Abstract
Curcumin is a potential anticancer drug with poor bioavailability, which limits its clinical use as a therapeutic agent. The aim of this study was a preliminary evaluation of the curcumin analogue CH-5 as a cytotoxic agent in human osteosarcoma cell lines U2OS, MG-63, and Saos-2. CH-5 inhibited cell viability at lower concentrations than curcumin, leading to the induction of apoptosis. The cellular levels of the transcription factors p53 and Sp1 affect the expression of cellular pathways that lead to apoptosis. CH-5 increased p53 protein levels in U2OS cells and reduced Sp1 levels, with a consequent effect on the expression of their target genes DNA methyltransferase 1 (DNMT1) and growth arrest and DNA damage-inducible 45 alpha gene (Gadd45a). CH-5 repressed DNMT1 and increased Gadd45a mRNA expression, which was dependent on p53, as this effect was only observed in the colorectal cancer cell line HCT116 with active p53, but not in the isogenic p53-deficient HCT116 cells. CH-5 also reduced the protein levels of DNMT1, which led to the upregulation of Gadd45a. These results suggest that CH-5 has potentially higher anticancer activity than curcumin, which is associated with the expression of apoptosis-associated genes regulated by the transcription factors Sp1 and p53. Future work on CH-5 will define the therapeutic potential of this compound in vivo.
Highlights
Osteosarcoma (OS) is a rare but highly malignant cancer of the bone that occurs in any part of the skeleton and mostly affects children, adolescents, and young adults [1]
The results show that CH-5 is more potent than curcumin, and its anticancer activity could be mediated by the stabilization and downregulation of the transcription factors p53 and SP1, respectively, resulting in the activation of apoptosis by modulation of the expression of their target genes DNA methyltransferase 1 (DNMT1) and Gadd45a
We performed the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) reduction colorimetric assay to determine the effect of CH-5 and curcumin on cell viability of OS cell lines U2OS, Saos-2, and MG-63
Summary
Osteosarcoma (OS) is a rare but highly malignant cancer of the bone that occurs in any part of the skeleton and mostly affects children, adolescents, and young adults [1]. The current treatment includes local control surgery associated with multidrug systemic chemotherapy. Despite the efficacy of these drugs, the very high propensity for local invasion and distant metastasis negatively affects the survival rate, which for metastatic patients is roughly 20% to 30% [3]. In these patients, multidrug resistance (MDR) is a major mechanism of resistance to chemotherapy that becomes an obstacle to successful treatment [4]. There are considerable side effects associated with the drugs used in OS chemotherapy, which include cardiotoxicity, nephrotoxicity, neurotoxicity, and induction of secondary neoplasia. More selective and effective chemotherapeutics are needed for OS
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