Page 229 - 2014 Printable Abstract Book
P. 229
radiation therapy by selectively targeting cancer cells and sparing normal tissues. Ionizing radiation
activates cytosolic phospholipase A2 (cPLA2), which cleaves phosphatidylcholine (PC) to yield
lysophosphatidylcholine (LPC). Autotaxin (ATX) converts extracellular LPC to lysophosphatidic acid (LPA)
through its lysophospholipase D activity. The cellular effects of LPA are mediated through six distinct G-
protein coupled receptors (GPCRs). Activation of the Lysophosphatidic Acid Receptor-1 (LPA1), causes
increased angiogenesis, enhanced proliferation and invasion of cancer cells. Several cancers over-express
LPA1-3 including lung, ovarian, and glioblastoma. We have found two lung cancer cell lines, human A549
and murine LLC that overexpress LPA1 mRNA. Both A549 and LLC cells showed increased proliferation
when treated with 10µM LPA. We used VPC12249 or Ki16425, specific inhibitors of LPA1 and LPA3 to inhibit
LPA receptors 1 and 3. In combination with treatment with VPC12249(10µM) or Ki16425(10µM) with 6Gy
irradiation led to decreased proliferation of A549 and LLC cells when compared to cell treated with either
agent alone. Also, radiosensitization was observed in cells treated with these combinations. This
combined treatment also let to reduced cell migration as monitored with a transwell matrigel invasion
assay. Radiation activated Akt and Erk 1/2, which was attenuated by the inhibition of LPA receptors.
Conversely, treatment with LPA in the presence and absence of IR let to increased activation of Akt and
Erk 1/2. Our results indicate that LPA receptors play an important role in proliferation and invasion of lung
cancer. Thus using LPA receptor inhibitors in combination with radiation therapy may lead to more
effective treatment of lung cancer.
(PS3-73) Therapeutic strategies protect mucin and microbiota changes affected during early phase of
2
1
radiation damage or during infection by citrobacter rodentium. Ishfaq Ahmed ; Shauna McLaughlin ;
1
1
3
Shahid Umar ; Rao V. Papineni ; University of Kansas, Kansas, MO ; Precision X-ray Inc, North Branford,
3
CT ; and PACT & Health and University of Kansas, Branford, CT
2
Citrobacter rodentium (CR) is a natural bacterial pathogen that infects the distal colon of mice
and induces transmissible murine colonic hyperplasia (TMCH). Previously, we demonstrated early
inflammatory response (ROS activity) to intestinal infection by CR in real-time. The reactive oxygen species
generation in the colon is akin to what is observed upon a single exposure of 10 Gy whole body X-ray
irradiation. We report here that the Clostridium cluster XIVa that accounts for almost 60% of the mucin-
adhered microbiota is significantly increased in the fecal samples as compared to the total bacteria both
during radiation injury, or upon CR infection. Clostridium cluster XIVa has been proposed to be the
mucosal butyrate producers producing butyrate close to the epithelium. This enhances butyrate
bioavailability required in treating diseases such as inflammatory bowel disease. Further, significant loss
in inner mucus layer were observed in the alcian blue stained colon sections from Swiss-albino Mice
subjected to 10 Gy X-ray whole body irradiation doses using commercially available X-RAD 320 irradiator
(1Gy/min; F2 beam hardening filter 1.5mm Al, 0.25mm Cu, 0.75mm Sn; Precision X-ray inc, USA). We
demonstrate that the similar loss in mucin evident during CR infection is restored using natural
compounds resulting in 3-4 fold increase in the beneficial microbiota. Thus the commonalities in
mechanisms of CR infection, and Radiation Injury to gastrointestinal tract provide opportunities for the
development of better intervention strategies.
227 | P a g e
activates cytosolic phospholipase A2 (cPLA2), which cleaves phosphatidylcholine (PC) to yield
lysophosphatidylcholine (LPC). Autotaxin (ATX) converts extracellular LPC to lysophosphatidic acid (LPA)
through its lysophospholipase D activity. The cellular effects of LPA are mediated through six distinct G-
protein coupled receptors (GPCRs). Activation of the Lysophosphatidic Acid Receptor-1 (LPA1), causes
increased angiogenesis, enhanced proliferation and invasion of cancer cells. Several cancers over-express
LPA1-3 including lung, ovarian, and glioblastoma. We have found two lung cancer cell lines, human A549
and murine LLC that overexpress LPA1 mRNA. Both A549 and LLC cells showed increased proliferation
when treated with 10µM LPA. We used VPC12249 or Ki16425, specific inhibitors of LPA1 and LPA3 to inhibit
LPA receptors 1 and 3. In combination with treatment with VPC12249(10µM) or Ki16425(10µM) with 6Gy
irradiation led to decreased proliferation of A549 and LLC cells when compared to cell treated with either
agent alone. Also, radiosensitization was observed in cells treated with these combinations. This
combined treatment also let to reduced cell migration as monitored with a transwell matrigel invasion
assay. Radiation activated Akt and Erk 1/2, which was attenuated by the inhibition of LPA receptors.
Conversely, treatment with LPA in the presence and absence of IR let to increased activation of Akt and
Erk 1/2. Our results indicate that LPA receptors play an important role in proliferation and invasion of lung
cancer. Thus using LPA receptor inhibitors in combination with radiation therapy may lead to more
effective treatment of lung cancer.
(PS3-73) Therapeutic strategies protect mucin and microbiota changes affected during early phase of
2
1
radiation damage or during infection by citrobacter rodentium. Ishfaq Ahmed ; Shauna McLaughlin ;
1
1
3
Shahid Umar ; Rao V. Papineni ; University of Kansas, Kansas, MO ; Precision X-ray Inc, North Branford,
3
CT ; and PACT & Health and University of Kansas, Branford, CT
2
Citrobacter rodentium (CR) is a natural bacterial pathogen that infects the distal colon of mice
and induces transmissible murine colonic hyperplasia (TMCH). Previously, we demonstrated early
inflammatory response (ROS activity) to intestinal infection by CR in real-time. The reactive oxygen species
generation in the colon is akin to what is observed upon a single exposure of 10 Gy whole body X-ray
irradiation. We report here that the Clostridium cluster XIVa that accounts for almost 60% of the mucin-
adhered microbiota is significantly increased in the fecal samples as compared to the total bacteria both
during radiation injury, or upon CR infection. Clostridium cluster XIVa has been proposed to be the
mucosal butyrate producers producing butyrate close to the epithelium. This enhances butyrate
bioavailability required in treating diseases such as inflammatory bowel disease. Further, significant loss
in inner mucus layer were observed in the alcian blue stained colon sections from Swiss-albino Mice
subjected to 10 Gy X-ray whole body irradiation doses using commercially available X-RAD 320 irradiator
(1Gy/min; F2 beam hardening filter 1.5mm Al, 0.25mm Cu, 0.75mm Sn; Precision X-ray inc, USA). We
demonstrate that the similar loss in mucin evident during CR infection is restored using natural
compounds resulting in 3-4 fold increase in the beneficial microbiota. Thus the commonalities in
mechanisms of CR infection, and Radiation Injury to gastrointestinal tract provide opportunities for the
development of better intervention strategies.
227 | P a g e
