Biology Reference
In-Depth Information
Recently, griseofulvin has been identified as to inhibit centrosomal clustering
(Rebacz et al.
2007
). Griseofulvin has been used for many years for the treatment
of dermatophyte infections (Loo
2006
). Mechanistically, it inhibits mitosis in
sensitive fungi (Gull and Trinci
1973
) and mammalian cells (Grisham et al.
1973
)
but whether mitotic arrest is a consequence of MT depolymerization or some other
action on MTs in both fungi and human cells is still unclear (Grisham et al.
1973
;
Weber et al.
1976
). Despite extensive studies, the mechanism by which the drug
inhibits mitosis in human cells remains obscure. Although griseofulvin has been
reported to bind to mammalian brain tubulin and to inhibit MT polymerization in
vitro, it does so only at concentrations significantly higher than those needed for
spindle multipolarity induction in cancer cells with extra centrosomes (Panda et al.
2005
). Also, whether griseofulvin binds to tubulin directly or to MT associated
proteins remains conflicting (Panda et al.
2005
; Wehland et al.
1977
; Roobol et al.
1977
). Already more than 30 years ago it was reported that griseofulvin treatment
induces spindle multipolarity with each mitotic center containing two centrioles in
HeLa cells (Grisham et al.
1973
). While at lower concentrations the drug leads to
multipolar spindles with centrosomes at each pole in cells with extra centrosomes,
at higher concentrations spindle multipolarity with acentrosomal spindle pole
formation is induced as well, consistent with the above concept that clustering
extra centrosomes in cancer cells might be similar to focusing MTs into a bipolar
spindle array in normal cells. For detailed mechanistic understanding it will be
important to clearly determine the sequence of events: Does the drug at low
concentrations indeed cause declustering of supernumerary centrosomes with
subsequent multipolar spindle formation or does spindle multipolarity occur first
with successive distribution of centrosomes to each pole?
Additional evidence for an effect of griseofulvin on centrosomal clustering
comes from the finding that the drug, in contrast to other MT interacting com-
pounds, induces hepatomas in mice and rats (Epstein et al.
1967
). In these animals
the majority of hepatocytes are polyploid and therefore contain supernumerary
centrosomes which are usually efficiently clustered into bipolar spindle arrays
(Guidotti et al.
2003
; Duncan et al.
2010
).
Findings similar to those reported for griseofulvin have recently been described
for the MT-modulating noscapinoid EM011 (Karna et al.
2011
). In contrast to
griseofulvin, EM011 seems to induce centrosome amplification prior to declus-
tering, thereby potentially reducing its specificity to cancer cells with supernu-
merary centrosomes. Further supporting the candidacy of centrosomal clustering
for a largely cancer-selective target, at low drug concentrations sufficient for
spindle multipolarity induction in cancer cells, MT poisons including nocodazole
and taxol induce greater cell death in tumor cells than in non-transformed cells
(Brito and Rieder
2009
).
Most recently, it has been described that a phenanthrene-derived poly(ADP-
ribose) polymerase (PARP) inhibitor also prevents centrosome clustering and
thereby leads to cell death of tumor cells with supernumerary centrosomes (Castiel
et al.
2011
). Poly(ADP-ribose) (PAR) is enriched in the mitotic spindle and
required for bipolar spindle formation (Chang et al.
2004
). In addition, several
