Page 10 - 2014 Printable Abstract Book
P. 10
ONE- ELECTRON AND TWO-ELECTRON SIGNALING IN THE REDOX BIOLOGY OF CANCER: APPLICATION
TO PHARMACOLOGICAL ASCORBATE IN THE CLINIC
(P001) One-electron and two-electron signaling in the redox biology of cancer: Application to
pharmacological ascorbate in the clinic. Garry R. Buettner, University of Iowa, Iowa City, IA
For life on earth, organisms must establish and maintain an intra-organism redox environment
that is considerably more reduced than the surroundings. Many reversible redox couples contribute to
the status of this redox environment. The actual redox state of these couples is set by the ebb and flow
of electrons. Movement of electrons releases the energy contained in carbon-based molecules, captured
in ATP. A small fraction of these electrons are not used for energy production, but are shunted to oxygen
to make superoxide and hydrogen peroxide. These two species initiate cascades of redox chemistry that
are central to redox biology. A network of redox active small molecules and enzymes keeps the steady-
state levels of superoxide and hydrogen peroxide very low. Different redox couples sense changes in the
flux of superoxide and hydrogen peroxide, each leading to distinct patterns of gene expression. As a
signaling molecule, hydrogen peroxide is a two-electron oxidant, ideal for changing the redox poise of
thiols, thereby activating signaling pathways. In contrast, the prime target of superoxide is a subset of
iron-containing enzymes. Changes in the activity of these enzymes after reaction with superoxide leads to
changes in metabolism and patterns of gene expression that promote cell division. Examples are the
inactivation of aconitase and the activation of the HIF-system via prolyl hydroxylases. Superoxide
dismutase is at the fulcrum of these two signaling pathways, contributing to the balance between 1-
electron and 2-electron signaling. Thus, the traditional view of antioxidant enzymes needs to be
expanded. The antioxidant network of small-molecules, proteins, and enzymes, which senses changes in
the flux of ROS/RNS, provides the appropriate balance between 1-electron and 2-electron signaling. Thus,
this apparent antioxidant network is best viewed as a set of interconnected redox networks that establish
the basic biology of cells, tissues, and organisms. These concepts can be used to understand aspects of
the basic biology of cancer and cancer treatment. Pharmacological ascorbate as an adjuvant in cancer
treatment is an example of the application of these concepts.
MICROVESICLES, INTERCELLULAR SIGNALING AND THE RADIORESPONSE
(P002) Microvesicles, Intercellular Signaling and the Radioresponse. Nicholas Dainiak, Department of
Internal Medicine and Department of Therapeutic Radiology, Yale University School of Medicine, New
Haven, CT
Microvesicles (MV) have been visualized with a variety of techniques, including TEM, freeze
fracture EM, confocal fluorescence imaging, fluorescein correlation spectroscopy, live cell fluorescence
microscopy and atomic force microscopy. Here, images obtained with these tools will be used to facilitate
a review our current understanding of the nomenclature, biogenesis, mechanisms of release and
targeting, and pleiotropic biological functions of MV (or microparticles) with an emphasis on their role in
cell-cell communication and the radioresponse. The classification of subtypes of MV is under review by
concerned investigators who have recently formed the International Society of Extracellular Vesicles. MV
include (1) plasma membrane (PM)-derived, shed vesicles (i.e., shedding microvesicles or ectosomes) and
8 | P a g e
TO PHARMACOLOGICAL ASCORBATE IN THE CLINIC
(P001) One-electron and two-electron signaling in the redox biology of cancer: Application to
pharmacological ascorbate in the clinic. Garry R. Buettner, University of Iowa, Iowa City, IA
For life on earth, organisms must establish and maintain an intra-organism redox environment
that is considerably more reduced than the surroundings. Many reversible redox couples contribute to
the status of this redox environment. The actual redox state of these couples is set by the ebb and flow
of electrons. Movement of electrons releases the energy contained in carbon-based molecules, captured
in ATP. A small fraction of these electrons are not used for energy production, but are shunted to oxygen
to make superoxide and hydrogen peroxide. These two species initiate cascades of redox chemistry that
are central to redox biology. A network of redox active small molecules and enzymes keeps the steady-
state levels of superoxide and hydrogen peroxide very low. Different redox couples sense changes in the
flux of superoxide and hydrogen peroxide, each leading to distinct patterns of gene expression. As a
signaling molecule, hydrogen peroxide is a two-electron oxidant, ideal for changing the redox poise of
thiols, thereby activating signaling pathways. In contrast, the prime target of superoxide is a subset of
iron-containing enzymes. Changes in the activity of these enzymes after reaction with superoxide leads to
changes in metabolism and patterns of gene expression that promote cell division. Examples are the
inactivation of aconitase and the activation of the HIF-system via prolyl hydroxylases. Superoxide
dismutase is at the fulcrum of these two signaling pathways, contributing to the balance between 1-
electron and 2-electron signaling. Thus, the traditional view of antioxidant enzymes needs to be
expanded. The antioxidant network of small-molecules, proteins, and enzymes, which senses changes in
the flux of ROS/RNS, provides the appropriate balance between 1-electron and 2-electron signaling. Thus,
this apparent antioxidant network is best viewed as a set of interconnected redox networks that establish
the basic biology of cells, tissues, and organisms. These concepts can be used to understand aspects of
the basic biology of cancer and cancer treatment. Pharmacological ascorbate as an adjuvant in cancer
treatment is an example of the application of these concepts.
MICROVESICLES, INTERCELLULAR SIGNALING AND THE RADIORESPONSE
(P002) Microvesicles, Intercellular Signaling and the Radioresponse. Nicholas Dainiak, Department of
Internal Medicine and Department of Therapeutic Radiology, Yale University School of Medicine, New
Haven, CT
Microvesicles (MV) have been visualized with a variety of techniques, including TEM, freeze
fracture EM, confocal fluorescence imaging, fluorescein correlation spectroscopy, live cell fluorescence
microscopy and atomic force microscopy. Here, images obtained with these tools will be used to facilitate
a review our current understanding of the nomenclature, biogenesis, mechanisms of release and
targeting, and pleiotropic biological functions of MV (or microparticles) with an emphasis on their role in
cell-cell communication and the radioresponse. The classification of subtypes of MV is under review by
concerned investigators who have recently formed the International Society of Extracellular Vesicles. MV
include (1) plasma membrane (PM)-derived, shed vesicles (i.e., shedding microvesicles or ectosomes) and
8 | P a g e
