RESUMO
In this work, we report 14 novel quinazoline derivatives as immune checkpoint inhibitors, IDO1 and PD-L1. The antitumor screening of synthesized compounds on ovarian cancer cells indicated that compound V-d and V-l showed the most activity with IC50 values of about 5 µM. Intriguingly, compound V-d emerges as a stand out, triggering cell death through caspase-dependent and caspase-independent manners. More importantly, V-d presents its ability to hinder tumor sphere formation and re-sensitized cisplatin-resistant A2780 cells to cisplatin treatment. These findings suggest that compound V-d emerges as a promising lead candidate for the future development of immuno anticancer agents.
Assuntos
Antineoplásicos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Checkpoint Imunológico , Quinazolinas , Humanos , Quinazolinas/farmacologia , Quinazolinas/química , Quinazolinas/síntese química , Relação Estrutura-Atividade , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/síntese química , Inibidores de Checkpoint Imunológico/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Estrutura Molecular , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Proliferação de Células/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismoRESUMO
Pavetta indica L. is used in traditional medicine for the treatment of various diseases including hemorrhoids, headache, urinary conditions, ulcerated nose, and dropsy. However, no study has evaluated the anticancer effect of P. indica L. In this study, we found that a methanol extract of the leaves and branches of P. indica L. (MEPI) caused cellcycle arrest at the sub-G1 phase and induced apoptosis, as indicated by the activation of caspase-8, -3, -7, and c-PARP. Western blotting revealed that MEPI significantly reduced the levels of markers of the epithelial-mesenchymal transition, such as Vimentin, Snail, Slug, and matrix metallopeptidase 9. Notably, the expression of multidrug resistance-associated protein 1 in triple negative breast cancer (TNBC) was significantly decreased by MEPI. Moreover, the co-treatment with MEPI and doxorubicin resulted in a synergistic reduction in cell viability. MEPI also induced radiation sensitization of TNBC cells. Gas chromatography-mass spectrometry analysis revealed that 5,6-dehydrokawain (DK) is the major constituent of MEPI. Interestingly, DK exerted significant anti-invasive and anti-metastatic effects. Our results provide a strong rationale for investigating the molecular mechanisms of action of MEPI in TNBC.
