ABSTRACT
We examined the anticancer effects of a novel sirtuin inhibitor, MHY2256, on HCT116 human colorectal cancer cells to investigate its underlying molecular mechanisms. MHY2256 significantly suppressed the activity of sirtuin 1 and expression levels of sirtuin 1/2 and stimulated acetylation of forkhead box O1, which is a target protein of sirtuin 1. Treatment with MHY2256 inhibited the growth of the HCT116 (TP53 wild-type), HT-29 (TP53 mutant), and DLD-1 (TP53 mutant) human colorectal cancer cell lines. In addition, MHY2256 induced G0/G1 phase arrest of the cell cycle progression, which was accompanied by the reduction of cyclin D1 and cyclin E and the decrease of cyclin-dependent kinase 2, cyclin-dependent kinase 4, cyclin-dependent kinase 6, phosphorylated retinoblastoma protein, and E2F transcription factor 1. Apoptosis induction was shown by DNA fragmentation and increase in late apoptosis, which were detected using flow cytometric analysis. MHY2256 downregulated expression levels of procaspase-8, -9, and -3 and led to subsequent poly(ADP-ribose) polymerase cleavage. MHY2256-induced apoptosis was involved in the activation of caspase-8, -9, and -3 and was prevented by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor. Furthermore, the autophagic effects of MHY2256 were observed as cytoplasmic vacuolation, green fluorescent protein-light-chain 3 punctate dots, accumulation of acidic vesicular organelles, and upregulated expression level of light-chain 3-II. Taken together, these results suggest that MHY2256 could be a potential novel sirtuin inhibitor for the chemoprevention or treatment of colorectal cancer or both.
ABSTRACT
BACKGROUND AND OBJECT: Cheiro-oral syndrome (COS) is characterized by a sensory disturbance in the unilateral hand and ipsilateral mouth corner. It is usually due to a lesion in the parietal cortex, thatamocortical projections, thalamus, or rarely brain stem. However, the syndrome is relatively unknown and rarely mentioned in most neurological textbooks. We presented ten cases of COS with a review of the clinical symptoms and signs and the neuroradiological methods used to demonstrate the responsible site. METHODS AND RESULTS: We studied 10 patients with stroke who showed restricted sensory disturbance on the one hand and ispilateral mouth. The study forms consisted of clinical manifestaion, neurological examination, electrophysiological, and neuroradiologic studies. Computed tomography and/or magnetic resonance imaging identified lesion in the thalamus in 5, brain stem in 3, and corona radiata in 1 patient. But, the anatomical responsible site for one case was not founded. Infarction had occurred in nine cases and hemorrhage in one. Seven of the 10 patients showed sensory disturbances restricted to the perioral area, hands, fingers when they were first examined; the remaining patients complained more diffuse sensory disturbances at first, but it had become restricted to perioral and fingers, usually within 2-3 weeks. The durations of symptom varied from 5 days to more than 15 months and these symptoms were improved within 2-3 weeks to 4 months in treated patients. CONCLUSION: When the symptoms and signs of the COS were presented, especially if a history of migraine is lacking, neuroradiological methods such as CT or MRI should be undertaken to localize and diffentiate the nature of lesion.