Kinetic suppression of microtubule dynamic instability by griseofulvin: implications for its possible use in the treatment of cancer.
The antifungal drug griseofulvin inhibits mitosis strongly in fungal cells and weakly in mammalian cells by affecting mitotic spindle microtubule (MT) function. Griseofulvin also blocks cell-cycle progression at G(2)/M and induces apoptosis in human tumor cell lines. Despite extensive study, the mechanism by which the drug inhibits mitosis in human cells remains unclear. Here, we analyzed the ability of griseofulvin to inhibit cell proliferation and mitosis and to affect MT polymerization and organization in HeLa cells together with its ability to affect MT polymerization and dynamic instability in vitro. Griseofulvin inhibited cell-cycle progression at prometaphase/anaphase of mitosis in parallel with its ability to inhibit cell proliferation. At its mitotic IC(50) of 20 muM, spindles in blocked cells displayed nearly normal quantities of MTs and MT organization similar to spindles blocked by more powerful MT-targeted drugs. Similar to previously published data, we found that very high concentrations of griseofulvin (>100 microM) were required to inhibit MT polymerization in vitro. However, much lower drug concentrations (1-20 microM) strongly suppressed the dynamic instability behavior of the MTs. We suggest that the primary mechanism by which griseofulvin inhibits mitosis in human cells is by suppressing spindle MT dynamics in a manner qualitatively similar to that of much more powerful antimitotic drugs, including the vinca alkaloids and the taxanes. In view of griseofulvin's lack of significant toxicity in humans, we further suggest that it could be useful as an adjuvant in combination with more powerful drugs for the treatment of cancer.
Panda
Dulal
D
School of Biosciences and Bioengineering, Indian Institute of Technology, Bombay 400076, India. panda@iitb.ac.in
Rathinasamy
K
K
Santra
Manas K
MK
Wilson
Leslie
L
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006118:Griseofulvin / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects*; D008941:Spindle Apparatus / Q000187:drug effects*; D014404:Tubulin / Q000378:metabolism
D014404:Tubulin; D006118:Griseofulvin