Alkaloid from Geissospermum sericeum Benth. & Hook.f. ex Miers (Apocynaceae) Induce Apoptosis by Caspase Pathway in Human Gastric Cancer Cells.
Mirian Letícia Carmo BastosJoão Victor Silva-SilvaJorddy Nevez CruzAmanda Roberta Palheta da SilvaAlexandre Augusto Bentaberry-RosaGisele da Costa RamosJosé Edson de Sousa SiqueiraMárlia Regina Coelho-FerreiraSandro PercárioPatrícia Santana Barbosa MarinhoAndrey Moacir do Rosario MarinhoMarcelo de Oliveira BahiaMaria Fani DolabelaPublished in: Pharmaceuticals (Basel, Switzerland) (2023)
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 (IC 50 12.06 µg/mL). However, geissoschizoline N4-methylchlorine showed lower cytotoxicity in the VERO (CC 50 476.0 µg/mL) and HepG2 (CC 50 503.5 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.
Keyphrases
- cell cycle arrest
- cell death
- induced apoptosis
- endoplasmic reticulum stress
- oxidative stress
- pi k akt
- endothelial cells
- ms ms
- signaling pathway
- magnetic resonance
- mass spectrometry
- risk factors
- radiation therapy
- risk assessment
- induced pluripotent stem cells
- human health
- rectal cancer
- high grade
- aqueous solution
- living cells
- drug induced
- molecular docking