Clinical Relevance of Differential RARα and PPARß/δ Expression in Myelodysplastic Syndromes.

BACKGROUND/AIM: Myelodysplastic syndromes (MDS) are clinically heterogeneous hematological malignancies with an increased risk of transformation to acute myeloid leukemia, emphasizing the importance of identifying new diagnostic and prognostic markers. This study sought to investigate the predictive ability of all-trans retinoic acid (ATRA)-dependent nuclear transcription factors RARα and PPARß/δ gene expression in MDS patients. MATERIALS AND METHODS: Peripheral blood specimens were collected from 49 MDS patients and 15 healthy volunteers. The specimens were further separated in Ficoll density gradient to obtain the mononuclear cells fractions. Gene expression analysis was carried out using quantitative real-time polymerase chain reaction (qRT-PCR) technique. RESULTS: In the mononuclear cell fractions of MDS patients, RARα expression was increased (p<0.05) and PPARß/δ expression was decreased (p<0.01) compared to healthy volunteers. When RARα and PPARß/δ expression was compared in groups of MDS patients with different risks of disease progression, no statistically significant difference was found for RARα expression, while PPARß/δ expression was significantly lower in the high-risk group of patients compared to the low-risk group (p<0.05). The expression of RARα was significantly associated with overall survival (p<0.05). ROC analysis showed that the expression of PPARß/δ, rather than RARα expression, could have potential diagnostic value for MDS patients (AUC=0.75, p=0.003 and AUC=0.65, p=0.081, respectively). CONCLUSION: RARα and PPARß/δ genes are putative biomarkers that may be associated with the diagnosis and prognosis of MDS.

Evaluation of VEGF and VEGFR gene expression as prognostic markers in low and intermediate­1 risk patients with myelodysplastic syndromes.

Vascular endothelial growth factors (VEGFs) are angiogenic factors playing a key role in tumor development. VEGFs are produced by different normal and tumor cells, including platelets, lymphocytes and mononuclear cells of peripheral blood. VEGF (VEGF-A, VEGF-C and VEGF-D) and VEGFR (VEGFR1, VEGFR2 and VEGFR3) gene expression was studied in patients with myelodysplastic syndrome (MDS) to evaluate the possible prognostic role of the expression of these genes. Gene expression levels were determined using peripheral blood samples of 51 patients with MDS and 15 healthy volunteers by quantitative PCR. Expression of all VEGF and VEGFR genes was elevated in patients with MDS compared with healthy volunteers. No association of VEGF-A expression with the hemoglobin content in peripheral blood was found. The analyses of gene expression in patients with MDS stratified by risk groups according to the International Prognostic Scoring System showed progressive augmentation of VEGF-A gene expression from low to high-risk groups and VEGFR1 and VEGFR2 expression from intermediate-1 to high-risk groups. The statistically significant difference in survival time of patients with high and low levels of VEGFR1 expression was revealed. VEGF-A/VEGFR1 expression may be important for risk evaluation of patients with MDS.

A novel glycosylated indolocarbazole derivative LCS1269 effectively inhibits growth of human cancer cells in vitro and in vivo through driving of both apoptosis and senescence by inducing of DNA damage and modulating of AKT/mTOR/S6K and ERK pathways.

In recent decades, indolocarbazole glycosides containing sugar moieties have attracted attention due to their diverse anti-tumor activities. In the present study, a series of new indolo [2,3-a]pyrrolo [3,4-c]carbazole derivatives were synthesized for the first time. First of all, we have shown that compound 6e (LCS1269) had the most pronounced effect on inhibiting tumor growth in the transferable solid and non-solid murine tumors as compared with other synthesized indolocarbazole derivatives. The results of the in vivo nude mice xenoraft study also confirmed that LCS1269 treatment strongly suppressed the growth of human colon cancer SW620 xenografts. It is important to note that the antiproliferative activity of LCS1269 against three human cancer cell lines (MCF-7, HCT-116 and A549) was considerably higher than that against the non-tumor cell lines (immortalized breast cells and normal embryonic fibroblasts). Furthermore, the treatment of MCF-7, HCT-116 and A549 cells with LCS1269 caused the statistically significant inhibition of anchorage-dependent and anchorage-independent colony formation. We further revealed that LCS1269 treatment of investigated human cancer cells resulted in the DNA damage and G2/M cell cycle arrest followed by the decrease of mitochondrial membrane potential with subsequent initiation of intrinsic apoptosis and the triggering of senescence via p53-dependent mechanisms. In addition, our western blotting findings and molecular docking data suppose that LCS1269 could at least partially attenuate cancer cells growth by modulation of AKT/mTOR/S6K and ERK signaling pathways. Therefore, we concluded that LCS1269 might be the promising compound for implementation and probable use in the clinical practice.