Abstract
Hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with refractory lymphomas. Nucleoside analogs (NAs) and DNA alkylating agents are efficacious in treating hematologic malignancies. To design an efficacious and more economical pretransplant regimen for lymphoma patients, we analyzed the cytotoxicity of cladribine (Clad), gemcitabine (Gem), busulfan (Bu), and suberoylanilide hydroxamic acid (SAHA) in lymphoma cell lines. J45.01 and U937 lymphoma cell lines were exposed to drugs, alone or in combination, for 48hours and analyzed with the MTT and annexin V assays, Western blotting, and flow cytometry. On the basis of the IC5-10 values of the drugs, the Clad+Gem+Bu combination inhibited the proliferation of both cell lines to ∼55%-60%. Addition of SAHA to this combination decreased proliferation further to ∼30%. Exposure to the Clad+Gem+Bu+SAHA combination activated the DNA damage response and ATM-CHK2 pathway; modified histones; decreased mitochondrial membrane potential, which caused leakage of apoptosis-inducing factors; and activated apoptosis. Pretreatment of cells with the pan-caspase inhibitor Z-VAD-FMK blocked the phosphorylation of histone 2AX and cleavage of PARP-1 and caspases. The Clad+Gem+Bu+SAHA combination provides synergistic cytotoxicity in lymphoma cell lines. Our results may be a basis for using this combination as a pretransplant conditioning regimen in a clinical trial for lymphoma patients undergoing hematopoietic stem cell transplantation, replacing the more expensive nucleoside analog clofarabine.
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