page 67) find a way to distinguish normally cycling cells from cancer cells using actin inhibitors that cause an RB-dependent cell cycle arrest.
High levels of actin inhibitors prevent cell cleavage and thus lead to a doubling of cellular DNA and subsequent cell death. However, cells usually sense the problem and halt the cell cycle in G1.
The authors found that very low levels of actin inhibitors that do not affect most cellular processes still induce a reversible G1 arrest. This sensitive response requires the function of RB pocket proteins (RB, p107, and p130) but is independent of p53.
The arrest may arise because the drug-treated cells believe that they are contact inhibited. As in contact-inhibited cells, membrane ruffling is suppressed and levels of NF2/merlin increase. NF2/merlin is an actin-associated tumor suppressor protein that is related to the cytoskeletal linkers ezrin, radixin, and moesin. It has been shown to mediate G1 arrest in response to contact inhibition, and may function in a similar manner in response to low levels of actin inhibitors.
Low doses of actin inhibitors should selectively arrest normal cells but not tumor cells, which generally lack an RB-dependent G1 arrest. Follow-up treatments that induce the death of cycling cells should then effectively target tumor cells. Lohez et al. do not directly test this scheme, but use slightly higher actin inhibitor concentrations to induce tetraploidy and thus aneuploid cell death in several tumor cell lines that lack RB pocket proteins. Practical applications of either scheme await. ▪