UNBS1450: a new hemisynthetic cardenolide with promising anticancer activity

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Several reports have suggested the sodium pump (Na⁺/K⁺-ATPase) as a potentially interesting oncology target given that the expression of its subunits is markedly altered in cancer (Mijatovic et al, BBA Rev Cancer 2007). Additionally, epidemiological studies of patients treated for heart failure have suggested the possible use of cardenolides (high-affinity sodium pump ligands) in oncology. By binding to sodium pump cardenolides elicit marked effects on cancer cells, however their narrow therapeutic index has prevented their development as anti-cancer drugs.
 Chemical modification of 2”-oxovoruscharin (a novel cardenolide extracted from Calotropis procera) has led to the identification of UNBS1450; a compound characterized by more potent anti-tumor activity and lower toxicity than classic cardenolides (Van Quaquebeke et al, J Med Chem 2005). UNBS1450-induced anti-proliferative activity in vitro was assessed in 58 human cancer cell lines from 11 histopathological types using the colorimetric MTT assay. UNBS1450 reveals marked anti-proliferative activity in vitro with IC₅₀ values in the 10-50nM range and is more than 10 times more toxic to cancer than normal cell lines tested to date. UNBS1450 anti-proliferative activity is similar to that of taxol but markedly higher than that of adriamycin, etoposide, oxaliplatin and SN-38. In vivo in aggressive and metastatic orthotopic models of NSCLC, refractory prostate cancer and diffusely invasive glioma in immunocompromized mice, UNBS1450 displays similar or even higher activity compared to reference compounds, including taxol, irinotecan, oxaliplatin, mitoxantrone and temozolomide. The general mechanism of action associated with UNBS1450-mediated anti-cancer effects relates to the disorganization of the actin cytoskeleton, which seems to be mediated by compound-induced cellular ATP depletion, which in turn leads to duration-dependent dissociation of the sodium pump from the actin cytoskeleton and the redistribution of fibrillar actin from a primarily cortical to a perinuclear location. UNBS1450 can thus be considered both anti-proliferative (cytotoxic) and anti-migratory given that the actin cytoskeleton is essential to cytokinesis and to cancer cell migration. UNBS1450 also induces non-apoptotic cell death processes (such as lysosome membrane permeabilization and autophagy) and thus may overcome major apoptosis resistance pathways responsible for the failure of chemotherapy in certain cancers. UNBS1450 overcomes in vitro the multi-drug resistance phenotype. Structurally UNBS1450 differs notably from classic cardenolides ouabain, digitoxin and digoxin and it displays a markedly higher binding affinity for the alpha subunits of the sodium pump. These features could explain, at least partly, why UNBS1450 displays higher in vitro anti-cancer activity when compared to classic cardenolides. Preliminary in vivo safety data have shown separation of the compound’s anti-tumor activity from its potential cardiotoxicity and thus a superior therapeutic margin compared to other cardenolides for the treatment of cancer.
 The structural uniqueness of UNBS1450 taken with its novel mechanism of action, support its development as an anti-cancer agent targeting cancers that over-express sodium pump alpha subunits. UNBS1450 is currently in preclinical development and should reach Phase I clinical trials in 2008.