Characterization of the biological effect of semisynthetic compound derived from Euphorbia tirucalli in vitro and in vivo, from the establishment of patients-derived xenografts with gastrointestinal tract tumors

Abstract

Cancer is responsible for a significant and growing number of patients worldwide, and represents the second leading cause of death in many countries. In the search for new therapies, research with natural products has emerged as an alternative and successful source in the development of potential drugs. The species Euphorbia tirucalli, popularly known as ''aveloz'' is used in folk medicine with antiviral and analgesic properties. Our group has carried out a bioprospecting program that includes the evaluation of cytotoxicity in a wide panel of human tumor lines using the extract as well as compounds derived from this plant. Results from our group have shown the cytotoxic effect and the anti-tumor potential of eufol, the main constituent of E. tirucalli latex. In addition to eufol, the genus Euphorbia also has diterpenes as bioactive constituents, among which stands out the ingenol-3-angelate (I3A) known clinically as Picato ® used in the treatment of actinic keratosis, but which also has great antineoplastic activity modulating the activity of protein kinases C (PKCs), related to different cellular functions and processes involved in carcinogenesis. Another diterpene that has antitumor action is the compound ingenol-3,20-dibenzoate (IDB), considered a potent activator of PKCs and a promoter of caspase-3-dependent apoptosis. Recently, three new semi-synthetic ingenol esters have been described. The potential effect of Ingenol C (IngC) was evidenced by our group in a large panel of tumor lines, promoting greater cytotoxicity in esophageal cell lines, in addition to demonstrating a synergistic effect after combination with the chemotherapy used in clinical practice, paclitaxel. Considering that esophageal and colorectal Cancer occupy the sixth and second position in terms of mortality in the world with a low rate of global survival, the search for new targets and new therapies that help in the treatment and improve the prognosis of these diseases has increased. Thus, it is expected with this work the characterization of the biological effects as well as the cytotoxic, genotoxic damages and the carcinogenic potential of IngC linked to the development of an in vitro study of 3D organoid culture and in vivo from the establishment of a model xenographic derived from patients and in the context of chemoprotection in order to faithfully reproduce the original tumor microenvironment and the response to treatment. We hope that the approaches used for IngCs characterization and biological study will allow the development of a new antineoplastic drug originating in Brazilian biodiversity. (AU)