Identification of Novel Small-Molecule Inhibitors for Human Transketolase by High-Throughput Screening with Fluorescent Intensity (FLINT) Assay

Du, Mark; Sim, Janet; Fang, Lijuan; Yin, Zheng; Koh, Sean; Stratton, Jennifer; Pons, Jaume; Wang, John Jian-Xin; Carté, Brad

doi:10.1177/1087057104263913

Cited by 32 publications

(19 citation statements)

References 17 publications

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“…Metabolic control analysis and inhibition of transketolase enzyme reactions have already shown that tumor proliferation can be inhibited by anti-transketolase approaches. 9,17 The most effective way to inhibit tumour proliferation should be to block the generation of energy for tumor growth. We believe future TKTL1 gene might become a novel hot spot of study in anticancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of transketolase protein TKTL1 is associated with occurrence and progression in nasopharyngeal carcinoma: A potential therapeutic target in nasopharyngeal carcinoma

Zhang

Yue²,

Yang³

et al. 2008

Cancer Biology & Therapy

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Over 80 years ago, Warburg identified a particular metabolic pathway in carcinomas characterised by the anaerobic degradation of glucose even in the presence of oxygen that leads to the production of large amounts of lactate (known as the Warburg effect). Now, widespread clinical use of positron-emission tomography (PET) has confirmed that there exists enhanced glucose degradation in tumors. Recent research demonstrated that pentose phosphate pathway (PPP) was augmented in some tumors, especially non-oxidative part of PPP. The non-oxidative part of PPP is controlled by transketolase enzyme reactions. The present study designed to evaluate the effect of transketolase activity on nasopharyngeal carcinoma. It was found that the transketolase activity was significantly stronger in human nasopharyngeal carcinoma tissues than those in human chronic nasopharyngitis tissues. There is a strong upregulation of the transketolase-like-1 (TKTL1) in human nasopharyngeal carcinoma tissues and cell line (CNE), whereas transketolase (TKT) and transketolase-like-2 (TKTL2) were not upregulated. After inhibited the expression of TKTL1 by RNAi, we found that total transketolase activity was dramatically downregulated and the proliferation of cancer cells was significantly inhibited in CNE cells. These results indicate that TKTL1 gene influences total transketolase activity and cell proliferation in human nasopharyngeal carcinoma cells, suggesting that TKTL1 gene plays an important role on glycometabolism in tumors and it might become a novel target for tumor gene therapy.

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Section: Discussionmentioning

confidence: 99%

Overexpression of transketolase protein TKTL1 is associated with occurrence and progression in nasopharyngeal carcinoma: A potential therapeutic target in nasopharyngeal carcinoma

Zhang

Yue²,

Yang³

et al. 2008

Cancer Biology & Therapy

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show abstract

“…The most effective way to inhibit tumour proliferation should be to block the generation of energy for tumour growth. Metabolic control analysis and inhibition of transketolase enzyme reactions have already shown that tumour proliferation can be inhibited by anti-transketolase approaches (Rais et al, 1999;Boros et al, 2001a, b;Comin-Anduix et al, 2001Du et al, 2004). These successful results have been attributed to TKT transketolase.…”

Section: Discussionmentioning

confidence: 99%

“…This approach resulted in the identification of two novel small-molecule inhibitors, which inhibit human TKT and suppress proliferation of cancer cell lines (Du et al, 2004).…”

mentioning

confidence: 99%

Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted

et al. 2006

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Tumours ferment glucose to lactate even in the presence of oxygen (aerobic glycolysis; Warburg effect). The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis and glucose degradation to lactate. The nonoxidative part of the PPP is controlled by transketolase enzyme reactions. We have detected upregulation of a mutated transketolase transcript (TKTL1) in human malignancies, whereas transketolase (TKT) and transketolase-like-2 (TKTL2) transcripts were not upregulated. Strong TKTL1 protein expression was correlated to invasive colon and urothelial tumours and to poor patients outcome. TKTL1 encodes a transketolase with unusual enzymatic properties, which are likely to be caused by the internal deletion of conserved residues. We propose that TKTL1 upregulation in tumours leads to enhanced, oxygen-independent glucose usage and a lactatebased matrix degradation. As inhibition of transketolase enzyme reactions suppresses tumour growth and metastasis, TKTL1 could be the relevant target for novel anti-transketolase cancer therapies. We suggest an individualised cancer therapy based on the determination of metabolic changes in tumours that might enable the targeted inhibition of invasion and metastasis.

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“…Similar to the relevance of Her2/neu as a 'drugable' target for an individualized anti-cancer therapy (22)(23)(24)(25), TKTL1 might also be a future target for small molecule drug design and individualized treatment strategies in breast cancer: metabolic control analysis and inhibition of transketolase enzyme reactions have shown in vitro as well as in vivo that tumor proliferation can be inhibited by antitransketolase approaches (5)(6)(7)(26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Transketolase protein TKTL1 overexpression: A potential biomarker and therapeutic target in breast cancer

Földi¹,

Stickeler²,

Bau³

et al. 2007

Oncol Rep

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Abstract. Malignant tumors degrade glucose to lactate even in the presence of oxygen via the pentose phosphate pathway (ppp). The non-oxidative part of the ppp is controlled by thiamine-dependant transketolase enzyme reactions. Overexpression of the transketolase-like-1-gene (TKTL1) in urothelial and colorectal cancer is associated with poor patient outcome. We analyzed the expression of the TKTL1 protein in a retrospective institution-based patient cohort with invasive breast cancer by immunohistochemical analysis of 124 paraffin-embedded breast cancer tissues. Our study revealed TKTL1 expression in 86% of breast cancer specimens with 45% showing high expression levels. In contrast, only 29% of corresponding non-neoplastic breast tissues were TKTL1 immunopositive, including 9% with high expression levels. High expression levels of TKTL1 correlated significantly to Her2/neu overexpression (p=0.015). However, TKTL1 expression failed to reach statistical significance for other common prognostic parameters. In contrast to recent data for e.g. colorectal cancer TKTL1 overexpression did not correlate to patient outcome and survival. However, in the context of novel insights into TKTL1-related tumor metabolism and the high proportion of TKTL1 overexpressing breast cancers, this enzyme represents a potential candidate for targeted inhibition of tumor growth in this tumor entity.

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Identification of Novel Small-Molecule Inhibitors for Human Transketolase by High-Throughput Screening with Fluorescent Intensity (FLINT) Assay

Cited by 32 publications

References 17 publications

Overexpression of transketolase protein TKTL1 is associated with occurrence and progression in nasopharyngeal carcinoma: A potential therapeutic target in nasopharyngeal carcinoma

Overexpression of transketolase protein TKTL1 is associated with occurrence and progression in nasopharyngeal carcinoma: A potential therapeutic target in nasopharyngeal carcinoma

Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted

Transketolase protein TKTL1 overexpression: A potential biomarker and therapeutic target in breast cancer

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