Taxane- and epothilone-based chemotherapy: from molecule cargo cytoskeletal logistics to management of castration-resistant prostate carcinoma.

Challenges in the discovery of more potent agents to treat the castration-resis - tant prostate carcinoma (CRPC) reflect the frus - trating condition due to development of its drug- resistance in addition to hormone-refractori - ness. Although among the different CRPC thera - py modalities, the chemotherapy regimens might seem conceptually outclassed as exhibiting a scant tumor cell-selectivity if compared with new molecular mechanism-based agents (so- called "smart drugs"), nevertheless, combo- therapies which combine the chemotherapeutic highly killing potential with specific mechanism- targeting products, seem to be effective antitu - mor measures. Thus, both microtubule (taxanes, epothilones, noscapine, Vinca-derivatives) and actin filament (pertenotoxins, cytochalasin D)- targeting agents may supply valuable outcomes in CRPC, either alone or in combination with "smart drugs" such as tyrosine- or multi-kinase receptor blockers, mTOR (mammalian target of rapamicin) inhibitors, monoclonal antibodies against various growth factor signaling recep - tors. Among the microtubule-inhibiting drugs, taxanes are able, by binding the tubulin, to cause polymerization and stabilization of the mi - crotubules with following suppression of their dynamic properties at the mitotic spindle, that results in cancer cell cycle block at G2/M phase together with apoptosis. Cabazitaxel, a novel taxane-based agent, unlike other taxane com - pounds, exhibits low propensity for P-glycopro - tein (Pgp)-mediated plasmalemmal drug efflux pump, thus, avoiding the development of taxane- resistance. Epothylones are a family of novel mi - crotubule-targeting drugs, like taxane inhibiting mi - crotubule dynamic behaviour at mitotic spindle and, therefore, preventing cancer cells from mito - sis. Unlike docetaxel and paclitaxel, epothilones maintain their cytotoxic performance even in can - cer overexpressing Pgp. Epothilone B-promoted radiosensitivity enhancement has been shown in radioresistant human prostate cancer cells, be - cause such agent is able to delay DNA- strand break repair together with prolonging cell cycle block. To insightfully understand either micro - tubule or actin filament meshwork-targeting drug pharmacodynamics, functional cytoskeletal fea -