Breaking the invulnerability of cancer stem cells: two-step strategy to kill the stem-like cell subpopulation of multiple myeloma.

In multiple myeloma, the presence of highly resistant cancer stem cells (CSC) that are responsible for tumor metastasis and relapse has been proven. Evidently, for achieving complete response, new therapeutic paradigms that effectively eradicate both, CSCs and bulk cancer populations, need to be developed. For achieving that goal, an innovative two-step treatment combining targeting of thymidine de novo synthesis pathway and a nanoirradiation by the Auger electron emitting thymidine analogue (123/125)I-5-iodo-4'-thio-2'-deoxyuridine ((123/125)I-ITdU) could be a promising approach. The pretreatment with thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine (FdUrd, 1 μmol/L for 1 hour) efficiently induced proliferation and terminal differentiation of isolated myeloma stem-like cells. Moreover, FdUrd stimulation led to a decreased activity of a functional CSC marker, aldehyde dehydrogenase (ALDH). The metabolic conditioning by FdUrd emerged to be essential for enhanced incorporation of (125)I-ITdU (incubation with 50 kBq/2 × 10(4) cells for 4 days) and, consequently, for the induction of irreparable DNA damage. (125)I-ITdU showed a pronounced antimyeloma effect on isolated tumor stem-like cells. More than 85% of the treated cells were apoptotic, despite activation of DNA repair mechanisms. Most important, exposure of metabolically conditioned cells to (125)I-ITdU resulted in a complete inhibition of clonogenic recovery. This is the first report showing that pretreatment with FdUrd sensitizes the stem-like cell compartment in multiple myeloma to apoptosis induced by (125)I-ITdU-mediated nanoirradiation of DNA.