Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Taxol is the prototype of a new class of microtubule stabilizing agents with promising anticancer activity. Several studies show that taxol mimics the actions of lipopolysaccharide (LPS) on murine macrophages. To investigate the mechanism of taxol-induced macrophage stimulation, we evaluated the ability of Rhodobacter sphaeroides diphosphoryl lipid A (RsDPLA) and SDZ 880.431 to block taxol-induced effects. RsDPLA and SDZ 880.431 are lipid A analogues that lack LPS-like activity, but inhibit the actions of LPS, presumably by blocking critical cellular binding sites. We report that RsDPLA and SDZ 880.431 potently inhibited taxol-induced TNF secretion, gene activation, and protein-tyrosine phosphorylation. The role of microtubules in taxol signaling was investigated. Taxol-induced microtubule bundling in primary and transformed RAW 264.7 macrophages was not blocked by RsDPLA or SDZ 880.431. Taxotere, a semisynthetic taxoid, was more potent than taxol as an inducer of microtubule bundling, but did not induce tumor necrosis factor alpha secretion and gene activation. These data dissociate the microtubule effects of taxol from macrophage stimulation and suggest that taxol stimulates macrophages through an LPS receptor-dependent mechanism. The results underscore the potential of taxol as a tool for studying LPS receptor activation and provide insights into possible therapeutic actions of this new class of drugs.
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PMID:Lipopolysaccharide antagonists block taxol-induced signaling in murine macrophages. 810 63

Paclitaxel (Taxol) and docetaxel (Taxotere) are among the most unique, and successful, chemotherapeutic agents used for the treatment of breast and ovarian cancer. Both agents have anti-mitotic properties derived from binding to tubulin and excessive stabilization of microtubules. Their anti-neoplastic effects derive from this mechanism. Distinct from their effects on microtubule stabilization, paclitaxel, docetaxel, and related taxanes display immunopharmacological traits. In this review, we discuss their induction of pro-inflammatory genes and proteins; the current hypotheses on the molecular mechanism for this induction, especially its relationship to the lipopolysaccharide (LPS) signaling pathway. We also discuss the structure-activity relationships (SAR) that govern gene induction, especially the striking differences between the SAR for murine and human cells in vitro. Lastly, we discuss the immunopharmacological traits of paclitaxel and docetaxel in terms of their relevance to human clinical pharmacology and toxicology and their activity in animal models of autoimmune disorders.
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PMID:The immunopharmacology of paclitaxel (Taxol), docetaxel (Taxotere), and related agents. 1463 22