β-Carboline derivatives are potent against Acute Myeloid Leukemia in vitro and in vivo

Author(s)

Bueno, Maura Lima Pereira ; Foglio, Mary Ann ; Barea, Paula ; de Oliveira, Aline Rufino ; Sarragiotto, Maria Helena ; Saad, Sara T. Olalla ; Roversi, Fernanda Marconi

• Document type: Journal article
• Source: PHARMACOLOGICAL REPORTS; v. 76, n. 4, p. 13-pg., 2024-06-20.

Abstract

Background beta-carboline alkaloids exert a distinguished ability to impair cell growth and induce cell death in a variety of cancers and the evaluation of such new therapeutic candidates may denote new possibilities for leukemia treatment. In this present study, we screened 12 beta-carboline derivatives containing different substituents at 1- and 3-positions of beta-carboline nucleus for their antineoplastic activities in a panel of leukemia cell lines.MethodsThe cytotoxic effects of the beta-carboline derivatives were evaluated in different leukemia cell lines as well as reactive oxygen species (ROS) generation, autophagy, and important signaling pathways.ResultsTreatment with the beta-carboline derivatives resulted in a potent antineoplastic activity leading to a reduced cell viability that was associated with increased cell death in a concentration-dependent manner. Interestingly, the treatment of primary mononuclear cells isolated from the peripheral blood of healthy donors with the beta-carboline derivatives showed a minor change in cell survival. The antineoplastic activity occurs by blocking ROS production causing consequent interruption of the PI3K/AKT and MAPK/ERK signaling and modulating autophagy processes. Notably, in vivo, AML burden was diminished in peripheral blood and bone marrow of a xenograft mouse model.ConclusionsOur results indicated that beta-carboline derivatives have an on-target malignant cell-killing activity and may be promising candidates for treating leukemia cells by disrupting crucial events that promote leukemia expansion and chemotherapy resistance. (AU)

• FAPESP's process: 17/21801-2 - Predictors of severity and new treatments for bone marrow neoplasias
• Grantee: Sara Teresinha Olalla Saad
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/25247-5 - Study of inhibitory and antitumor activity of natural substance-associated MAPK and WNT inhibitors in in vitro models
• Grantee: Maura Lima Pereira Bueno
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 21/05320-0 - Profile of Brazilian undergraduates who use electronic cigarettes: an epidemiological study on forbidden use
• Grantee: Gabriella dos Santos Maximino
• Support Opportunities: Scholarships in Brazil - Scientific Initiation