In acute promyelocytic leukemia NB4 cells, the synthetic retinoid CD437 induces contemporaneously apoptosis, a caspase-3-mediated degradation of PML/RAR alpha protein and the PML retargeting on PML-nuclear bodies

CD437-induced apoptosis has been investigated in NB4, a human t(15;17) acut e promyelocytic leukemia (APL) cell line, and in the retinoic acid (RA)-res istant NB4-R1 derivative subclone. Both NB4 and NB4-R1 cells underwent rapi d apoptosis in response to low doses of CD437 (10(-7) M). This apoptosis di d not require the activation of classical retinoid receptors and like arsen ic (As)-induced apoptosis was preceded by the rapid activation of a caspase -3-like enzymatic activity as indicated by the increase of DEVD-pNA hydroly tic activity, by the processing of procaspase-3 protein and by the cleavage of poly(ADP-ribose) polymerase (PARP). Furthermore, it was demonstrated th at the caspase-3-like proteolytic activity is responsible for the degradati on of both the PML/RAR alpha oncogenic protein and the normal RAR alpha pro teins. In CD437-treated cells, PML proteins were not degraded and PML reloc alization on PML-NBs occurred in all the cells before death. CD437-induced apoptosis and receptor degradation were proteasome independent and not infl uenced either by inhibitors of protein tyrosine kinases (PTK), protein tyro sine phosphatases (PTPases) and serine proteases or by glutathione levels. Moreover, our data suggested that as for As2O3-induced apoptosis Bc12 modul ation is not significant for CD437-induced apoptosis of NB4 cells. Since CD 437 induces in vitro the rapid apoptosis of both RA-sensitive and -resistan t APL cells, it could represent the first retinoid potentially able to erad icate in vivo malignant leukemia blasts.