Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

Ebbesen, Peter; Pettersen, Erik O.; Gorr, Thomas A.; Jobst, G.; Williams, Kaye J.; Kieninger, Jochen; Wenger, Roland H.; Pastorekova, S; Dubois, Ludwig; Lambin, Philippe; Wouters, Bradly G.; Beucken, Twan van den; Supuran, Claudiu T.; Poellinger, Lorenz; Ratcliffe, Peter J.; Kanopka, Arvydas; Görlach, Agnes; Gasmann, M; Harris, Adrian L.; Maxwell, Patrick H.; Scozzafava, Andrea

doi:10.1080/14756360902784425

Cited by 176 publications

(120 citation statements)

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“…However, a large number of derivatives showed effective or very effective inhibitory activity against this isoform, which represents a new drug target for developing antitumor therapies or diagnostic agents. 7,9 Thus, thiocoumarin 17 and several coumarins (18,19,21, and 23) showed low nanomolar affinity for this enzyme, with inhibition constants in the range of 45-98 nM. These coumarins incorporate the 6-hydroxymethyl-and 3-ester moieties (18 and 19), with no important differences of activity between the methyl and ethyl esters in this case.…”

Section: Resultsmentioning

confidence: 99%

“…Coumarins/thiocoumarins may possess various tautomeric forms, such as the zwitterionic benzo(thio)pyrylium phenoxides, which may bind within the CA active site similarly to phenols (Chart 2, step A), 7 i.e., by anchoring to the zinc-bound water molecule/hydroxide ion. 22 Alternatively, the chromenone tautomer may bind to the enzyme, similarly to phenols, as illustrated in Chart 2A.…”

Section: Resultsmentioning

confidence: 99%

“…Data reported in Table 1 show the inhibition after 6 h incubation, which led to the completion of the in situ hydrolysis of the (thio)coumarin and formation of the hydroxy/mercapto-cinnamic acid. 1 The inhibition constants were obtained by nonlinear leastsquares methods using PRISM 3, as reported earlier, 1,6,7 and represent the mean from at least three different determinations.…”

Section: Experimental Protocolsmentioning

confidence: 99%

“…2,[4][5][6][7][8][9][10][11] In addition to the established role of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently emerged that they have potential as anticonvulsant, antiobesity, anticancer, and antiinfective drugs. 2,[4][5][6][7][8][9][10][11] Many of the mammalian CA isozymes involved in these processes are important therapeutic targets with the potential to be inhibited or activated to treat a wide range of disorders. 2,4 However a critical barrier to the design of CAIs as therapeutic agents is related to the high number of isoforms in humans, their rather diffuse localization in many tissues/organs, and the lack of isozyme selectivity of the presently available inhibitors of the sulfonamide/sulfamate type.…”

Section: Introductionmentioning

confidence: 99%

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Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins

et al. 2009

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Coumarin derivatives were recently shown to constitute a totally new class of inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), being hydrolyzed within the CA active site to 2-hydroxycinnamic acids. We explore here a new series of variously substituted coumarins and a thiocoumarin for their interaction with 13 mammalian CA isoforms, detecting low nanomolar and isoform selective inhibitors. The mechanism of action of this class of inhibitors is delineated in detail by resolving the X-ray crystal structure of CA II in complex with trans-2-hydroxy-cinnamic acid, the in situ hydrolysis product of simple coumarin. Thiocoumarins also act as efficient CAIs, similarly to coumarins. The versatility of the (thio)coumarin chemistry, the cis-trans isomerization evidenced here, and easy derivatization of the (thio)coumarin rings, coupled with the nanomolar inhibition range of several isozymes, afford isoform-selective CAIs with various biomedical applications, which render these classes of compounds superior to the clinically used sulfonamides.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Experimental Protocolsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins

et al. 2009

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“…The tumor microenvironment is characterized by reducing/hypoxic conditions [17] that protect DAMPs from losing their biological activity due to oxidation. Consistent with our results showing diminished biological activity of DAMPs following oxidation, HMGB1 and S100 (another DAMP member with shown biological activity) are both known to lose their activity after oxidation.…”

Section: Discussionmentioning

confidence: 99%

Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material

et al. 2011

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Necrosis is a characteristic feature of advanced solid tumors. Released necrotic factors, also referred to as damage associated molecular patterns (DAMPs), are known to critically impact the tumor microenvironment by enhancing angiogenesis or influencing the immune response. We have recently shown that DAMPs can act as chemoattractants and activators of granulocytes. We demonstrate that necrotic material from both normal and tumor cells promotes proliferation and trafficking of human mesenchymal stem cells (MSCs). We characterize the protein high mobility group box 1 (HMGB1) as a crucial member of DAMPs within necrotic material. In addition, we show that DAMPs interfere with expression of indoleamine 2, 3-dioxygenase (IDO) in MSCs. The biological activity of necrotic material toward MSCs is abolished once these DAMPs are oxidized. MSCs found within tumor tissue can act as immunoregulatory cells and are able to promote tumor metastasis, thus playing a crucial role within the tumor microenvironment. Here, we reveal DAMPs to be crucial factors in the setting of MSC biology within the tumor microenvironment. The tumor microenvironment is characterized by reducing and hypoxic conditions that protect DAMPs from oxidation. Based on our results, oxidizing conditions should be considered for therapeutic approaches that target the tumor microenvironment.Key words: Chemotaxis . Damage associated molecular patterns . Mesenchymal stem cells . Proliferation . Supporting Information available online See accompanying Commentary by Pistoia and Raffaghello IntroductionRegardless of the origin and site of neoplastic cells, necrotic cell death is a characteristic feature of advanced solid tumor mainly due to three conditions: (i) inadequate nutrition supply to tumor cells as a consequence of imbalance between tumor growth and angiogenesis, (ii) the host's cytotoxic immune response to the tumor, and (iii) downregulation of programmed (apoptotic) cell death by the tumor itself. Released factors following necrotic cell death are also referred to as damage associated molecular patterns (DAMPs). DAMPs can critically impact the tumor microenvironment by enhancing angiogenesis or influencing [5,6]. MSCs are pluripotent progenitor cells that contribute to the maintenance and regeneration of a variety of connective tissues, including bone, adipose, cartilage, and muscle [7]. Although MSCs reside predominantly in the bone marrow, they are also distributed throughout many other tissues, where they are thought to serve as local sources of dormant stem cells [8]. The contributions of MSCs to tissue formation become apparent in cases of tissue remodelling after injury or chronic inflammation. These conditions are typically accompanied by mobilization of multipotent MSCs from bone marrow and their subsequent recruitment to the site of damage [8]. MSCs have been shown to contribute to the formation of fibrous scars after injury [9]. Systemically transferred MSCs have been described to migrate into colon carcinomas [10]. In the setting of wound he...

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The Radiopharmaceutical Chemistry of Technetium and Rhenium

Dilworth

Pascu

2014

The Chemistry of Molecular Imaging

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Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

Cited by 176 publications

References 337 publications

Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins

Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins

Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material

The Radiopharmaceutical Chemistry of Technetium and Rhenium

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