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Introduction
Multiple myeloma (MM) is the second most common hematological malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (1). The first-line treatment strategies for MM are combination regimens, including proteasome inhibitors and immunomodulatory agents. Bortezomib (BTZ) is the first proteasome inhibitor to be approved by the Food and Drug Administration (USA) for clinical use in patients with MM. The degradation of damaged or misfolded proteins is crucial in myeloma plasma cells, and BTZ treatment leads to a wide number of intracellular pleiotropic effects, including cell cycle arrest, induction of apoptosis and deregulation of nuclear factor-κB (NF-κB) activity by preventing the normal breakdown of proteins in MM (2,3). In addition, the incorporation of BTZ and novel immunomodulatory therapeutic agents, particularly thalidomide and lenalidomide, has markedly improved the rate of complete remission, progression-free survival, and overall survival in patients with MM (4,5). However, despite available therapeutic strategies, MM remains incurable (6).
MM has a complex pathogenesis, which involves chromosomal instability (7), microRNA expression (8) and DNA methylation (9). DNA methylation is an epigenetic event that occurs at the cytosine residues in CpG dinucleotides and is catalyzed by DNA methyltransferase enzymes (DNMTs). DNA methylation is associated with gene silencing, which is important for the occurrence and development of MM (10). Therefore, it is possible that DNA methyltransferase inhibitors may be of benefit in the current clinical therapy of MM. Decitabine (5-aza-2′-deoxycytidin; DAC) is an epigenetic therapeutic agent that inhibits DNA methylation, which has been approved for the treatment of myelodysplastic syndrome and older patients with acute myeloid leukemia (AML) (11,12). In addition to its use in hematological malignancy, DAC also exhibits antineoplastic effects against solid tumors (13–16). The molecular mechanism underlying its antitumor activity is that DAC induces DNMT inhibition, which contributes to DNA hypomethylation, gene activation, cell differentiation and apoptosis (17,18).
Therapeutic agents used in combination often have synergistic anti-tumor effects and reduced side effects as lower concentrations of each individual agent are used. The present study investigated whether DAC may synergize with the frequently used anti-myeloma agent, BTZ. The results of the current study indicated that the anti-MM activity of the two agents was mutually reinforced, which resulted in an enhanced effect of proliferation inhibition, increased apoptosis and G0-G