Rodrigues, M. S., Reddy, M. M. & Sattler, M. Cell cycle regulation by oncogenic tyrosine kinases in myeloid neoplasias: from molecular redox mechanisms to health implications. Antioxid. Redox Signal. 10, 1813-1848
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.
- SourceAvailable from: Maqusood Ahamed
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- "Although the precise pathways leading to ROS stress in cancer cells remain unclear. Activation of oncogenes (Ras, Bcr-Abl, c-Myc, etc.), aberrant metabolism (higher metabolism associated with unregulated growth), activation of the ROS-producing enzyme NADPH oxidase, mitochondrial dysfunction, and loss of functional p53 are intrinsic factors known to cause increased ROS production (Bosanquet and Bell 2004; Wu 2006; Brandon et al. 2006; Rodrigues et al. 2008 "
ABSTRACT: There has been little focus on the promising ability of metal-based nanoparticles (NPs) to kill cancer cells while sparing normal cells. Many in vitro and in vivo reports suggest that certain metal-based NPs are able to induce apoptosis and autophagy in cancer cells at specific concentrations that are not significantly toxic to non-cancerous cells. Those NPs are thought to exploit the oxidative stress conditions that prevail in cancer cells, which are largely exhausted of antioxidant ability. This review considers the induction of reactive oxygen species (ROS) by metal-based NPs as a mechanism for the specific killing of cancer cells. The article concomitantly provides a comprehensive description of the important pathways and molecules leading to programmed cell death (PCD), which occurs mainly via apoptosis, autophagy, and necroptosis. The PCD pathways are followed as ROS-burdened cancer cells succumb to ROS-generating metal-based NPs. Exploration of nanotechnology interventions in anticancer therapy demands further research into the mechanism of intracellular induction of ROS by metal-based NPs. Furthermore, the induction of ROS by NPs should be strictly controlled if ROS-based therapy is to become a paradigm in cancer therapy.Archives of Toxicology 07/2015; DOI:10.1007/s00204-015-1570-1 · 5.08 Impact Factor
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- "Increased levels of reactive oxygen species (ROSs) have also been found to be associated with the R970C and T992I variants [Jagadeeswaran et al. 2007]. ROS in most cancer cells are of mitochondrial origin and do not only play a role in cancer cell signaling, but may also contribute to genomic instability [Rodrigues et al. 2008]. "
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