Oxidative Cyclization-Induced Activation of a Phosphoinositide 3-Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics.

Oxidative Cyclization-Induced Activation of a Phosphoinositide 3-Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics. ChemMedChem. 2019 Nov 07;: Authors: Zhu H, Mishra R, Yuan L, Abdul Salam SF, Liu J, Gray G, Sterling AD, Wunderlich M, Landero-Figueroa J, Garrett JT, Merino EJ Abstract In this work, we designed a prodrug that reacts with cellular oxidative equivalents leading to ether cleavage and cyclization to release an active phosphatidylinositol 3-kinase (PI3K) inhibitor. We show that the compound reduces affinity for PI3KA relative to the PI3K inhibitor, is slow to intercellularly oxidize, and is resistant to liver microsomes. We observed modest activity in untreated acute myeloid leukemia cells and 14-fold selectivity relative to non-cancerous cells. The cellular activity of the compound can be modulated by the addition of antioxidants or oxidants, indicating the compound activity is sensitive to cellular reactive oxygen species (ROS) state. Co-treatment with cytosine arabinoside or doxorubicin was used to activate the compound inside cells. We observed strong synergistic activity specifically in acute myeloid leukemia (AML) cancer cells with an increase in selective anticancer activity of up to 90-fold. Thus, these new self-cyclizing compounds can be used to increase the selectivity of anticancer agents. PMID: 31696673 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research

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Publication date: Available online 11 December 2019Source: Life SciencesAuthor(s): Huifang Sun, Yongfa Sun, Qing Chen, Zhaoying XuAbstractAimsAcute myeloid leukemia (AML) is an aggressive cancer that invariably produces drug resistance after treatment. The aim is to explore the role of lncRNA potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1 (KCNQ1OT1) and associated novel mechanisms in the progression and chemoresistance of AML.Main methodsThe expression of KCNQ1OT1, miR-193a-3p, and Tspan3 was measured by qRT-PCR. The values of IC50 for adriamycin (ADR) and the ability of proliferation were an...
Source: Life Sciences - Category: Biology Source Type: research
The anti-leukemia activity of NK cells helps prevent relapse during hematopoietic stem cell transplantation (HSCT) in leukemia patients. However, the factors that determine the sensitivity or resistance of leukemia cells in the context of NK-mediated cytotoxicity are not well-established. Here, we performed a genome-wide CRISPR screen in the human chronic-myelogenous-leukemia (CML) cell line K562 to identify genes that regulate the vulnerability of leukemia cells to killing by primary human NK cells. The distribution of guide RNAs (gRNAs) in K562 cells that survived co-incubation with NK cells showed that loss of NCR3LG1, ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Publication date: 9 December 2019Source: Cancer Cell, Volume 36, Issue 6Author(s): Andrei V. Krivtsov, Kathryn Evans, Jayant Y. Gadrey, Benjamin K. Eschle, Charlie Hatton, Hannah J. Uckelmann, Kenneth N. Ross, Florian Perner, Sarah N. Olsen, Tara Pritchard, Lisa McDermott, Connor D. Jones, Duohui Jing, Ali Braytee, Diego Chacon, Eric Earley, Brian M. McKeever, David Claremon, Andrew J. Gifford, Heather J. LeeSummaryInhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally b...
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research
lncRNA PCAT-1 interacting with FZD6 contributes to the malignancy of acute myeloid leukemia cells through activating Wnt/β-catenin signaling pathway. Am J Transl Res. 2019;11(11):7104-7114 Authors: Yuan Y, Wang Q, Ma SL, Xu LQ, Liu MY, Han B, Du N, Sun XL, Yin XL, Cao FF Abstract Accumulating evidence has suggested the involvement of long noncoding RNAs (lncRNAs) on the acute myeloid leukemia (AML). Therefore, this study aimed to investigate the unknown function of lncRNA Prostate cancer-associated transcript-1 (PCAT-1) in AML cells. Our data found that PCAT-1 was highly expressed in AML-M1/2 and ...
Source: American Journal of Translational Research - Category: Research Tags: Am J Transl Res Source Type: research
(St. Jude Children's Research Hospital) Findings presented as a late-breaking abstract at the American Society of Hematology annual meeting by St. Jude Children's Research Hospital showcase the power and potential of combining genomic and transcriptomic data.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
Authors: Winters A, Gore L Abstract Although almost 90% of children with acute lymphoblastic leukemia (ALL) and ∼60% of children with acute myeloid leukemia are cured with frontline therapy, relapse and chemotherapy resistance are significant challenges that contribute to morbidity and mortality. Even with long-term survival, the acute and chronic burdens of therapy are major issues for patients and families. Long-term side effects occur, including cardiac, endocrinologic, neurcognitive, orthopedic, and psychosocial problems, and healthy survivorship is frequently compromised. With goals of minimizing relapse a...
Source: Hematology ASH Education Program - Category: Hematology Tags: Hematology Am Soc Hematol Educ Program Source Type: research
This article reviews the current landscape of antibody-based and cellular immunotherapies under current clinical evaluation with an emphasis on active or soon-to-open phase 1 trials for children with relapsed/refractory AML. PMID: 31808843 [PubMed - in process]
Source: Hematology ASH Education Program - Category: Hematology Tags: Hematology Am Soc Hematol Educ Program Source Type: research
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Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
CONCLUSIONS: The webinars met the educational needs of learners and improved knowledge gaps. This study provided novel insights into the learning needs of clinicians who care for patients with AML and a roadmap for future educational interventions. PMID: 31805525 [PubMed - in process]
Source: Journal of the National Comprehensive Cancer Network : JNCCN - Category: Cancer & Oncology Tags: J Natl Compr Canc Netw Source Type: research
ng Jung Salih Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism by which antitumor antibodies mediate therapeutic efficacy. At present, we evaluate an Fc-optimized (amino acid substitutions S239D/I332E) FLT3 antibody termed 4G8-SDIEM (FLYSYN) in patients with acute myeloid leukemia (NCT02789254). Here we studied the possibility to induce NK cell ADCC against B-cell acute lymphoblastic leukemia (B-ALL) by Fc-optimized FLT3 antibody treatment. Flow cytometric analysis confirmed that FLT3 is widely expressed on B-ALL cell lines and leukemic cells of B-ALL patients. FLT3 expression did not correlat...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
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