Mechanism of action of antimitotic drugs: a new hypothesis based on the role of cellular calcium.
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.
Gupta
R S
RS
Department of Biochemistry, McMaster University, Hamilton, Canada.
Dudani
A K
AK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D014404:Tubulin; D002118:Calcium