Investigação translacional dos compostos bioativos n-acilidrazona e homoisoflavona: perspectivas pré-clínicas para o desenvolvimento de novos agentes antineoplásicos

Abstract

Cancer remains one of the leading causes of morbidity and mortality worldwide, highlighting the need for the development of more effective and safer therapeutic approaches. In this context, the present study aimed to investigate, under a translational approach, the anticancer potential of the bioactive compounds homoisoflavone LQB-859 and the N-acilidrazone LASSBio-1920 through different experimental strategies. For LQB-859, assays were performed in acute myeloid leukemia cell lines to determine its cytotoxic activity and to elucidate its mechanisms of action. The compound exhibited significant cytotoxic effects associated with the induction of oxidative stress, mitochondrial dysfunction, and DNA damage. Differences in sensitivity among the evaluated cell lines were observed, possibly related to variations in antioxidant defense systems and ferroptosis regulation. In silico studies suggested interactions with key proteins involved in this process, such as FSP1 and DHODH, supporting the experimental findings. For LASSBio-1920, toxicity studies were conducted NOD-SCID mice, including the determination of acute toxicity (LD50 ) and maximum tolerated dose, as well as the evaluation of antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116). The results demonstrated a dose-dependent toxicity and limitations related to bioavailability in the murine model. Despite these limitations, intratumoral administration significantly delayed tumor growth, highlighting its in vivo antitumor potential. Taken together, the results indicate that LQB-859 stands out due to its mechanism of action involving oxidative stress induction and eventual ferroptosis in leukemic cells, while LASSBio-1920 shows potential as an in vivo antitumor agent, although optimization of its pharmacokinetic properties is required. Therefore, both compounds represent promising candidates for the development of novel anticancer therapies, contributing to the advancement of translational research in oncology.