The Chemistry and Biology of Epothilones — The Wheel Keeps Turning

Altmann, Karl‐Heinz; Pfeiffer, Bernhard; Arseniyadis, Stellios; Pratt, Benjamin A.; Nicolaou, K. C.

doi:10.1002/chin.200728239

Cited by 7 publications

(8 citation statements)

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“…Among them, patupilone (epothilone B, EPO906) has shown a promising anticancer activity in vitro and in vivo and is currently undergoing phase III clinical trials. It is interesting that epothilones are active against P-gp-overexpressing cancer cells resistant to paclitaxel (Taxol) (Altmann et al, 2007). Elsewhere, although epothilones bind to the same ␤-tubulin site as tax-anes (Bollag et al, 1995;Nettles et al, 2004), they remain active against cells and xenograft models that have developed resistance to taxanes as a result of tubulin subtype mutations or overexpression (Nicolaou et al, 1997;Lee et al, 2008).…”

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confidence: 99%

Patupilone-Induced Apoptosis Is Mediated by Mitochondrial Reactive Oxygen Species through Bim Relocalization to Mitochondria

Khawaja¹,

Carré²,

Kovacic³

et al. 2008

Mol Pharmacol

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Among the new microtubule-targeted agents, the epothilone family of molecules has shown promising anticancer potential, and clinical trials are currently underway for patupilone (epothilone B) in various cancer indications. In this study, we characterized novel aspects of patupilone's cellular action that may underlie its potent cytotoxicity in human neuroblastoma cells. Patupilone induced mitochondrial membrane potential collapse, mitochondrial morphological changes, and cytochrome c release, leading to apoptosis. Within the first 2 h, patupilone increased the generation of reactive oxygen species (ROS; i.e., superoxides and hydrogen peroxide, 33 Ϯ 6 and 51 Ϯ 3% increase, respectively), specifically from mitochondria. ROS scavengers and mitochondrial DNA depletion [ (Ϫ) cells] significantly protected cells against patupilone cytotoxicity, indicating that ROS generation is a key event in the initial phase of apoptosis. Although the Bim expression level was not modified by patupilone, this proapoptotic protein accumulated in the mitochondrial compartment (2.4-fold increase at IC 70 ) after only a 6-h treatment. In contrast, Bax and Bcl-2 mitochondrial levels were not changed during treatment. It is noteworthy that ROS inhibition prevented Bim relocalization to mitochondria and mitochondrial membrane changes induced by patupilone. Altogether, our data reveal that patupilone-mediated ROS production by mitochondria initiates the intrinsic signaling cascade by inducing Bim accumulation in mitochondria. These results might explain the superior activity of patupilone in tumor cells compared with paclitaxel that is, until now, the clinical reference among microtubule-stabilizing agents. Furthermore, our data highlight the importance of mitochondria that simultaneously assume the role of activator and integrator of apoptotic signals triggered by patupilone.

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confidence: 99%

Patupilone-Induced Apoptosis Is Mediated by Mitochondrial Reactive Oxygen Species through Bim Relocalization to Mitochondria

Khawaja¹,

Carré²,

Kovacic³

et al. 2008

Mol Pharmacol

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“…Epothilone D has potent antitumor activity against multidrug-resistant CCRF-CEM/ VBL100 cancer cells similar to epothilone B (IC 50 s for epothilone B and D are 2 and 17 nmol/L, respectively; refs. 26,27). In mouse models, epothilone D showed less toxicity to mice and higher antitumor activity than epothilone B.…”

Section: Preclinical Development Of Epothilonesmentioning

confidence: 99%

“…Among epothilones with a modified heterocycle side chain, BMS-310705 (C21-aminoepothilone B) and ABJ879 (20-desmethy-20-methylsulfanylepothilone B) have been evaluated in early clinical trials (27,30).…”

Section: Preclinical Development Of Epothilonesmentioning

confidence: 99%

The Epothilones: Translating from the Laboratory to the Clinic

Lee

Swain

2008

Clinical Cancer Research

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The epothilones are macrolide compounds that have been shown to stabilize microtubules.The epothilones are strong promoters of tubulin polymerization in vitro and have significant antitumor activity against human cancer cells that are taxane resistant, express the multidrug resistance gene MDR-1 (ABCB1), and have acquired tubulin mutations. Several epothilones have been evaluated in clinical trials in a variety of tumor types. Ixabepilone (aza-epothilone B) has significant antitumor activity in breast cancer resistant to an anthracycline and a taxane, and has been approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic or locally advanced breast cancer. There have been sustained efforts to develop pharmacodynamic markers to monitor the pharmacologic effect of the epothilones on tumors and normal tissues.The development of predictive markers for epothilone chemotherapy is highly desired to provide more tailored therapy for patients with cancer.

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“…Over the past several years, considerable effort has been directed towards the synthesis and the biological evaluation of the epothilones [67-69]. Currently, Ixabepilone (Ixempra™, Bristol-Myers Squibb) is the only epothilone approved for the treatment of cancer [70], however, several other congeners are in advanced stages of development.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Protein-Protein Interactions as a Therapeutic Strategy for the Treatment of Neurodegenerative Tauopathies

Ballatore¹,

Brunden²,

Trojanowski³

et al. 2011

CTMC

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The recognition that malfunction of the microtubule (MT) associated protein tau is likely to play a defining role in the onset and/or progression of a number of neurodegenerative diseases, including Alzheimer's disease, has resulted in the initiation of drug discovery programs that target this protein. Tau is an endogenous MT-stabilizing agent that is highly expressed in the axons of neurons. The MT-stabilizing function of tau is essential for the axonal transport of proteins, neurotransmitters and other cellular constituents. Under pathological conditions, tau misfolding and aggregation results in axonal transport deficits that appear to have deleterious consequences for the affected neurons, leading to synapse dysfunction and, ultimately, neuronal loss. This review focuses on both progress and unresolved issues surrounding the development of novel therapeutics for the treatment of neurodegenerative tauopathies, which are based on (A) MT-stabilizing agents to compensate for the loss of normal tau function, and (B) small molecule inhibitors of tau aggregation.

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The Chemistry and Biology of Epothilones — The Wheel Keeps Turning

Abstract: PFEIFFER, B.; ARSENIYADIS, S.; PRATT, B. A.; NICOLAOU, K. C.; ChemMedChem 2 (2007) 4, 397-423; Dep. Chem. Appl. Biosci., ETH-Hoenggerberg, CH-8093 Zuerich, Switz.; Eng.) -Lindner 28-239

Cited by 7 publications

References 1 publication

Patupilone-Induced Apoptosis Is Mediated by Mitochondrial Reactive Oxygen Species through Bim Relocalization to Mitochondria

Patupilone-Induced Apoptosis Is Mediated by Mitochondrial Reactive Oxygen Species through Bim Relocalization to Mitochondria

The Epothilones: Translating from the Laboratory to the Clinic

Modulation of Protein-Protein Interactions as a Therapeutic Strategy for the Treatment of Neurodegenerative Tauopathies

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