Abstract
Abstract 4352
Background:
Triptolide, a diterpenoid derived from the Chinese herb Tripterygium wilfordii Hook f., has shown anti-tumor effects in various leukemia and solid tumor cell lines in vitro. Previous studies have shown that triptolide synergizes with various chemotherapeutic agents in both leukemia and solid tumor cell lines. Triptolide has been shown to synergize with cytarabine in the THP-1 acute myeloid leukemia (AML) cell line (Pigneux et al 2008). This is of particular interest because cytarabine forms the backbone of AML therapy in both children and adults, and cytarabine resistance poses a significant challenge in the setting of refractory or relapsed AML. Therefore, an agent that works synergistically with cytarabine is of particular interest as a potential new agent for the treatment of relapsed or refractory AML. The aim of this study was to assess the cytotoxicity of triptolide, both as a single agent and in combination with cytarabine, in human AML cell lines representing low-, intermediate-, and high-relapse risk groups.
Methods:
The following cell lines were selected: Kasumi-1 (low risk, t(8;21)), HL-60 and THP-1 (intermediate risk), and MV4-11 (high risk, FLT3 ITD). Kasumi-1 and HL-60 cells were cultured in RPMI 1640 media with 20% fetal bovine serum (FBS). MV4-11 cells were cultured in IMDM media with 10% FBS and THP-1 cells were cultured in RPMI with 10% FBS. We performed the following drug treatments: triptolide alone; cytarabine alone; co-treatment with triptolide and cytarabine. Drug-induced cytotoxicity after 48 hours of treatment was assessed using the MTT assay. The combination index (CI) was determined using Calcusyn software (Biosoft, Cambridge, UK).
Results:
Single-agent triptolide induced cell death in all human AML cell lines tested, including cytarabine-resistant Kasumi-1 cells, at low nanomolar concentrations (average Ic50 ranging from 6–15 nM). The combination of triptolide and cytarabine acted synergistically to induce cell death in THP-1 cells as has been previously reported. Interestingly, the combination of triptolide and cytarabine acted in an antagonistic fashion in all other cell lines tested, except for at low drug concentrations in MV4-11 cells.
Conclusion:
Single-agent triptolide exerts a cytotoxic effect on human AML cell lines, including those that are relatively resistant to cytarbine. The effect of the combination of triptolide and cytarabine was cell-line dependent. The results of this study warrant further investigation on the potential role of triptolide as an anti-leukemic agent in combination with cytarabine.
Disclosures:
No relevant conflicts of interest to declare.
Modular Synthesis and Antiproliferative Activity of New Dihydro-1H-pyrazolo[1,3-b]pyridine Embelin Derivatives
