Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effect of tannic acid, a potent inhibitor of poly(ADP-ribose) glycohydrolase, on human viral gene transcription, by using chloramphenicol acetyl transferase (CAT) assay experiments transfecting Jurkat cells with CAT reporter constructs that contain the promoter region of human immunodeficiency virus (HIV) or of human T-cell leukemia virus type I (HTLV-1). The activity of HIV promoter induced by treatment with 12-O-tetradecanoylphorbol-13-acetate was suppressed by the addition of tannic acid. On the other hand, HTLV-1 promoter activity induced by the p40(tax) expression plasmid was not affected by tannic acid treatment. Deletion analysis of the HIV promoter revealed that a 30-bp element located immediately upstream of NF-kappa B motifs was responsible for the suppressive effect of tannic acid. This was supported by the observations that the negative effect of tannic acid was introduced to tannic acid-non-responsive thymidine kinase promoter by the insertion of this element 5'-upstream of the promoter.
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PMID:Inhibitory effect of tannic acid on human immunodeficiency virus promoter activity induced by 12-O-tetra decanoylphorbol-13-acetate in Jurkat T-cells. 864 19

Targeting Bruton's tyrosine kinase (BTK) with the small molecule BTK inhibitor ibrutinib has significantly improved patient outcomes in several B-cell malignancies, with minimal toxicity. Given the reported expression and constitutive activation of BTK in acute myeloid leukemia (AML) cells, there has been recent interest in investigating the anti-AML activity of ibrutinib. We noted that ibrutinib had limited single-agent toxicity in a panel of AML cell lines and primary AML samples, and therefore sought to identify ibrutinib-sensitizing drugs. Using a high-throughput combination chemical screen, we identified that the poly(ADP-ribose) glycohydrolase (PARG) inhibitor ethacridine lactate synergized with ibrutinib in TEX and OCI-AML2 leukemia cell lines. The combination of ibrutinib and ethacridine induced a synergistic increase in reactive oxygen species that was functionally important to explain the observed cell death. Interestingly, synergistic cytotoxicity of ibrutinib and ethacridine was independent of the inhibitory effect of ibrutinib against BTK, as knockdown of BTK did not sensitize TEX and OCI-AML2 cells to ethacridine treatment. Thus, our findings indicate that ibrutinib may have a BTK-independent role in AML and that PARG inhibitors may have utility as part of a combination therapy for this disease.
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PMID:Ibrutinib synergizes with poly(ADP-ribose) glycohydrolase inhibitors to induce cell death in AML cells via a BTK-independent mechanism. 2662 83