Reversine selectively induces cell death in tumor cells

Reversine is a synthetic 2,6-distribuited purine1, which has been shown to increase cell plasticity with the ability to reprogram lineage-committed cells to a more primitive multipotent state. In particular, reversine-treated dermal fibroblasts could be then induced to differentiate to skeletal muscle both in vitro and in vivo2. Nevertheless, reversine mechanism of action is still not fully demonstrated, although it has been shown that the molecule inhibits MEK1, nonmuscle myosin II heavy chain3, and aurora kinases. Although it is still unclear if these effects are strictly related to de-differentiation, it is now quite clear that the molecule inhibits cell growth. Thus, it has been already reported that reversine inhibits cell growth and colony formation in tumor cells. Surprisingly and remarkably, in our hands, treatment of several types of cancer cells (including neuroblastoma, fibrosarcoma, and glioblastoma cancer stem cells) with reversine at micromolar concentration, not only inhibited tumor cells growth, but extensively induced cell death. On the other hand, we did not observe the same lethal effects on normal cells (including human and murine primary dermal fibroblast, murine myoblasts, rat and human mesenchymal stem cells, and murine mesangioblasts), but only a reversible cell growth arrest. Moreover, we found that tumor cells seem to undergo different death pathways. In fact, while neuroblastoma SK-N-BE cells revealed all the canonical signs of apoptosis (chromatin condensation, caspase 3 activation), we could not find the same evidences in fibrosarcoma cells HT1080. Nevertheless, cell cycle analysis and morphological features, after reversine treatment, seem to point out that cell death may be due to mitotic catastrophe, which may be caspase dependent or independent. In fact, reversine treatment leads to the formation of large cells with several micronuclei, possibly due to the aberrant chromosome segregation and the inhibition of cytokinesis. Reversine inhibition of aurora kinase and nonmuscle myosin II heavy chain, which hold crucial roles in the correct mitotic division, may result in the observed effects. Cell cycle analysis shows that reversine induces endoreplication, but while normal cells can control this effect and block cells in G1 phase, tumor cells, where G1 checkpoint is de-regulated, keep cycling to a point where micronucleated polyploid populations start to die.