Homoharringtonine (HHT) is a natural product alkaloid from the Cephalotaxus evergreen family. HHT is currently being evaluated clinically for the treatment of CML resistant to current tyrosine kinase (TK) inhibitor therapies, including imatinib mesylate and dasatinib. Additional phase II activity in AML and MDS has been reported. Identified initially for its inhibitory effects on protein synthesis (elongation step), recent laboratory studies have also demonstrated that HHT upregulates apoptotic pathways and inhibits angiogenic processes. In addition, clinical studies in CML have demonstrated that HHT treatment reduces bcr/abl mRNA transcript levels in patients resistant to imatinib mesylate suggesting that more specific molecular targets may be affected by this agent. To further delineate the cellular pathways affected by HHT, in vitro studies examining the expression and nuclear levels of various transcription factors (TF) after HHT treatment were performed. Using the K562 leukemia cell line and a multiplex transcription factor assay (Marligen Biosciences, Ijamsville, MD) the expression of 50 TF was examined after exposure to 10nM HHT for 15 min, 30 min, 2 hr, 4 hr and 24hr. Several TF involved in differentiation were overexpressed relative to untreated controls. These included GATA, PPAR, EGR, PAX6, AR and AP2. In contrast, treatment of the mouse macrophage cell line, RAW 264.7, with 10 nM HHT for the same treatment exposures, did not induce any increased expression of these particular TF. However, treatment of RAW 264.7 cells with HHT followed by LPS stimulation did induce overexpression of some other TF compared to treatment of cells with LPS alone. These included EGR, NF-kappaB, PBX, CEBPa, CEBPd, ER, TRE-AP1, LEF1 and HIC1.

These studies indicate that HHT may affect some cellular processes at the level of transcriptional control. Furthermore, differences in the expression of certain TF between malignant and normal cells may exist after HHT treatment. These differences may be of therapeutic value allowing for the opportunity to further optimize the therapeutic use of HHT.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA