Page 283 - 2014 Printable Abstract Book
P. 283
maximal value at Day 3 in 1 Gy and at Day 14 in 3 Gy irradiated group, respectively. Further, intracellular
ROS contents increased, and reached maximal value at same time point, respectively. On the other hand,
DSB frequency transitory increased at Day 1, and gradually decreased in time-dependent manner.
Interestingly, the expression of senescence marker dramatically increased during Day 3 after irradiation.
These results suggested possibility that cell proliferation, to fill a space of death cells, after irradiation may
be a cause of cell senescence.
(PS4-83) Inducing tumor targeted DNA damage and inhibiting repair by eliminating NAD+ with the
radiosensitizer ß-lapachone and NamPT inhibition. Zachary Moore and David A. Boothman, University of
Texas Southwestern Medical Center, Dallas, TX
+
Cancer cells require increased NAD synthesis to support anabolic metabolism, to sustain signaling
processes such as sirtuin activity and ADP-ribosylation, and to maintain redox balance and minimize ROS
induced DNA damage. Inhibitors of nicotinamide phosphoribosyltransferase (NamPT), the rate-limiting
+
step in NAD biosynthesis, have anti-tumor activity in vitro and in vivo, but have failed clinical trials due to
+
a lack of tumor specificity which results from the necessity of NAD synthesis in normal proliferating cells.
We find that the tumor specificity and efficacy of NamPT inhibition is synergistically increased when small
molecule NamPT inhibitors such as FK866 are used in combination with the DNA damaging, NQO1
bioactivated therapeutic ß-lapachone (ß-lap). The majority of solid tumors overexpress NQO1, which
catalyzes a futile redox cycle with ß-lap, resulting in the formation of a burst of reactive oxygen species
(ROS). This results in substantial DNA single strand breaks and base damage in a tumor-specific manner
+
that hyperactivates poly(ADP-ribose) polymerase-1 (PARP1), a DNA repair enzyme which utilizes NAD to
+
generate poly(ADP-ribose) (PAR) moieties. Rapid NAD and ATP loss occurs and tumor cells die by
+
+
programmed necrosis. PARP1 mediated NAD depletion caused by ß-lap synergizes with reduced NAD
synthesis caused by NamPT inhibition to result in increased cancer cell death at lower doses and shorter
treatment times of both therapeutics while maintaining tumor specificity for NQO1 overexpressing cells.
With combination treatment, cells are primed for ROS mediated damage due to reduced glutathione and
+
NADP levels; they are unable to recover ATP, NAD , and NADP synthesis after a 2 hour co-treatment, and
they rapidly die through a caspase-independent mechanism. This novel therapeutic approach is highly
effective against a variety of tumor cell lines from pancreatic, breast, and non-small cell lung cancers and
further in vivo experiments will drive potential clinical application. This research was supported by NIH/NCI
grant CA102971.
(PS4-84) Novel compounds from radiolytic transformation of rotenone with potential anti-adipogenic
1
2
1
1
activity. Hyoungwoo Bai ; Chul-Hong Park ; Tae Hoon Kim ; and Byung Yeoup Chung, Korea Atomic
1
Energy Research Institute, Jeongeup-Si, Jeollabuk-Do, Korea, Republic of and Daegu Haany University,
Daegu, Korea, Republic of
2
Radiolytic transformation of the isoflavonoid rotenone (1) with gamma-irradiation afforded two
new degraded products, rotenoisins A (2) and (3). The structures of the two new rotenone derivatives
were elucidated on the basis of spectroscopic methods. The new products 2 and 3 exhibited significantly
enhanced inhibitory activities against pancreatic lipase and adipocyte differentiation in 3T3-L1 cells with
low toxicity when compared to parent rotenone.
281 | P a g e
ROS contents increased, and reached maximal value at same time point, respectively. On the other hand,
DSB frequency transitory increased at Day 1, and gradually decreased in time-dependent manner.
Interestingly, the expression of senescence marker dramatically increased during Day 3 after irradiation.
These results suggested possibility that cell proliferation, to fill a space of death cells, after irradiation may
be a cause of cell senescence.
(PS4-83) Inducing tumor targeted DNA damage and inhibiting repair by eliminating NAD+ with the
radiosensitizer ß-lapachone and NamPT inhibition. Zachary Moore and David A. Boothman, University of
Texas Southwestern Medical Center, Dallas, TX
+
Cancer cells require increased NAD synthesis to support anabolic metabolism, to sustain signaling
processes such as sirtuin activity and ADP-ribosylation, and to maintain redox balance and minimize ROS
induced DNA damage. Inhibitors of nicotinamide phosphoribosyltransferase (NamPT), the rate-limiting
+
step in NAD biosynthesis, have anti-tumor activity in vitro and in vivo, but have failed clinical trials due to
+
a lack of tumor specificity which results from the necessity of NAD synthesis in normal proliferating cells.
We find that the tumor specificity and efficacy of NamPT inhibition is synergistically increased when small
molecule NamPT inhibitors such as FK866 are used in combination with the DNA damaging, NQO1
bioactivated therapeutic ß-lapachone (ß-lap). The majority of solid tumors overexpress NQO1, which
catalyzes a futile redox cycle with ß-lap, resulting in the formation of a burst of reactive oxygen species
(ROS). This results in substantial DNA single strand breaks and base damage in a tumor-specific manner
+
that hyperactivates poly(ADP-ribose) polymerase-1 (PARP1), a DNA repair enzyme which utilizes NAD to
+
generate poly(ADP-ribose) (PAR) moieties. Rapid NAD and ATP loss occurs and tumor cells die by
+
+
programmed necrosis. PARP1 mediated NAD depletion caused by ß-lap synergizes with reduced NAD
synthesis caused by NamPT inhibition to result in increased cancer cell death at lower doses and shorter
treatment times of both therapeutics while maintaining tumor specificity for NQO1 overexpressing cells.
With combination treatment, cells are primed for ROS mediated damage due to reduced glutathione and
+
NADP levels; they are unable to recover ATP, NAD , and NADP synthesis after a 2 hour co-treatment, and
they rapidly die through a caspase-independent mechanism. This novel therapeutic approach is highly
effective against a variety of tumor cell lines from pancreatic, breast, and non-small cell lung cancers and
further in vivo experiments will drive potential clinical application. This research was supported by NIH/NCI
grant CA102971.
(PS4-84) Novel compounds from radiolytic transformation of rotenone with potential anti-adipogenic
1
2
1
1
activity. Hyoungwoo Bai ; Chul-Hong Park ; Tae Hoon Kim ; and Byung Yeoup Chung, Korea Atomic
1
Energy Research Institute, Jeongeup-Si, Jeollabuk-Do, Korea, Republic of and Daegu Haany University,
Daegu, Korea, Republic of
2
Radiolytic transformation of the isoflavonoid rotenone (1) with gamma-irradiation afforded two
new degraded products, rotenoisins A (2) and (3). The structures of the two new rotenone derivatives
were elucidated on the basis of spectroscopic methods. The new products 2 and 3 exhibited significantly
enhanced inhibitory activities against pancreatic lipase and adipocyte differentiation in 3T3-L1 cells with
low toxicity when compared to parent rotenone.
281 | P a g e
