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)

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of cytokine superfamily, induces apoptosis in a number of tumor cells through the activation of extrinsic apoptotic pathway but shows little or no cytotoxicity toward normal cells. However some tumor cells are inherently resistant to TRAIL-mediated apoptosis, which needs to be addressed to establish TRAIL as a potential chemotherapeutic drug. In this study, our aim was to manipulate TRAIL-apoptosis pathway by hydroxychavicol (HCH), a polyphenol from Piper betel leaf, for the induction of apoptosis in TRAIL resistant chronic myeloid leukemia cell. When imatinib-resistant K562 cells were treated with HCH, it made these K562 cells sensitive to TRAIL. It was observed that HCH downregulated antiapoptotic proteins XIAP and FLIP, whereas the expression of TRAIL receptors, DR4 and DR5, remains unchanged. Moreover, we observed that reactive oxygen species or ROS played a crucial role in the downregulation of FLIP and XIAP because ROS scavenger significantly reversed the decrease of XIAP, and FLIP. Ubiquitin-proteasome pathway was observed to play a crucial role in the downregulation of XIAP and FLIP, as proteasomal inhibitor MG132 significantly reversed the downregulation of XIAP and FLIP. In conclusion, this study demonstrates the combinatorial treatment of TRAIL and HCH as promising alternative therapeutic approach to treat the imatinib-resistant leukemia, which are also resistant to TRAIL.
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PMID:Hydroxychavicol sensitizes imatinib-resistant chronic myelogenous leukemia cells to TRAIL-induced apoptosis by ROS-mediated IAP downregulation. 3041 93

Ubiquitin-specific peptidase 39 (USP39) is one member of the cysteine proteases of the USP family, which represents the largest group of DeUbiquitinases with more than 50 members in humans. The roles of USP39 in human cancer have been widely investigated. However, the roles of USP39 in human leukemia and the underlying mechanism remain unknown. Here we reported the function of USP39 in human leukemia. We observed that the expression of USP39 was up-regulated in human leukemia cells and the high expression of USP39 was correlated with poor survival of the patients with leukemia. Lentivirus-mediated knockdown of USP39 repressed the proliferation and colony formation of human leukemia cell lines HL-60 and Jurkat cells. Mechanism study showed that USP39 knockdown induced the arrest of cell cycle and apoptosis of leukemia cells. In addition, our microarray and bioinformatic analysis demonstrated that USP39 regulated diverse cellular signaling pathways that were involved in tumor biology, and several pivotal genes (IRF1, Caspase 8, and SP1) have been validated by quantitative real-time polymerase chain reaction. Knockdown or IRF1 partially restored the proliferation rate of leukemia cells with USP39 knockdown. Taken together, our findings implicate that USP39 promotes the development of human leukemia by regulating cell cycle, survival, and proliferation of the cells.
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PMID:USP39 regulates the cell cycle, survival, and growth of human leukemia cells. 3089 77

Thymoquinone (TQ), a natural anticancer agent exerts cytotoxic effects on several tumors by targeting multiple pathways, including apoptosis. Difluoromethylornithine (DFMO), an irreversible inhibitor of the ornithine decarboxylase (ODC) enzyme, has shown promising inhibitory activities in many cancers including leukemia by decreasing the biosynthesis of the intracellular polyamines. The present study aimed to investigate the combinatorial cytotoxic effects of TQ and DFMO on human acute T lymphoblastic leukemia Jurkat cells and to determine the underlying mechanisms. Here, we show that the combination of DFMO and TQ significantly reduced cell viability and resulted in significant synergistic effects on apoptosis when compared to either DFMO or TQ alone. RNA-sequencing showed that many key epigenetic players including Ubiquitin-like containing PHD and Ring finger 1 (UHRF1) and its 2 partners DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) were down-regulated in DFMO-treated Jurkat cells. The combination of DFMO and TQ dramatically decreased the expression of UHRF1, DNMT1 and HDAC1 genes compared to either DFMO or TQ alone. UHRF1 knockdown led to a decrease in Jurkat cell viability. In conclusion, these results suggest that the combination of DFMO and TQ could be a promising new strategy for the treatment of human acute T lymphoblastic leukemia by targeting the epigenetic code.
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PMID:Thymoquinone and Difluoromethylornithine (DFMO) Synergistically Induce Apoptosis of Human Acute T Lymphoblastic Leukemia Jurkat Cells Through the Modulation of Epigenetic Pathways. 3291 61


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