Molecular basis for lipopolysaccharide mimetic action of Taxol&lt;SUP&gt;™&lt;/SUP&gt; and flavolipin

Kawasaki, Kiyoshi; Gomi, Katsushige; Kawai, Yohko; Shiozaki, Masao; Nishijima, Masahiro

doi:10.1179/096805103225002548

Cited by 11 publications

(5 citation statements)

References 13 publications

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“…93 More recently, increased levels of COX-2 have been documented in patients undergoing Taxol Rtreatment, suggesting that the effects on COX-2 observed in vitro might be clinically relevant. 94 Taxol has also been described as a lipopolysaccharide (LPS) mimetic 95,96 and in this context was discussed to potentially interact with the mouse toll-like receptor-4 (TLR-4)-MD2 complex. 96,97 However, no experimental evidence is available at this point that would support an interaction of taxol with human CD14 or toll-like receptors.…”

Section: Taxolmentioning

confidence: 99%

Anticancer drugs from nature—natural products as a unique source of new microtubule-stabilizing agents

2007

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This review article provides an overview on the current state of research in the area of microtubule-stabilizing agents from natural sources, with a primary focus on the biochemistry, biology, and pharmacology associated with these compounds. A variety of natural products have been discovered over the last decade to inhibit human cancer cell proliferation through a taxol-like mechanism. These compounds represent a whole new range of structurally diverse lead structures for anticancer drug discovery.

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Section: Taxolmentioning

confidence: 99%

Anticancer drugs from nature—natural products as a unique source of new microtubule-stabilizing agents

2007

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“…The species-specific activation of TLR4-expressing cells requires murine MD-2; thus, PTX is presumed to bind to murine MD-2 (47). The interaction between PTX and human MD-2 has not been studied.…”

Section: Hek293 Cells Transfected With Human Tlr4 and Md-2 Do Notmentioning

confidence: 99%

Paclitaxel Binding to Human and Murine MD-2

Zimmer

Liu

Clayton

et al. 2008

Journal of Biological Chemistry

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Paclitaxel (PTX) is an important cancer chemotherapeutic agent that binds to ␤-tubulin and prevents mitosis through microtubule overstabilization. Recent evidence also implicates PTX in the induction of apoptosis of cancer cells via the TLR4 innate immune pathway. The TLR4 accessory protein, MD-2, is an essential component for the species-specific proinflammatory activity of PTX on murine cells. However, whether PTX binds to human MD-2 and how MD-2 and TLR4 interact with PTX are not well defined. Recombinant human MD-2 (rhMD-2) was produced in a Pichia pastoris expression system, and the interaction between rhMD-2 and PTX was assessed by an enzyme-linked immunosorbent assay to show that PTX binds rhMD-2. Formation of the latter complex was found to be dose-dependent and inhibited by anti-MD-2 antibody but not by an isotype control antibody. As measured by human tumor necrosis factor ␣ production, human THP-1 monocytes expressing TLR4 and MD-2 were poorly responsive to the addition of PTX, but murine macrophages expressing TLR4 and MD-2 responded in a dose-dependent manner. Human embryonic kidney (HEK293) cells transfected with both human TLR4 and human MD-2 or human MD-2 and murine TLR4 were also poorly responsive to PTX (10 M). However, HEK293 cells transfected with murine MD-2 and human TLR4 or murine MD-2 and murine TLR4 were highly responsive to PTX (10 M), indicating that the murine MD-2/PTX interaction is required for TLR4 activation. To further define the structural differences for MD-2/TLR4 activation, crystal structures of both murine and human MD-2 were subjected to PTX docking by computational methods. These models indicate that PTX binds in the pocket of both human and mouse MD-2 structures. The species-specific difference between human and murine MD-2 activation of TLR4 by PTX can be explained by alterations of surface charge distribution (i.e. electrostatic potential), binding pocket size, and the locus of PTX binding within the MD-2 pocket, which results in reorganization of the 123-130 amino acid loop. In particular, Phe 126 appears to operate as a bridge for TLR4⅐MD-2 dimerization in the mouse but not the human protein. Paclitaxel (PTX)3 (Fig. 1) is a potent anti-cancer agent derived from the Pacific yew tree, which acts through overstabilization of cellular microtubules. The natural product leads to disruption of mitotic machinery and inhibition of cell growth (1-3). Structurally, the PTX molecule and its interaction with ␤-tubulin have been well characterized (4 -6). PTX also exhibits antiangiogenic properties, and these have expanded the application of the family of drugs known as taxanes to a variety of tumor types (breast, prostate, ovarian, lung) (7) and to treatment of coronary atherosclerosis via paclitaxel-coated coronary stents (8). The contribution of innate immunity pathways to the mechanism of action of PTX has not been well studied. However, the wide ranging applications of this family of drugs and the known interaction of PTX with TLR4 (Toll-like receptor 4) (9, 10) suggest a pote...

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“…Furthermore, compound GLA‐58 was shown to be active as an LPS antagonist in human cells. Interestingly, it was found recently that some substances with chemical structures totally unrelated to that of lipid A, such as taxol, flavolipin,8 and vitamin D,9 have LPS‐mimetic activity towards TLR4.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Lipid A Stimulated Activation of Human Dendritic Cells and Macrophages by Amino and Hydroxylamino Monosaccharides

et al. 2007

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Innovative Mimetika von Lipid A hemmen effizient die Lipid‐A‐induzierte Cytokinproduktion in humanen dendritischen Zellen und Makrophagen. Die D‐Glucose‐Derivate, die an C6 eine Amin‐, Ammonium‐ oder Hydroxylamingruppe mit einem fünfgliedrigen Ring tragen (siehe Strukturen), bieten sich als vielversprechende Leitstrukturen für Sepsismedikamente an, da sie nicht toxisch sind und selektiv am TLR4‐Rezeptor wirken.

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Molecular basis for lipopolysaccharide mimetic action of Taxol<SUP>™</SUP> and flavolipin

Cited by 11 publications

References 13 publications

Anticancer drugs from nature—natural products as a unique source of new microtubule-stabilizing agents

Anticancer drugs from nature—natural products as a unique source of new microtubule-stabilizing agents

Paclitaxel Binding to Human and Murine MD-2

Inhibition of Lipid A Stimulated Activation of Human Dendritic Cells and Macrophages by Amino and Hydroxylamino Monosaccharides

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