Elesclomol (STA-4783)

Elesclomol significantly induces the expression of heat shock stress response genes and metallothionein genes, a signature transcription profile indicative of oxidative stress in Hs294T cells. Elesclomol (100 nM) rapidly induces Hsp70 RNA levels with a 4.8-fold increase at 1 hour and a 160-fold increase at 6 hours in Ramos Burkitt's lymphoma B cells in consistent with the intracellular ROS content which increases by 20% as early as 0.5 hour and 385% at 6 hours, and the induction of Hsp70 can be blocked by antioxidants NAC and Tiron pretreatment. Elesclomol increases the number of early and late apoptotic cells with 3.7- and 11-fold through the induction of oxidative stress, which can be completely blocked by NAC, while having little effect on normal cells. ^[1] Elesclomol significantly inhibits the cell viability of SK-MEL-5, MCF-7, and HL-60 with IC50 of 110 nM, 24 nM and 9 nM, respectively. ^[2] Elesclomol induces copper-dependent ROS generation and cytoxicity in yeast. Instead of working through a specific cellular protein target, Elesclomol interacts with the electron transport chain (ETC), a biologically coherent set of processes occurring in the mitochondrion, to generate high levels of ROS within the organelle and consequently cell death. ^[3]

Although Elesclomol (25-100 mg/kg) as a single agent shows no antitumor activity in nude mouse xenograft models of human breast cancers (MDA435, MCF7 and ZR-75-1), lung cancer (RER) or lymphoma (U937), Elesclomol substantially enhances the efficacy of chemotherapeutic agents in these models, both in terms of tumor regression and extended survival of mice. ^[4]

• Cell lines

  Hs294T, HSB2, and Ramos

• Concentrations

  Dissolved in DMSO at a concentration of 10 mM, final concentrations ~500 nM

• Incubation Time

  18, or 24 hours

• Method

  Cells are treated with various concentrations of Elesclomol for 18 or 24 hours. The level of intracellular ROS is monitored using the DCFDA probe, which emits a green fluorescence on oxidation. Cell death is determined by flow cytometry of cells double stained with Annexin V/FITC and propidium iodide (PI) using a Vybrant Apoptosis assay kit.

• Animal Models

  Female CD-1 nude mice bearing established MDA435 breast cancer xenograft tumors

• Dosages

  ~100 mg/kg

• Administration

  Intravenous injection