Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines

Yi-He Ling, Leonard Liebes, Jian-Dong Jiang, James F Holland, Peter J Elliott, Julian Adams, Franco M Muggia, Roman Perez-Soler
Clinical Cancer Research 2003, 9 (3): 1145-54

PURPOSE: PS-341 is a novel dipeptide boronic acid proteasome inhibitor with in vitro and in vivo antitumor activity that induces mechanisms of apoptosis by unknown mechanisms.

EXPERIMENTAL DESIGN: Human non-small cell lung cancer cell lines were used to investigate effects PS-341 on cell proliferation, cell cycle progression, and the induction of apoptosis.

RESULTS: PS-341 was 38-360-fold more cytotoxic against H460 cells when compared with the proteasome inhibitors MG-132 and PSI. Differential PS-341 cytotoxic effects were found with respect to P53 function: H322 cells (p53 mutant) were 6-fold less sensitive as compared with H460 cells (p53 wild type); and H358 cells (p53 null) were 1.6-fold more sensitive as compared with H460 cells (p53 wild type). A concentration- and time-dependent cell cycle blockade at G(2)-M phase was seen for H460 cells without any direct effects on microtubule polymerization or depolymerization. PS-341 exposure in H460 cells led to stabilization of p53, induction of p21(cip/waf-1) and MDM2 expression, an increase in cyclin B and cyclin A, and the activation of cyclin B and cyclin A kinases. MDM2 induction was found only in H460 cells, whereas in H322 and H358 cells, G(2)-M-phase arrest, p21(cip/waf-1) induction, and an increase in cyclin B1 were found. The commitment of G(2)-M-phase cells to apoptosis was verified by the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in drug-free medium.

CONCLUSIONS: Our data suggest that the PS-341-induced G(2)-M-phase arrest may be associated with the inhibition of degradation of cell cycle regulators and that the up-regulation of p21(cip/waf-1) expression may be via p53-dependent and/or -independent pathways. The resulting disturbance of cell cycle progression leads either to growth inhibition or to the initiation of apoptotic pathways.

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