Cell cycle regulation by oncogenic tyrosine kinases in myeloid neoplasias: from molecular redox mechanisms to health implications.

Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Antioxidants & Redox Signaling (Impact Factor: 7.67). 08/2008; 10(10):1813-48. DOI: 10.1089/ars.2008.2071
Source: PubMed

ABSTRACT Neoplastic expansion of myeloid cells is associated with specific genetic changes that lead to chronic activation of signaling pathways, as well as altered metabolism. It has become increasingly evident that transformation relies on the interdependency of both events. Among the various genetic changes, the oncogenic BCR-ABL tyrosine kinase in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) has been a focus of extensive research. Transformation by this oncogene is associated with elevated levels of intracellular reactive oxygen species (ROS). ROS have been implicated in processes that promote viability, cell growth, and regulation of other biological functions such as migration of cells or gene expression. Currently, the BCR-ABL inhibitor imatinib mesylate (Gleevec) is being used as a first-line therapy for the treatment of CML. However, BCR-ABL transformation is associated with genomic instability, and disease progression or resistance to imatinib can occur. Imatinib resistance is not known to cause or significantly alter signaling requirements in transformed cells. Elevated ROS are crucial for transformation, making them an ideal additional target for therapeutic intervention. The underlying mechanisms leading to elevated oxidative stress are reviewed, and signaling mechanisms that may serve as novel targeted approaches to overcome ROS-dependent cell growth are discussed.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocyte growth factor receptor (HGFR), the product of the MET gene, plays an important role in normal cellular function and oncogenesis. In cancer, HGFR has been implicated in cellular proliferation, cell survival, invasion, cell motility, metastasis and angiogenesis. Activation of HGFR can occur through binding to its ligand, hepatocyte growth factor (HGF), overexpression/amplification, mutation, and/or decreased degradation. Amplification of HGFR can occur de novo or in resistance to therapy. Mutations of HGFR have been described in the tyrosine kinase domain, juxtamembrane domain, or semaphorin domain in a number of tumors. These mutations appear to have gain of function, and also reflect differential sensitivity to therapeutic inhibition. There have been various drugs developed to target HGFR, including antibodies to HGFR/HGF, small-molecule inhibitors against the tyrosine kinase domain of HGFR and downstream targets. Different HGFR inhibitors are currently in clinical trials in lung cancer and a number of solid tumors. Several phase I trials have already been completed, and two specific trials have been reported combining HGFR with epidermal growth factor receptor (EGFR) inhibition in non-small cell lung cancer. In particular, trials involving MetMAb and ARQ197 (tivantinib) have gained interest. Ultimately, as individualized therapies become a reality for cancers, HGFR will be an important molecular target.
    rapeutic Advances in Medical Oncology, The 07/2011; 3(4):171-84. DOI:10.1177/1758834011408636
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress is often defined as an imbalance of pro-oxidants and antioxidants, which can be quantified in humans as the redox state of plasma GSH/GSSG. Plasma GSH redox in humans becomes oxidized with age, in response to oxidative stress (chemotherapy, smoking), and in common diseases (type 2 diabetes, cardiovascular disease). However, data also show that redox of plasma GSH/GSSG is not equilibrated with the larger plasma cysteine/cystine (Cys/CySS) pool, indicating that the "balance" of pro-oxidants and antioxidants cannot be defined by a single entity. The major cellular thiol/disulfide systems, including GSH/GSSG, thioredoxin- 1 (-SH(2)/-SS-), and Cys/CySS, are not in redox equilibrium and respond differently to chemical toxicants and physiologic stimuli. Individual signaling and control events occur through discrete redox pathways rather than through mechanisms that are directly responsive to a global thiol/disulfide balance such as that conceptualized in the common definition of oxidative stress. Thus, from a mechanistic standpoint, oxidative stress may be better defined as a disruption of redox signaling and control. Adoption of such a definition could redirect research to identify key perturbations of redox signaling and control and lead to new treatments for oxidative stress-related disease processes.
    Antioxidants and Redox Signaling 09/2006; 8(9-10):1865-79. DOI:10.1089/ars.2006.8.1865 · 7.67 Impact Factor