Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.2.1.13 (glyceraldehyde-3-phosphate dehydrogenase)
 6,511 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Imatinib mesylate is widely used for the treatment of patients with chronic myelogenous leukemia (CML). This compound is very efficient in killing Bcr-Abl-positive cells in a caspase-dependent manner. Nevertheless, several lines of evidence indicated that caspase-mediated cell death (i.e., apoptosis) is not the only type of death induced by imatinib. The goal of our study was to evaluate the importance of the newly described caspase-independent cell death (CID) in Bcr-Abl-positive cells. We established in several CML cell lines that imatinib, in conjunction with apoptosis, also induced CID. CID was shown to be as efficient as apoptosis in preventing CML cell proliferation and survival. We next investigated the potential implication of a recently identified mechanism used by cancer cells to escape CID through overexpression of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We showed here, in several CML cell lines, that GAPDH overexpression was sufficient to induce protection from CID. Furthermore, imatinib-resistant Bcr-Abl-positive cell lines were found to spontaneously overexpress GAPDH. Finally, we showed that a GAPDH partial knockdown, using specific short hairpin RNAs, was sufficient to resensitize those resistant cells to imatinib-induced cell death. Taken together, our results indicate that CID is an important effector of imatinib-mediated cell death. We also established that GAPDH overexpression can be found in imatinib-resistant Bcr-Abl-positive cells and that its down-regulation can resensitize those resistant cells to imatinib-induced death. Therefore, drugs able to modulate GAPDH administered together with imatinib could find some therapeutic benefits in CML patients.
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PMID:Modulation of caspase-independent cell death leads to resensitization of imatinib mesylate-resistant cells. 1931 79

Imatinib mesylate has significantly improved the outcome of patients with CML. In the IRIS trial, major molecular response (MMR), which is defined as the achievement of > or =3 log reduction in bcr-abl mRNA from the standardized baseline, was observed in 40% of CML patients by 12 months. Achievement of an MMR at 18 months is associated with 100% probability of transformation-free survival at 60 months, and MMR is an important goal of therapy. The nucleic acid quantitative "DNA probe FR Amp-CML" kit based on the transcription-mediated amplification method, can measure major bcr-abl mRNA in peripheral blood leukocytes. In this study, we studied the clinical usefulness of Amp-CML for monitoring minimum residual disease by comparison with the European standard nucleic acid quantitative method and real-time quantitative PCR (RQ-PCR) with GAPDH as an internal control, using peripheral leukocytes obtained from patients receiving imatinib treatment. The results indicated that Amp-CML had a significant correlation with Fusion Quant M-BCR (R>0.971, P<0.01), a standard nucleic acid quantitative method used in Europe and RQ-PCR (R>0.974, P<0.01), especially in samples with more than 100 copies/microg RNA of major bcr-abl mRNA. These data suggest that Amp-CML is reliable for monitoring major bcr-abl mRNA in patients having achieved an MMR.
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PMID:[Correlation of quantification of major bcr-abl mRNA between TMA (transcription mediated amplification) method and real-time quantitative PCR]. 1957 8