RESUMEN
As life expectancy increases, the number of people affected by cancer is increasing. The available drugs still cause several adverse reactions, and it is important to look for less toxic drugs that act on resistant cancers. The present study evaluated the antitumor potential of acetogenins. Through a literature review, 44 acetogenins isolated from Annona muricata were selected and subjected to in silico studies to predict the physicochemical properties, pharmacokinetics (Preadmet and Admet lab), toxicity (Preadmet and Protox II) and molecular docking in caspase 3 (DockThor). For muricatacin, a literature review was carried out for antitumor activity and cytotoxicity. Only muricatacin met all physicochemical criteria, while all compounds showed high cutaneous and intestinal absorption (HIA), moderate permeability in Madin-Darby canine kidney and Caco2 cells, strongly bound plasma proteins, freely crossed the blood-brain barrier, inhibited CYP2C19, CYP2C9 and CYP3A4 and have an affinity for CYP3A4, being metabolized by it, an undesirable characteristic for antitumor drugs. All compounds were toxic in at least one model, while compound 28 was not carcinogenic in rats and mice. Compounds 13, 14, 15, 16, 17 and 28 were selected for molecular docking into Caspase 3. Docking showed hydrophobic interactions, hydrogen and covalent bonds performed to maintain the stability of caspase 3, and cis-uvariamicin IV stood out more through the energies and chemical bonds of this parameter. The chloroform fraction from the methanolic extract of the seeds showed activity against triple-negative breast cancer, both in vitro and in vivo, and only muricatacin has studies in which the antitumor activity was evaluated in vitro and showed to be very promising. In summary, muricatacin and cis-uvariamicin IV appear to be very promising as antitumors, especially cis-uvariamicin IV.
RESUMEN
Gastric cancer is among the major causes of death from neoplasia leading causes of death worldwide, with high incidence rates and problems related to its treatment. Here, we outline how Geissospermum sericeum exerts antitumor activity on the ACP02 cell line (human gastric adenocarcinoma) and the mechanism of cell death. The ethanol extract and fractions, neutral fraction and alkaloid fraction, were characterized by thin-layer chromatography and HPLC-DAD, yielding an alkaloid (geissoschizoline N4-methylchlorine) identified by NMR. The cytotoxicity activity of the samples (ethanol extract, neutral fraction, alkaloid fraction, and geissoschizoline N4-methylchlorine) in HepG2 and VERO cells was determined by MTT. The ACP02 cell line was used to assess the anticancer potential. Cell death was quantified with the fluorescent dyes Hoechst 33342, propidium iodide, and fluorescein diacetate. The geissoschizoline N4-methylchlorine was evaluated in silico against caspase 3 and 8. In the antitumor evaluation, there was observed a more significant inhibitory effect of the alkaloid fraction (IC50 18.29 µg/mL) and the geissoschizoline N4-methylchlorine (IC50 12.06 µg/mL). However, geissoschizoline N4-methylchlorine showed lower cytotoxicity in the VERO (CC50 476.0 µg/mL) and HepG2 (CC50 503.5 µg/mL) cell lines, with high selectivity against ACP02 cells (SI 39.47 and 41.75, respectively). The alkaloid fraction showed more significant apoptosis and necrosis in 24 h and 48 h, with increased necrosis in higher concentrations and increased exposure time. For the alkaloid, apoptosis and necrosis were concentration- and time-dependent, with a lower necrosis rate. Molecular modeling studies demonstrated that geissoschizoline N4-methylchlorine could occupy the active site of caspases 3 and 8 energetically favorably. The results showed that fractionation contributed to the activity with pronounced selectivity for ACP02 cells, and geissoschizoline N4-methylchlor is a promising candidate for caspase inhibitors of apoptosis in gastric cancer. Thus, this study provides a scientific basis for the biological functions of Geissospermum sericeum, as well as demonstrates the potential of the geissoschizoline N4-methylchlorine in the treatment of gastric cancer.