Cytoskeleton structure and dynamic behaviour: quick excursus from basic molecular mechanisms to some implications in cancer chemotherapy.
Novel nanoscale microscopic technologies are driving dramatic advances in the knowledge of cytoskeleton structure and dynamics. Cytoskeleton, that is organized into microtubules, actin meshwork and intermediate filaments, besides providing cells with important mechanical properties, allows, within the cell, not only the molecule cargo transport, but also the charged particle/biophoton transmission, so that the cell signaling might be considered as consisting of both molecule/chemically- and charged particle/physically-addressed systems. Molecular motors that drive molecule cargo translocation along the cytoskeletal highway, either through endocytic or secretory-exocytic mechanisms, include kinesin and cytoplasmic dynein, traveling on microtubule, and myosin family members, traveling along actin meshwork. The membrane-bound organelles and protein complexes are sorted with high specificity to their various destinations. In the field of highly structured cell signaling machinery, the endocytosis appears to play an important role with following specific changes in gene expression. In the opposite direction, the exocytosis involves many intracellular steps toward the vesicle fusion with the plasma membrane. Insights into cytoskeletal structure and dynamics are providing important progress in identifying proper targets for cancer therapy. Taxane and Vinca alkaloids, by stabilizing the polymerized microtubules, are able to suppress their dynamic behaviour with subsequent cell death. Epithelones, by acting in same way, are emerging as a new class of anticancer drugs, moreover their toxicity resulting unaffected also towards taxane-resistant cancer cells. Even the alkylating agent nitrogen mustard exerts some cytotoxic effects at the level of the microtubule, whereas azaspiracid-1 induces cytoskeletal actin disorganization without affecting microtubule architecture. Regarding the influences of extracellular mechanical forces on changes in cell adhesion gene expression, the iatrogenic pressure-induced tumor cell implantation within surgical wounds may be prevented by perioperative administration of microtubule/actin inhibitors. Even though, among the different cancer therapy strategies, the chemotherapy could appear to be conceptually outclassed because of its low cancer cell-selectivity in comparison with novel molecular mechanism-based agents. However "combo-strategies", that combine the chemotherapeutic high killing potential with new molecule targeted agents, may be an effective curative measure. Some anticytoskeleton agents are under evaluation for their applications in tumor chemotherapy; benomyl, griseofulvin, sulfonamides, that are used as antimycotic and antimicrobial drugs, appear to have a powerful antitumor potential by targeting microtubule assembly dinamics, together with exhibiting, in comparison with taxane and Vinca alkaloids, a more limited toxicity. An exciting challenge for the next future will be to properly define the cytoskeleton structure and dynamic behaviour to design more effective drugs for cancer chemotherapy.
Alberti
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L.D. of Surgical Semeiotics, University of Parma, Italy.
D003599:Cytoskeleton / Q000502:physiology* / Q000648:ultrastructure*; D016503:Drug Delivery Systems; D004579:Electron Transport / Q000502:physiology; D006801:Humans; D050997:Nanomedicine; D009369:Neoplasms / Q000188:drug therapy*