FOSTRIECIN-MEDIATED G(2)-M-PHASE GROWTH ARREST CORRELATES WITH ABNORMAL CENTROSOME REPLICATION, THE FORMATION OF ABERRANT MITOTIC SPINDLES,AND THE INHIBITION OF SERINE THREONINE PROTEIN PHOSPHATASE-ACTIVITY/
Ay. Cheng et al., FOSTRIECIN-MEDIATED G(2)-M-PHASE GROWTH ARREST CORRELATES WITH ABNORMAL CENTROSOME REPLICATION, THE FORMATION OF ABERRANT MITOTIC SPINDLES,AND THE INHIBITION OF SERINE THREONINE PROTEIN PHOSPHATASE-ACTIVITY/, Cancer research, 58(16), 1998, pp. 3611-3619
Fostriecin, a structurally unique phosphate ester, is presently under
evaluation in clinical trials to determine its potential use as an ant
itumor drug in humans. Fostriecin has been reported as having inhibito
ry activity against DNA topoisomerase type II and protein phosphatases
implicated in cell-cycle control. However, the relative contribution
of these mechanisms to the antitumor activity of fostriecin has not ye
t been elucidated. In this study, after confirming that fostriecin is
a potent inhibitor of serine/threonine protein phosphatase type 2A and
a weak inhibitor of serine/threonine protein phosphatase type 1, we s
how that fostriecin inhibits similar to 50% of the divalent cation ind
ependent serine/threonine protein phosphatase (PPase) activity contain
ed in whole cell homogenates of Chinese hamster ovary cells at concent
rations associated with antitumor activity (1-20 mu M). Investigations
into the cellular effects produced by fostriecin treatment reveal tha
t 1-20 mu M fostriecin induces a dose-dependent arrest of cell growth
during the G(2)-M phase of the cell cycle. Immunostaining of treated c
ells indicates that growth arrest occurs before the completion of mito
sis and that fostriecin-induced growth arrest is associated with the a
berrant amplification of centrosomes, which results in the formation o
f abnormal mitotic spindles, The ''mitotic block'' induced by fostriec
in is reversible if treatment is discontinued in <24 h, However, after
similar to 24-30 h of continuous treatment, growth arrest is not reve
rsible, and treated cells die even when placed in fostriecin-free medi
a. Correlative studies conducted with established PPase inhibitors rev
eal that, when applied at concentrations that inhibit PPase activity t
o a comparable extent, both okadaic acid and cantharidin also induce a
berrant centrosome replication, the appearance of multiple aberrant mi
totic spindles, and G(2)-M-phase growth arrest. These studies add addi
tional support to the concept that PPase inhibition underlies the anti
tumor activity of fostriecin and suggest that other type-selective PPa
se inhibitors should be evaluated for potential antitumor activity.