Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death

Download
2015-06-15
Lee, Eric A.
Angka, Leonard
Rota, Sarah-Grace
Hanlon, Thomas
Mitchell, Andrew
Hurren, Rose
Wang, Xiao Ming
Gronda, Marcela
Boyacı, Ezel
Bojko, Barbara
Minden, Mark
Sriskanthadevan, Shrivani
Datti, Alessandro
Wrana, Jeffery L.
Edginton, Andrea
Pawliszyn, Janusz
Joseph, Jamie W.
Quadrilatero, Joe
Schimmer, Aaron D.
Spagnuolo, Paul A.
Treatment regimens for acute myeloid leukemia (AML) continue to offer weak clinical outcomes. Through a high-throughput cell-based screen, we identified avocatin B, a lipid derived from avocado fruit, as a novel compound with cytotoxic activity in AML. Avocatin B reduced human primary AML cell viability without effect on normal peripheral blood stem cells. Functional stem cell assays demonstrated selectivity toward AML progenitor and stem cells without effects on normal hematopoietic stem cells. Mechanistic investigations indicated that cytotoxicity relied on mitochondrial localization, as cells lacking functional mitochondria or CPT1, the enzyme that facilitates mitochondria lipid transport, were insensitive to avocatin B. Furthermore, avocatin B inhibited fatty acid oxidation and decreased NADPH levels, resulting in ROS-dependent leukemia cell death characterized by the release of mitochondrial proteins, apoptosis-inducing factor, and cytochrome c. This study reveals a novel strategy for selective leukemia cell eradication based on a specific difference in mitochondrial function. (C) 2015 AACR.
CANCER RESEARCH

Suggestions

Studies directed towards The synthesis Of İmatinib Mesylate ((Gleevec), 4-(4-Methyl-Piperazin-1- Ylmethyl)-N-[4- Methyl-3-(4-Pyridin-3-Yl-Pyrimidin-2- Ylamino)-Phenyl]- Benzamide Methanesulfonate) Analogs
Günay, Neşet Batuhan; Demir, Ayhan Sıtkı; Department of Chemistry (2008)
Imatinib mesylate is indicated for the treatment of chronic myeloid leukemia (CML) and unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). By the application of this anticancer drug, problems occurs in terms of stability and activity. Computer assisted design (CAD) works showed that the modification of the B and C part molecule can increase the effectivity of the drug. The new derivatives of the drug will be obtained to change some part of the B and C segments. The total synthes...
Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation
BARAN, YUSUF; Bielawski, Jacek; Gündüz, Ufuk; Ogretmen, Besim (2011-10-01)
Purpose Drug resistance presents a major obstacle for the treatment of some patients with chronic myeloid leukemia (CML). Pro-apoptotic ceramide mediates imatinib-induced apoptosis, and metabolism of ceramide by glucosylceramide synthase (GCS) activity, converting ceramide to glucosyl ceramide, might contribute to imatinib resistance. In this study, we investigated the role of ceramide metabolism by GCS in the regulation of imatinib-induced apoptosis in drug-sensitive and drug-resistant K562 and K562/IMA-0....
Capture of circulating tumor cells from blood on modified gold surfaces inside the microfluidic channels
Çetin, Didem; Külah, Haluk; Department of Biomedical Engineering (2019)
Detection of circulating tumor cells (CTCs) from the bloodstream has a critical role in diagnosing and treatment of cancer. However, the number of CTCs in blood compared to other blood cells are extremely rare. In this thesis, various surface modifications strategies for detection of CTCs are studied in order to be used in the microfluidic detection systems. Functionalizing the gold surface with Self Assembled Monolayers (SAMs) used for attaching the EpCAM antibodies, which made possible to immobilize EpCAM...
Targeting PI3K/Akt/mTOR Pathway Identifies Differential Expression and Functional Role of IL8 in Liver Cancer Stem Cell Enrichment
Kahraman, Deniz Cansen; Atalay, Rengül (2019-11-01)
Activation of the PI3K/Akt/mTOR pathway is an important signaling mechanism involved in the development and the progression of liver cancer stem cell (LCSC) population during acquired Sorafenib resistance in advanced hepatocellular carcinoma (HCC). Therefore, identification of novel therapeutic targets involving this pathway and acting on LCSCs is highly essential. Here, we analyzed the bioactivities and the molecular pathways involved in the action of small-molecule PI3K/Akt/mTOR pathway inhibitors in comp...
Regulation of Glutathione S-Transferase Mu with type 1 diabetes and its regulation with antioxidants
SADİ, GÖKHAN; Kartal, Deniz Irtem; Güray, Nülüfer Tülün (2013-01-01)
Objective: Increased oxidative stress is now related with the pathogenesis and the chronic complications associated with the disease, diabetes mellitus. While roles of oxidative stress in diabetic complications are widely studied, the molecular mechanisms playing role in the regulations of detoxification enzymes in the presence of antioxidants have not been clearly established because of the complexity of the pathways.
Citation Formats
E. A. Lee et al., “Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death,” CANCER RESEARCH, pp. 2478–2488, 2015, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/47356.