, exhibiting a dose-dependent antiproliferative effect. However, this formulation induces significant histological changes in organs such as the liver and kidneys, in addition to demonstrating pro-angiogenic effects in the long term.