Induction of tumour necrosis factor and interferon-γ in cultured murine splenocytes by the antivascular agent DMXAA and its metabolites

Wang, Liang-Chuan S.; Reddy, Charu; Baguley, Bruce C.; Kestell, Philip; Sutherland, Robert M.; Li, Ching

doi:10.1016/j.bcp.2003.10.023

Cited by 27 publications

(26 citation statements)

References 23 publications

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“…At the present time, phase I clinical trials have been completed in the United Kingdom and New Zealand [222]. DMXAA (2) causes a fast vascular collapse and tumor necrosis by immunomodulation and cytokines induction, particularly of tumor necrosis factor-α (TNF-α) [193,194,[223][224][225][226][227][228], γ-interferon [229] and interferon-induced protein 10 [194]. It possesses inductive effects in 5-hydroxytryptamine (5-HT) [228,230], nitric oxide (NO) [228,231,232], and in transcription factors STAT and nuclear factor κB (NFκB) [224,229,233].…”

Section: Dmxaa An Antivascular Agentmentioning

confidence: 99%

Xanthone Derivatives: New Insights in Biological Activities

Pinto¹,

Sousa

Nascimento

2005

CMC

450

232

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Xanthones or xanthen-9H-ones (dibenzo-gamma-pirone) comprise an important class of oxygenated heterocycles whose role is well-known in Medicinal Chemistry. The biological activities of this class of compounds are associated with their tricyclic scaffold but vary depending on the nature and/or position of the different substituents. In this review, an array of biological/pharmacological effects is presented for both natural and synthetic xanthone derivatives, with an emphasis on some significant studies on structure-activity relationships. The antitumor activity of some xanthones as well as the related targets, particularly PKC modulation studies, is also discussed in detail. Examples of the "hit" compounds involved in cancer therapy, namely DMXAA, psorospermin, mangiferin, norathyriol, mangostins, and AH6809, a prostanoid receptor antagonist, are also mentioned. Finally, a historical perspective of these xanthonic derivatives, their relevance as therapeutic agents and/or their uses as pharmacological tools and as extract components in folk medicine are also highlighted.

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Section: Dmxaa An Antivascular Agentmentioning

confidence: 99%

Xanthone Derivatives: New Insights in Biological Activities

Pinto¹,

Sousa

Nascimento

2005

CMC

450

232

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“…Clinical studies have confirmed the antivascular effect, demonstrating an increase in tumor vascular permeability (Zhao et al, 2005), changes in tumor perfusion (Murata et al, 2001), and increased plasma concentrations of the serotonin metabolite 5-hydroxyindole acetic acid (Zhao et al, 2002b). DMXAA is thought to exert its antitumor effects through both induction of apoptosis in tumor vascular endothelial cells (Ching et al, 2002) and an indirect vascular effect involving production of a spectrum of cytokines and chemokines, including tumor necrosis factor-␣ (TNF-␣) (Wang et al, 2004), interferon-␤ (Shirey et al, 2011), interferon-inducible protein 10 (Cao and Ching, 2001), and inducible nitric oxide synthase (Peng et al, 2011). It has been reported that TNF-␣ is an important cytokine involved in mediating the antitumor effects of DMXAA .…”

Section: Introductionmentioning

confidence: 96%

p38 Mitogen-Activated Protein Kinase Is Required for the Antitumor Activity of the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-acetic Acid

Quan²,

Xu³

et al. 2012

J Pharmacol Exp Ther

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5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a potent vascular disrupting agent, selectively destroys established tumor vasculature, causing a rapid collapse in blood flow that ultimately leads to inhibition of tumor growth. Here, we demonstrate that p38 MAPK is critically involved in DMXAA-induced cytoskeleton reorganization in endothelial cells and tumor necrosis factor-␣ (TNF-␣) production in macrophages, both of which were essential for DMXAA-induced vascular disruption. Inhibition of p38 mitogen-activated protein kinase (MAPK) significantly attenuated DMXAA-induced actin cytoskeleton reorganization in human umbilical vein endothelial cells and TNF-␣ production in macrophages. In vivo, p38 MAPK inhibition attenuated the immediate reduction in tumor blood flow induced by DMXAA treatment (Ͻ30 min) by inhibiting actin cytoskeleton reorganization in tumor vascular endothelial cells and blunted the long-lasting (Ͼ4 h) DMXAA-induced shutdown of the tumor vasculature by inhibiting intratumoral TNF-␣ production. These results indicate that p38 MAPK plays a critical role in DMXAAinduced endothelial cell cytoskeleton reorganization and TNF-␣ production, thus regulating DMXAA-induced antitumor activity.

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“…For example, results indicate that the drug itself, rather than a metabolite, is responsible for some of the observed physiological responses [31]. Also, the two main metabolic routes reported are glucuronidation and hydroxylation of the 6-methyl group, neither of which produces an ET moiety [32].…”

Section: Active Form Of Dmxaamentioning

confidence: 97%

“…Substantial evidence indicates that ET and low levels of ROS play a role [7]. In regard to DMXAA biochemistry, participation of signaling events has been invoked previously [31]. The drug acts as a biological response modifier, activating a complex series of events that lead to observed physiological manifestations.…”

Section: Cell Signalingmentioning

confidence: 98%

Fundamental, Electron Transfer Mechanism by Pyrylium-Type Ions for the Anticancer Drugs 5,6-Dimethylxanthenone-4-Acetic Acid (DMXAA) and Flavone-8-Acetic Acid (FAA)

Kovacic

2005

CMCACA

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Pyrylium-type salts derived from DMXAA and FAA are proposed to play an important mechanistic role in anticancer action. Electron transfer (ET) processes apparently initiate cell signaling cascades that lead to the observed effects, such as, antivascular influences, cytokine induction, and apoptosis. Possible participation of nitric oxide and serotonin is discussed. Structure-activity relationships involving DMXAA, FAA, acridines, and quinolines support the hypothetical framework, as well as electrochemistry and photochemistry. Similarity is pointed out to the action of plant hormones, e.g. ethylene. Involvement of ET pathways places the cationic salts within the general mechanistic framework for other anticancer agents. Other drug activities of xanthenones are in accord with the ET approach. Insight into fundamental mechanistic aspects should aid in development of improved drugs in this class through rational design.

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Induction of tumour necrosis factor and interferon-γ in cultured murine splenocytes by the antivascular agent DMXAA and its metabolites

Cited by 27 publications

References 23 publications

Xanthone Derivatives: New Insights in Biological Activities

Xanthone Derivatives: New Insights in Biological Activities

p38 Mitogen-Activated Protein Kinase Is Required for the Antitumor Activity of the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-acetic Acid

Fundamental, Electron Transfer Mechanism by Pyrylium-Type Ions for the Anticancer Drugs 5,6-Dimethylxanthenone-4-Acetic Acid (DMXAA) and Flavone-8-Acetic Acid (FAA)

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