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Cardiac glycosides CGs prescribed to treat cardiovascular alterations display potent anti-cancer activities Despite their well-established target the sodium potassium Na K -ATPase downstream mechanisms remain poorly elucidated UNBS1450 is a hemi-synthetic cardenolide derived from 2 -oxovorusharin extracted from the plant Calotropis procera which is effective against various cancer cell types with an excellent differential toxicity By comparing adherent and non-adherent cancer cell types we validated Mcl-1 as a general and early target of UNBS1450 A panel of CGs including cardenolides ouabain digitoxin and digoxin as well as bufadienolides cinobufagin and proscillaridin A allowed us to generalize our findings Our results show that Mcl-1 but not Bcl-xL nor Bcl-2 is rapidly downregulated prior to induction of apoptosis From a mechanistic point of view we exclude an effect on transcription and demonstrate involvement of a pathway affecting protein stability and requiring the proteasome in the early CG-induced Mcl-1 downregulation without the involvement of caspases or the BH3-only protein NOXA Strategies aiming at preventing UNBS1450-induced Mcl-1 downregulation by overexpression of a mutated non-ubiquitinable form of the protein or the use of the proteasome inhibitor MG132 inhibited the compound s ability to induce apoptosis Altogether our results point at Mcl-1 as a ubiquitous factor downregulated by CGs whose modulation is essential to achieve cell death Cardiac glycosides CGs possess well-established pharmacological properties which were more recently reconsidered for novel clinical uses Originally prescribed to treat cardiovascular alterations CGs also display interesting anti-cancer activities Epidemiological studies correlated a reduced incidence of specific cancer types with the regular intake of selected CGs 1 2 Preclinical in vitro and in vivo research demonstrated the ability of CGs to impact cell proliferation and survival of a variety of cancer cell models 3 at low nanomolar concentrations Of interest CGs also affect cancer cell models typically resistant to canonical cytocidal agents 4 6 Furthermore combinational treatments triggered synergistic effects 7 9 Besides apoptosis CGs were also able to induce autopha-gic cell death anoikis or immunogenic cell death 10 12 This heterogeneity reflects the extraordinary cytocidal potential of these compounds and reveals cross-talks existing among different cell death modalities as described for other natural compound acting as anti-cancer agents 13 CGs possess a steroid core structure and are subdivided in two families depending on the chemical group on the D-ring at position 17 cardenolides UNBS1450 ouabain digitoxin and digoxin contain a butyrolactone group whereas bufadieno-lides cinobufagin and proscillaridin A exhibit an -pyrone group A sugar moiety on the A-ring of the steroid nucleus at position 3 determines pharmacokinetic and pharmacodynamic properties Sugar moiety and lactone are in cis-conformation 14

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Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450