Abstract
HDAC inhibitors, DNA alkylators and nucleoside analogs are effective components of combination chemotherapy. To determine a possible mechanism of their synergism, we analyzed the effects of HDAC inhibitors on the expression of drug transporters which export DNA alkylators. Exposure of PEER lymphoma T-cells to 15 nM romidepsin (Rom) resulted in 40%-50% reduction in mRNA for the drug transporter MRP1 and up to ~500-fold increase in the MDR1 mRNA within 32-48 hrs. MRP1 protein levels concomitantly decreased while MDR1 increased. Other HDAC inhibitors − panobinostat, belinostat and suberoylanilide hydroxamic acid (SAHA) − had similar effects on these transporters. The protein level of MRP1 correlated with cellular resistance to busulfan and chlorambucil, and Rom exposure sensitized cells to these DNA alkylators. The decrease in MRP1 correlated with decreased cellular drug export activity, and increased level of MDR1 correlated with increased export of daunorubicin. A similar decrease in the level of MRP1 protein, and increase in MDR1, were observed when mononuclear cells derived from patients with T-cell malignancies were exposed to Rom. Decreased MRP1 and increased MDR1 expressions were also observed in blood mononuclear cells from lymphoma patients who received SAHA-containing chemotherapy in a clinical trial. This inhibitory effect of HDAC inhibitors on the expression of MRP1 suggests that their synergism with DNA alkylating agents is partly due to decreased efflux of these alkylators. Our results further imply the possibility of antagonistic effects when HDAC inhibitors are combined with anthracyclines and other MDR1 drug ligands in chemotherapy.
Highlights
Most chemotherapy drugs with different mechanisms of action are more effective when used in combination
The HDAC inhibitor Romidepsin (Rom) has been reported to increase the expression of MDR1 in patient mononuclear cells [10], but whether and how this drug affects the expression of other drug transporters is unknown
We previously demonstrated the synergistic cytotoxicity of DNA alkylating agents, nucleoside analogs and HDAC inhibitors in various experimental models [3,4,5]
Summary
Most chemotherapy drugs with different mechanisms of action are more effective when used in combination. Their combined cytotoxicity efficiently kills tumor cells, decreases the possibility of developing resistant cells, and provides patient safety when given at optimal doses. Combination chemotherapy is a common part of pre-transplant conditioning regimens for patients undergoing hematopoietic stem cell transplantation (HSCT). DNA alkylating agents, nucleoside analogs, epigenetic modifiers, and proteasome inhibitors, among others, have been combined to minimize cancer burden prior to HSCT [1]. Pre-clinical and clinical studies by our group showed the synergistic cytotoxicity of combined DNA alkylating agents busulfan (Bu) and melphalan (Mel), nucleoside analog gemcitabine (Gem), and an HDAC inhibitor in lymphoma cells [3,4,5]. We proposed a mechanism of their synergism that includes www.impactjournals.com/oncotarget
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