The
antimitotic drugs such as
colchicine,
podophyllotoxin, etc. are currently believed to exert their cytotoxic and
antimitotic effects due to binding of the
drug-
tubulin complex to the growing ends of microtubules (MTs), leading to an "end-capping or
poisoning" effect. However, to account for a number of apparently puzzling observations regarding
antimitotic drugs (which cannot be readily explained by the current model) and the mitotic process, a new hypothesis regarding the mechanism of action of
antimitotic drugs is proposed. The key observations in this context are as follows: (i) The
antimitotic drugs bind specifically to free
tubulin. (ii) Cell growth by these drugs is specifically blocked in metaphase, and interphase microtubules do not seem to play any role in the drugs' cytotoxic or
antimitotic effects. (iii)
Tubulin is specifically associated with a number of membranous organelles (viz. mitochondria, plasma membranes, endoplasmic reticulum) which are responsible for intracellular Ca+2 homeostasis. (iv) Fluorescent derivatives of
antimitotic drugs also bind to the above membranous organelles and not to MTs. (v) Ca+2 plays a central role in the control of MT assembly/disassembly in vivo and a Ca+2 pulse is necessary for the metaphase to anaphase transition. (vi) Cellular mutants which exhibit specific resistance to various
antimitotic drugs are altered in either
tubulin(s) or mitochondrial matrix
proteins. To account for these observations, it is suggested that free
tubulin present in the above membranous organelles serves as the cellular receptor for these drugs and this binding interferes with the Ca+2 regulatory/signalling mechanism essential for anaphase chromosome movement. The effect of these drugs on interphase MTs appears to be a secondary consequence of this alteration in Ca+2 regulation. The observed changes in mitochondrial matrix
proteins in many of the mutants resistant to
antimitotic drugs further indicate that mitochondria should play an important role in Ca+2 homeostasis, as it relates to mitosis. The possible mechanisms by which these drugs may interfere with the Ca+2 regulation and some implications of this hypothesis are discussed.