Um novo complexo sulfonilditiocarbimato de índio(III) apresenta atividade anticâncer in vitro contra células de câncer colorretal

Abstract

Colorectal cancer (CRC) ranks among the most prevalent and lethal tumors worldwide. Despite therapeutic advances, available options still present limitations related to toxicity and chemoresistance, highlighting the need for novel alternatives. The aim of this study was to investigate the cytotoxic effect and molecular mechanisms associated with the action of the indium(III) sulfonyldithiocarbimate complex (InFP) in CRC cell lines. Using the MTT assay, the concentration capable of inhibiting 50% of cell viability (IC50) was evaluated in HCT-116, HT-29, LoVo, and HEK-293 cell lines, revealing that InFP was more cytotoxic to HCT-116 cells (IC50: 2.87 ± 0.14 μM). Doxorubicin (DXR) was used as the reference drug, showing an IC50 of 2.53 ± 0.14 μM. When compared to the non-tumorigenic HEK-293 cell line (IC50: 107.7 ± 2.07 μM), the selectivity index (SI) was 37.53 and 0.20 for InFP and DXR, respectively, indicating that the compound is more selective than the reference drug. InFP induced cell death by apoptosis, evidenced by chromatin condensation and fragmentation, as well as membrane blebbing, observed through confocal laser fluorescence microscopy using acridine orange (AO) and propidium iodide (PI). Quantification showed a significant increase in early apoptotic cells at the lowest concentration tested (1.5 μM: 71.62 ± 3.76%; p < 0.05), whereas higher concentrations significantly increased late apoptosis/necrosis (76.57 ± 1.15% and 84.29 ± 1.03% for 3 and 6 μM, respectively; p < 0.05). Hoechst 34580 staining confirmed chromatin condensation, with fluorescence increasing by 122.1 ± 12.36% and 173.0 ± 12.53% (3 and 6 μM, respectively; p < 0.01) in HCT-116 cells. JC-1 staining revealed that InFP induces loss of mitochondrial membrane potential (ΔΨm), indicating that apoptosis occurs via the intrinsic pathway. Moreover, the cytotoxic effect of InFP was dependent on oxidative stress. Pretreatment with the antioxidant N-acetylcysteine (NAC, 5 mM) significantly prevented compound-induced cytotoxicity (viability > 80% for 3 μM InFP). The involvement of MAPK signaling pathways was also investigated using the inhibitors SP600125 (JNK), U0126 (MEK/ERK1/2), and PD169316 (p38). Inhibition of JNK (viability < 23% at 1.5 μM InFP) and p38 (viability < 45% at 1.5 μM InFP) enhanced the cytotoxic effect of InFP. These findings demonstrate that InFP induces apoptosis in HCT-116 cells in an oxidative stress-dependent manner, modulated by MAPKs, establishing it as a promising candidate for CRC treatment.