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Introduction
Fibrosarcoma is a malignant cancer that originates in the connective tissue found at the ends of bones of the legs or arms, and then spreads to the surrounding soft tissues. Soft tissues include joint tissue, blood vessels, fat, muscles, tendons, and fibrous tissue. Although fibrosarcoma-related morbidity is rare, patient survival rates are low (1).
During the last few decades, epigenetics has been one of the emerging fields in cancer research (2). Epigenetics affects the transcription of cells, thereby regulating gene expression. Abnormal epigenetic changes can have adverse effects on the organism. Methylation of cytosine-phosphate-guanine (CpG) islands in the promoter region of a gene has now been strongly linked to gene silencing.
DNA methylation is regulated by DNA methyltransferases (DNMT1, DNMT3A and DNMT3B), which catalyze the transfer of a methyl group from S-adenosyl-l-methionine (SAM) to the cytosine of a CpG dinucleotide (adjacent within a single DNA strand), immediately following replication (3).
DNMTs are classified as maintenance or de novo methyltransferases. Maintenance DNMT1 binds methyl groups to methylated DNA during replication, whereas de novo DNMT3A and DNMT3B add methyl groups to CpG dinucleotides of unmethylated DNA. Previous reports have shown that some anticancer cascades abnormally activate the DNMT1, enzyme that maintains the DNA methylation pattern (3).
When the levels of DNMT1 decrease, as is the case following azacytidine or decitabine treatment, daughter strands are less likely to undergo maintenance to restore full methylation; thus, with each replication, CpG pairs become unmethylated, rendering their promoter regions more accessible to transcription factors.
DNA damage induced by 5′-azacytidine (5′-aza) is reversible, since the drug does not influence de novo DNMT synthesis (4–6). 5′-aza has been used clinically for treating diverse diseases such as acute myelogenous leukemia, hematological malignancies, gastrointestinal, lung, ovarian, prostate, breast, and head and neck cancers, melanoma, and malignant mesothelioma (7). Global hypomethylation is a hallmark of cancer (8). It was believed that global hypomethylation principally targets repetitive sequences, but some genes involved in metastasis were also previously indicated to be hypomethylated in cancers (9).
There are three major isoforms of cyclooxygenase (COX), COX-1, COX-2, and COX-3. COX-1, a constitutive isoform, plays a role in modulating physiologic activities in tissues. COX-2 is an inducible isoform of the enzyme that responds to specific stimuli such as growth factor,...