Avaliação in vitro do potencial citotóxico de rubrolídeos sintéticos em linhagens celulares tumorais humanas

Abstract

Cancer is a major public health problem worldwide, and in Brazil it represents the second group of diseases with the highest mortality rate. Chemotherapy is one of the main strategies to combat cancer, and the development of new drugs with anti-tumor properties is the main investment bias in the pharmaceutical industry. Rubrolides are naturally occurring compounds and have shown biological properties already described in the literature, which are; herbicidal, anti-bacterial and anti-cancer activities. This work aimed to study the cytotoxic potential, genotoxic and death patterns associated with the treatment with synthetic rubrolide analogues in tumor cell lines. Thus, 45 rubrol analogs converted to γ-hydroxy-γ-lactams, γ-alkylidene-γ-lactone and pyridazin-3 (2H) -one were tested against four tumor cell lines (HL-60, human leukemia; -116, human colon, SF-295, human central nervous system and OVCAR-8, human ovary). Among all compounds tested, seven caused the greatest percentage of cell viability reduction (% CVR> 80%) for tested cell lines and the more active compounds have halogen substituents on the aromatic ring. Compounds 10a and 14i were the most active (IC 50 = 0.66 and 1.78 μg / mL, respectively) against HL-60. Targeting a more detailed understanding on the mechanism underlying 10a and 14i cytotoxicity, studies involving DNA fragmentation, cell cycle analysis, phosphatidylserine externalization and mitochondrial depolarization, and analysis of caspase-7 expression performed on the HL-60 cell line, using doxorubicin as a positive control. The results indicate that the cytotoxicity of 10a and 14i involves the induction of cell death by apoptosis. Cell cycle analysis showed that 14i caused the accumulation of HL-60 cells in the G0 / G1 phase in 2.5 and 5 μM. The evaluation of the protein expression of cyclic E1 revealed a slight reduction of this expression by 14i, in the concentration of 5 μM. The molecules 10a and 14i present important mutagenic and selective genotoxic activity for HL-60 cells.