Background Cladribine or 2-chlorodeoxyadenosine (2-CDA) is a well-known purine nucleoside analog with particular activity against lymphoproliferative disorders, such while hairy cell leukemia (HCL). with cladribine lead in a significant G1 police arrest in U266 and RPMI8226 cells, but just a small boost in the G1 phase for MM1.S cells. Apoptosis assays with Annexin V-FITC/PI double staining indicated that cladribine induced apoptosis of U266 cells in a dose-dependent manner. Similar results were obtained with an apoptotic-ELISA showing that cladribine dramatically promoted MM1.S and RPMA8226 cells undergoing apoptosis. On the molecular level, cladribine induced PARP cleavage and activation of caspase-8 and caspase-3. Meanwhile, treatment with cladribine led to a remarkable reduction of the phosphorylated STAT3 (P-STAT3), but had little effect on Rabbit polyclonal to ACN9 STAT3 protein levels. The combinations of cladribine and a specific STAT3 inhibitor as compared to either agent alone significantly induced apoptosis in all three MM cell lines. Conclusions Cladribine exhibited inhibitory effects on MM cells in vitro. MM1.S is the only cell line showing significant response to the clinically achievable concentrations of cladribine-induced apoptosis and inactivation of STAT3. Our data suggest that MM patients with the features of MM1.S cells may particularly benefit from cladribine monotherapy, whereas cladribine in combination with STAT3 inhibitor exerts a broader therapeutic potential against MM. Background Multiple myeloma (MM) is a plasma cell malignancy characterized by specific genetic and epigenetic changes. Although many advances have been achieved in recent studies, MM remains an incurable disease and novel treatment strategies or agents are urgently needed [1,2]. A number of purine nucleoside analogs are rationally designed anticancer drugs that exert cytotoxicity via inhibition of DNA and RNA synthesis, and are currently used in the treatment of hematologic malignancies [3,4]. Cladribine (also known as 2-chlorodeoxyadenosine, 2-CDA) is an adenosine deaminase-resistant 2-deoxypurine nucleoside analog which requires phosphorylation by deoxycytidine kinase. Since this enzyme is mainly expressed in lymphocytes, cladribine is primarily active in lymphoid tissues [5]. Cladribine exerts remarkable activity in hairy cell leukemia (HCL), a chronic B-cell lymphoproliferative disorder, producing prolonged complete remissions in most patients [6,7]. Although cladribine is particularly cytotoxic to malignant B-cells and T-cells, and is widely used in HCL [8-10], it has not been approved to 243967-42-2 supplier treat other lymphoid malignancies. Increasing evidences suggest that cladribine administered in combination with recently approved novel agents may be a 243967-42-2 supplier valuable and safe treatment for patients with chronic lymphocutic leukemia (CLL) [11,12] and other lymphoid disorders, such as lymphoplasmacytic lymphoma, marginal zone lymphoma, and mantle cell lymphoma [13]. Although cladribine has been used for patients with low grade lymphoma and Waldenstrom’s macroglobulinemia [14], it has only been studied in a limited manner in patients with MM, without much success [15]. Several studies have suggested that since “cladribine has a narrow spectrum of activity within the B-cell progeny” it may yet prove to be useful in subsets of patients with MM [16], because the self-renewing population of MM, arises at early B-cell precursors [17]. In vitro, the inhibitory effects of cladribine on MM cell lines are conflicting. While some studies observe completely negative results [18,19], others showing that cladribine has a marked heterogeneous effect on different MM cell lines [5] and clearly inhibits proliferation of RPMI8226 cells at high concentrations [20]. The precise molecular mechanisms by which MM cells show different responsiveness to cladribine remain unclear. It has been reported that cladribine induces accumulation of DNA strand breaks, and subsequently activates 243967-42-2 supplier the tumor suppressor p53 in lymphocytes [21]. While mutation or deletion.