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Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, Bruce J, Lee EB, Xie SX, Joyce S, Li C, Toleikis PM, Lee VM, Trojanowski JQ. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):227-31. PubMed.
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University of Kansas
This paper describing the effects of Taxol on axonal transport deficits in a tauopathy mouse model represents a milestone in drug discovery efforts for a number of reasons, not the least of which is the targeting of tau rather than amyloid neurofibrillary pathology. An additional significant aspect of the report is the fact that the authors were able to take a very speculative hypothesis regarding a potential therapeutic intervention for tau pathology in (Lee et al. 1994) and provide the first in vivo proof-of-concept demonstration that the microtubule (MT) network may indeed be a viable target for drug development for neurodegenerative diseases.
The authors used a mouse tauopathy model that develops readily measurable indices of cytoskeletal disruption and reduced axonal transport in spinal cord projections to show that a drug known to stabilize MTs markedly slowed progression of these events in a mouse overexpressing human tau. The authors acknowledge that their findings cannot yet be extrapolated to tau neurofibrillary pathology in the brain, as Taxol does not cross the blood-brain barrier. Furthermore, although the stabilization of MTs to compensate for the loss of normal tau function is a reasonable mechanism to explain the beneficial effects of Taxol in the tau mouse, other cellular signaling events resulting from interaction of the drug with the cytoskeleton may certainly be contributing. Nevertheless, these initial results support the potential for such a novel strategy and warrant further research into the development of agents that target the cytoskeleton.
Another reason the in vivo findings are quite important for drug discovery approaches to progressive degenerative diseases has to do with preconceptions about agents used in other contexts with very different goals. The authors have taken a drug that is primarily used as a cytotoxic agent for cancer, targeted an exceedingly delicate and sensitive cellular system, the cytoskeleton, and shown that serious adverse reactions to such drugs can be avoided. Taxol is used in cancer chemotherapy because it inhibits cell proliferation by inducing a mitotic block that can lead to apoptosis in rapidly dividing cells. Although neurons are postmitotic and thus less susceptible to this action of the drug, high enough levels of the drug certainly overstabilize the MT network and produce toxicity in other types of cells with in vivo administration. This means that the therapeutic window is likely to be quite narrow; however, many widely used pharmacotherapies share this property. Clearly, the dosing regimen of a single weekly administration of either 10 or 25 mg/m2 for 12 weeks represents a protocol that differs significantly from that typically used in cancer patients. In oncology, Taxol is usually administered as an IV infusion over either three hours or 24 hours, with the final target dose of 135-175 mg/m2 and sometimes 250 mg/m2 (Rowinsky 1999). Such treatments are repeated every three weeks for several months. The pharmacokinetic properties of Taxol and the side effects in cancer patients have been studied extensively and, despite some temporary adverse sequelae resulting from direct infusions of the high doses of the drug over a short period of time, systemic toxicities have been fairly mild (Rowinsky, 1993). Some of the reports of serious drug toxicity are believed to be due to the cremaphor-ethanol vehicle in which this highly insoluble drug is dissolved (Rowinsky 1999). It is worth noting that Trojanowski and colleagues administered the Taxol as a novel formulation (Paxceed) that may also represent an important innovation in the handling of such difficult agents.
It should also be noted that, even though the use of cytotoxic agents for neurodegenerative diseases may seem heretical, there is a well-established precedent in the clinical use of the anti-cancer drug methotrexate at very low doses for the management of rheumatoid arthritis, another progressive degenerative disease (Jackson and Williams 1998). This agent is considered one of only a few disease-modifying drugs for arthritis. It can be taken at low doses, again on a once-per-week schedule, that significantly minimizes side effects encountered in its use in cancer chemotherapy. Thus we should not rule out the possibility that new MT-stabilizing agents with reasonable safety profiles under the right drug administration protocols could represent a novel therapeutic strategy for progressive degenerative diseases, for which we still have no disease-modifying therapies.
Another aspect of the report in PNAS is its timeliness with regard to several in vitro observations that preservation of cytoskeletal integrity may protect neurons against a very early and ubiquitous response to a variety of toxic stimuli. The cytoskeleton not only provides structure, it determines localization of proteins and organelles throughout the cell. As a consequence, it plays a critical role in cell signaling cascades from the plasma membrane to the nucleus. It is quite possible that the cytoskeletal network actually serves as a sensor for the overall state of the neurons and a first-line transducer of stress signals. This assertion is supported by the findings that Taxol enhances neuronal survival in several different models of neuronal toxicity. These include protection against the Ca2+ ionophore A23187 (Burke et al. 1994), glutamate-induced excitotoxicity (Furukawa and Mattson 1995), induction of reactive oxygen species (Sponne et al. 2003), the vulnerability to Ca2+ elevations in neurons from tau mutant mice (Furukawa et al. 2003), and the toxicity of Aβ peptides (Michaelis et al. 1998; Li et al. 2003; Michaelis et al. 2004).
Interestingly, Trushina and colleagues recently reported that expression of the toxic mutant huntingtin protein actually leads to destabilization of the MTs as a very early step in the cascade, and Taxol significantly enhanced survival of primary striatal neurons expressing this abnormal protein (Trushina et al., 2003). In these in vitro studies, primary neurons were directly exposed to Taxol or other MT-stabilizing agents at nanomolar concentrations. The drugs alone did not lead to neuronal cell death and, when added in the presence of an array of toxic stimuli, exhibited very promising protective activities. Cytoskeletal disruption may thus be a very early signaling event under a variety of stresses, and drugs that can moderate this initial response may provide cells the opportunity to mobilize protective cascades and thereby enhance survival. Although much remains to be learned about the mechanisms underlying the salutary effects of the MT-stabilizing drugs, development of parallel in vivo and in vitro approaches will greatly accelerate critical evaluation of targeting cytoskeletal integrity as a novel and, possibly, disease-modifying strategy for neurodegenerative diseases.
References:
Burke WJ, Raghu G, Strong R. Taxol protects against calcium-mediated death of differentiated rat pheochromocytoma cells. Life Sci. 1994;55(16):313-9. PubMed.
Furukawa K, Mattson MP. Taxol stabilizes [Ca2+]i and protects hippocampal neurons against excitotoxicity. Brain Res. 1995 Aug 14;689(1):141-6. PubMed.
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Jackson CG, Williams HJ. Disease-modifying antirheumatic drugs. Using their clinical pharmacological effects as a guide to their selection. Drugs. 1998 Sep;56(3):337-44. PubMed.
Lee VM, Daughenbaugh R, Trojanowski JQ. Microtubule stabilizing drugs for the treatment of Alzheimer's disease. Neurobiol Aging. 1994;15 Suppl 2:S87-9. PubMed.
Li G, Faibushevich A, Turunen BJ, Yoon SO, Georg G, Michaelis ML, Dobrowsky RT. Stabilization of the cyclin-dependent kinase 5 activator, p35, by paclitaxel decreases beta-amyloid toxicity in cortical neurons. J Neurochem. 2003 Jan;84(2):347-62. PubMed.
Michaelis ML, Ranciat N, Chen Y, Bechtel M, Ragan R, Hepperle M, Liu Y, Georg G. Protection against beta-amyloid toxicity in primary neurons by paclitaxel (Taxol). J Neurochem. 1998 Apr;70(4):1623-7. PubMed.
Michaelis ML, Ansar S, Chen Y, Reiff ER, Seyb KI, Himes RH, Audus KL, Georg GI. {beta}-Amyloid-induced neurodegeneration and protection by structurally diverse microtubule-stabilizing agents. J Pharmacol Exp Ther. 2005 Feb;312(2):659-68. PubMed.
Rowinsky EK. Clinical pharmacology of Taxol. J Natl Cancer Inst Monogr. 1993;(15):25-37. PubMed.
Rowinsky EK. On pushing the outer edge of the outer edge of paclitaxel's dosing envelope. Clin Cancer Res. 1999 Mar;5(3):481-6. PubMed.
Sponne I, Fifre A, Drouet B, Klein C, Koziel V, Pinçon-Raymond M, Olivier JL, Chambaz J, Pillot T. Apoptotic neuronal cell death induced by the non-fibrillar amyloid-beta peptide proceeds through an early reactive oxygen species-dependent cytoskeleton perturbation. J Biol Chem. 2003 Jan 31;278(5):3437-45. PubMed.
Trushina E, Heldebrant MP, Perez-Terzic CM, Bortolon R, Kovtun IV, Badger JD, Terzic A, Estévez A, Windebank AJ, Dyer RB, Yao J, McMurray CT. Microtubule destabilization and nuclear entry are sequential steps leading to toxicity in Huntington's disease. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12171-6. PubMed.
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In this study, John Trojanowski suggests drugs such as paclitaxel may be a useful therapy for AD.
The Kikuno group mentions the recent findings that paclitaxel induces thymidine phosphorylase in solid tumours (1).
A study by Yoshinaga et al suggests that PD-ECGF( thymidine phosphorylase ) may activate ROCK1 (2). They also report that actin fiber polymerization, which is a marker of activation of ROCK1, was higher in PD-ECGF transfectants (2).
What are the implications for paclitaxel therapy if it results in increased thymidine phosphorylase and subsequently ROCK1 and actin polymerization in AD?
Might the beneficial effect of statins be due to reduced actin polymerization?
References:
Kikuno N, Moriyama-Gonda N, Yoshino T, Yoneda T, Urakami S, Terashima M, Yoshida M, Kishi H, Shigeno K, Shiina H, Igawa M. Blockade of paclitaxel-induced thymidine phosphorylase expression can accelerate apoptosis in human prostate cancer cells. Cancer Res. 2004 Oct 15;64(20):7526-32. PubMed.
Yoshinaga K, Inoue H, Tanaka F, Mimori K, Utsunomiya T, Mori M. Platelet-derived endothelial cell growth factor mediates Rho-associated coiled-coil domain kinase messenger RNA expression and promotes cell motility. Ann Surg Oncol. 2003 Jun;10(5):582-7. PubMed.
View all comments by Mary ReidThis paper will lead to open more oppurtunities in drug discovery.
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