Microtubule stabilizing agents: their molecular signaling consequences and the potential for enhancement by drug combination.
Microtubule stabilization by chemotherapy is a powerful weapon in the war against cancer. Disruption of the mitotic spindle activates a number of signaling pathways, with consequences that may protect the cell or lead to its death via apoptosis. Taxol, the first microtubule stabilizing drug to be identified, has been utilized successfully in the treatment of solid tumors for two decades. Several features, however, make this drug less than ideal, and the search for next generation stabilizing drugs with increased efficacy has been intense and fruitful. Microtubule stabilizing agents (MSAs), including the taxanes, the epothilones, discodermolide, laulimalide, and eleutherobin, form an important and expanding family of chemotherapeutic agents. A strong understanding of their molecular signaling consequences is essential to their value, particularly in regard to their potential for combinatorial chemotherapy - the use of multiple agents to enhance the efficacy of cancer treatment. Here we present a critical review of research on the signaling mechanisms induced by MSAs, their relevance to apoptosis, and their potential for exploitation by combinatorial therapy.
Bergstralh
Daniel T
DT
Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, Campus Box #7295, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Ting
Jenny P-Y
JP
D000473:Alkanes / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D034261:Epothilones / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018942:Macrolides; D016200:Maturation-Promoting Factor / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D043823:Taxoids / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000473:Alkanes; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D002219:Carbamates; D004224:Diterpenes; D034261:Epothilones; D051034:Inhibitor of Apoptosis Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D007783:Lactones; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011753:Pyrones; D000077022:Survivin; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; C109551:eleutherobin; C117305:laulimalide; C071229:discodermolide; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016200:Maturation-Promoting Factor; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human