Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H et al.. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by -phenylethyl isothiocyanate. Cancer Cell 10: 241-252

Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Cell (Impact Factor: 23.52). 10/2006; 10(3):241-52. DOI: 10.1016/j.ccr.2006.08.009
Source: PubMed


Reactive oxygen species (ROS) stimulate cell proliferation and induce genetic instability, and their increase in cancer cells is often viewed as an adverse event. Here, we show that such abnormal increases in ROS can be exploited to selectively kill cancer cells using beta-phenylethyl isothiocyanate (PEITC). Oncogenic transformation of ovarian epithelial cells with H-Ras(V12) or expression of Bcr-Abl in hematopoietic cells causes elevated ROS generation and renders the malignant cells highly sensitive to PEITC, which effectively disables the glutathione antioxidant system and causes severe ROS accumulation preferentially in the transformed cells due to their active ROS output. Excessive ROS causes oxidative mitochondrial damage, inactivation of redox-sensitive molecules, and massive cell death. In vivo, PEITC exhibits therapeutic activity and prolongs animal survival.

Download full-text


Available from: Yusuke Demizu, Oct 06, 2015
1 Follower
47 Reads
    • "The ability to recognize and detoxify ROS is critical for the process of oncogenic transformation (DeNicola et al., 2011). In particular, the accumulation of ROS is associated with the high proliferative capacity and altered mitochondrial respiration of cancer cells and needs to be detoxified in order to maintain tumor growth (Raj et al., 2011; Trachootham et al., 2006). In line with decreased translation of ROS target genes, fluorescent staining with CM- H2DCFDA reveals that Eif4e +/À cells display elevated levels of intracellular ROS downstream of oncogenic transformation by Ras and Myc (Figure 6A). "
    [Show abstract] [Hide abstract]
    ABSTRACT: eIF4E, the major cap-binding protein, has long been considered limiting for translating the mammalian genome. However, the eIF4E dose requirement at an organismal level remains unexplored. By generating an Eif4e haploinsufficient mouse, we found that a 50% reduction in eIF4E expression, while compatible with normal development and global protein synthesis, significantly impeded cellular transformation. Genome-wide translational profiling uncovered a translational program induced by oncogenic transformation and revealed a critical role for the dose of eIF4E, specifically in translating a network of mRNAs enriched for a unique 5' UTR signature. In particular, we demonstrate that the dose of eIF4E is essential for translating mRNAs that regulate reactive oxygen species, fueling transformation and cancer cell survival in vivo. Our findings indicate eIF4E is maintained at levels in excess for normal development that are hijacked by cancer cells to drive a translational program supporting tumorigenesis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 06/2015; 162(1). DOI:10.1016/j.cell.2015.05.049 · 32.24 Impact Factor
  • Source
    • ". As could be expected from the role of hydrogen peroxide in signaling for cell proliferation and cell death, the redox changes seen in cancer cells can impact these processes. Cancer phenotypes of Ras V12 -transformed cells include anchorage-independent growth, an accelerated rate of proliferation and the ability to form tumors in immunocompromised mice [86]. These properties are seen in cells transfected with Nox1 [46], consistent with increased expression of Nox1 in cells carrying the Ras Val12 mutation [87]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the absence of oxygen human life is measured in minutes. In the presence of oxygen, normal metabolism generates reactive species (ROS) that have the potential to cause cell injury contributing to human aging and disease. Between these extremes, organisms have developed means for sensing oxygen and ROS and regulating their cellular processes in response. Redox signaling contributes to the control of cell proliferation and death. Aberrant redox signaling underlies many human diseases. The attributes acquired by altered redox homeostasis in cancer cells illustrate this particularly well. This teaching review and the accompanying illustrations provide an introduction to redox biology and signaling aimed at instructors of graduate and medical students. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
    04/2015; 87. DOI:10.1016/j.redox.2015.04.002
  • Source
    • "itates cellular disassembly and serves as a marker of cellular apoptosis ( Konopleva et al . , 1999 ; Oliver et al . , 1998 ) . Hence , PA most likely induce apoptosis through a caspase - dependent pathway . ROS generation in cancer cells is often increased after treatment with anticancer agents ( Szatrowski and Nathan , 1991 ; Schumacker , 2006 ; Trachootham et al . , 2006 ) . Previ - ous studies demonstrated that high ROS levels induce cellular damage ( Pelicano et al . , 2004 ; Valko et al . , 2006 ; Li et al . , 2007 ; Hseu et al . , 2008 ) and may play an important role in mediating apoptosis ( Garcia - Ruiz et al . , 1997 ; Coyle and Putt - farcken , 1993 ) . We determined that ROS are generated duri"
    [Show abstract] [Hide abstract]
    ABSTRACT: We previously identified Streptomyces griseus as an anti-cancer agent (Kim et al., 2014). In this study, we isolated compounds from S. griseus and evaluated their anticancer effect and toxicity in vitro and in vivo. Preparative centrifugal partition chromatography (CPC) was used to obtain three compounds, cyclo(L-[4-hydroxyprolinyl]- L –leucine], cyclo(L-Phe-trans-4-hydroxy-L-Pro) and phenethyl acetate (PA). We chose PA, which had the highest anticancer activity, as a target compound for further experiments. PA induced the formation of apoptotic bodies, DNA fragmentation, DNA accumulation in G0/G1 phase, and reactive oxygen species (ROS) formation. Furthermore, PA treatment increased Bax/Bcl-xL expression, activated caspase-3, and cleaved poly-ADP-ribose polymerase (PARP) in HL-60 cells. Simultaneous evaluation in vitro and in vivo, revealed that PA exhibited no toxicity in Vero cells and zebrafish embryos. We revealed, for the first time, that PA generates ROS, and that this ROS accumulation induced the Bcl signaling pathway.
    Fisheries and Aquatic Science 03/2015; 18(1):35-44. DOI:10.5657/FAS.2015.0035
Show more