The ATRA-induced differentiation of medulloblastoma cells is enhanced with LOX/COX inhibitors: an analysis of gene expression

Abstract

BackgroundA detailed analysis of the expression of 440 cancer-related genes was performed after the combined treatment of medulloblastoma cells with all-trans retinoic acid (ATRA) and inhibitors of lipoxygenases (LOX) and cyclooxygenases (COX). The combinations of retinoids and celecoxib as a COX-2 inhibitor were reported to be effective in some regimens of metronomic therapy of relapsed solid tumors with poor prognosis. Our previous findings on neuroblastoma cells using expression profiling showed that LOX/COX inhibitors have the capability of enhancing the differentiating action of ATRA. Presented study focused on the continuation of our previous work to confirm the possibility of enhancing ATRA-induced cell differentiation in these cell lines via the application of LOX/COX inhibitors. This study provides more detailed information concerning the mechanisms of the enhancement of the ATRA-induced differentiation of medulloblastoma cells.MethodsThe Daoy and D283 Med medulloblastoma cell lines were chosen for this study. Caffeic acid (an inhibitor of 5-LOX) and celecoxib (an inhibitor on COX-2) were used in combined treatment with ATRA. The expression profiling was performed using Human Cancer Oligo GEArray membranes, and the most promising results were verified using RT-PCR.ResultsThe expression profiling of the selected cancer-related genes clearly confirmed that the differentiating effects of ATRA should be enhanced via its combined administration with caffeic acid or celecoxib. This effect was detected in both cell lines. An increased expression of the genes that encoded the proteins participating in induced differentiation and cytoskeleton remodeling was detected in both cell lines in a concentration-dependent manner. This effect was also observed for the CDKN1A gene encoding the p21 protein, which is an important regulator of the cell cycle, and for the genes encoding proteins that are associated with proteasome activity. Furthermore, our results showed that D283 Med cells are significantly more sensitive to treatment with ATRA alone than Daoy cells.ConclusionsThe obtained results on medulloblastoma cell lines are in accordance with our previous findings on neuroblastoma cells and confirm our hypothesis concerning the common mechanism of the enhancement of ATRA-induced cell differentiation in various types of pediatric solid tumors.

Celecoxib-Loaded Solid Lipid Nanoparticles for Colon Delivery: Formulation Optimization and In Vitro Assessment of Anti-Cancer Activity

“…F9-induced cell death is also significantly higher than that observed with CXB-loaded PEGylated liposomes by Erdo g et al [72], who demonstrated that CXB-loaded PEGylated liposomes reduced the viability of HT-29 cells by about 0, 35 and 45% after 24, 48 and 72 h of incubation using a final liposomal CXB concentration of 100 µM (higher than our concentration of 89.15 µM). Despite the fact that CXB has been reported by many researchers to inhibit the growth of HepG2 [73] and Daoy cells [74], we believe we are the first to show the effects of CXB nanoparticles on these two cell lines. The significantly higher cytotoxicity observed with F9 than with F14 in the three cell lines suggests that Tween 80-stabilized SLN increases CXB cytotoxicity more than Cremophor EL-stabilized SLN, however the mechanism is unknown.…”

Caffeic acid, a dietary polyphenol, as a promising candidate for combination therapy

“…The mechanism target by this novel combination was cell proliferation, angiogenesis, and apoptosis for its anti-neoplastic effect (Paukovcekova et al 2020). The mechanism for the anti-neoplastic effect was further studied and even reported the synergistic effect of CA on ATRA in medulloblastoma cell lines (Chlapek et al 2014). These results warrant the scope of testing such a combination in the preclinical and clinical setup (Martinez-outschoorn et al 2017).…”

Why Differentiation Therapy Sometimes Fails: Molecular Mechanisms of Resistance to Retinoids

“…The capability of retinoids to induce cell differentiation of transformed cells was confirmed on various tumor types including promyelocytic leukemia [ 7 ], NBL [ 8 ], choriocarcinoma [ 9 ], and teratocarcinoma [ 10 ]. For example, the differentiating effects of retinoids encompass the increased expression of cell surface differentiation markers in myeloid leukemia cells [ 11 ], alterations in cell morphology and formation of neurite extensions in NBL [ 12 ], and growth inhibition and typical changes in gene expression in NBL and medulloblastoma cells [ 12 , 13 , 14 ].…”