Due to their high proliferation rate tumor cells are characterized by sensitivity to iron deprivation. With the aim to target this iron dependence, in the last decades diverse iron chelators have been developed for the treatment of cancer. Most promising among these are thiosemicarbazone-based drugs. Since the ribonucleotidereductase (RR) is known to be strongly dependent on intracellular iron pools, this enzyme is believed to be among the main targets for cytotoxic thiosemicarbazones. Disruption or inhibition of RR leads to dNTP pool depletion and, consequently, blocks DNA synthesis and cell cycle progression.
With regard to clinical practice, the first thiosemicarbazone, namely 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine), has already reached clinical evaluation. Triapine, one of the most potent RR inhibitors known, showed promising activity against advanced leukaemia. However, several phase II studies revealed that Triapine is ineffective against several solid tumor types.
One main focus is to gain more insights into the molecular mechanisms underlying the anticancer activity of thiosemicarbazones and to understand resistance development of cancer cells against this compounds class.
To address this issue, a new triapine-resistant cell line (SW480/tria) was recently generated by drug selection and investigated in our lab. Notably, these SW480/tria cells displayed broad cross-resistance against several known ABCB1 substrates due to high ABCB1 levels (induced by promoter hypomethylation). However, ABCB1 inhibition did not re-sensitize SW480/tria cells to triapine and subsequent analysis revealed that triapine is only a weak ABCB1 substrate without significant interaction with the ABCB1 transport function. Interestingly, in chemo-naive, parental SW480 cells short-time (24 h) treatment with triapine stimulated ABCB1 expression. These effects were based on activation of protein kinase C (PKC), a known response to cellular stress. In accordance, SW480/tria cells were characterized by elevated levels of PKC. Together, this led to the conclusion that increased ABCB1 expression is not the major mechanism of triapine resistance in SW480/tria cells. In contrast, increased ABCB1 expression was found to be a consequence of triapine stress-induced PKC activation
Additionally to these cell biological investigations, there is an intense attempt (in cooperation with Christian Kowol, Group of Prof. Bernhard K. Keppler, University of Vienna) to develop novel derivatives with higher tumor selectivity/activity as well as other novel RR inhibitors.