The results presented by J.J Manifredi and S.B.Horwitz ⁽¹⁾ suggest the following pathway for the cellular action of Taxol:-

Taxol crosses the plasma membrane, probably by passive diffusion. The drug binds directly to preexisting cytoplasmic microtubules conferring stability to calcium-induced depolymerization.The independent formation of parallel arrays of microtubules occurs subsequent to this binding. Since depolymerization of cellular microtubules facilitates taxol-induced bundle formation, the first step of bundle formation may be depolymerization of those microtubules. It is believed that an endogenous molecule (which is similar to colchicine in it's mode of action) is responsible for depolymerization.

The phenomenon of taxol-induced microtubule formation requires energy and two energy dependent steps have been postulated. The first is the depolymerization of taxol-treated microtubules and the second is the actual formation of the parallel arrays of microtubules. It is believed that a colchicine-like activity may depolymerize taxol-treated microtubules associated with the primary microtubule organising centre (MTOC) in an energy dependent step. Reassembly occurs at secondary sites in the cell periphery. These newly assembled microtubules are organised into parallel arrays by endogenous 'bundling' factors in another energy dependent step.

The signal for depolymerization by the colchicine-like activity may be the binding of taxol to cytoplasmic microtubules. This can be envisaged due the signal for depolymerization of the interphase microtubule complex at the start of mitosis may be the binding of Taxol like molecules. Hence, understanding the mechanism of action of Taxol may give us clues to the way in which the cell orchestrates the major reorganisation of it's microtubules during mitosis.

This is a hypothetical model and on going research should help to give the validity of this proposed model.

TAXOL-TUBULIN BINDING SITE

The Lawrence Berkeley Laboratory (LBL)has produced images ⁽²⁾ which indicate that taxol binds itself at the junction where tubulin protofilaments are linked, resulting in them being locked into a fixed position (see image 1). Taxol's active site when binding with tubulin has been narrowed down to a 31 amino acid sequence on the b-monomer.

Taxol causes inactive GDP-tubulin into assembly and each tubulin dimer is believed to bind one molecule of taxol in assembled microtubules. Taxol is believed to bind at the lateral contact sites between tubulin molecules in microtubules⁽³⁾.
The structural characterisation of the taxol binding site could lead to more effective anticancer agents to be designed and synthesised.

(1) J.J.Manfredi & S.B.Horwitz: Pharmac. Ther. Vol.25 pp 83-125, 1984

(2) http://www.lbl.gov/LBL-Science-Articles/Archive/big-taxol-image.html

(3) http://alilonia.cib.csic.es/research.html