The Experts below are selected from a list of 1749 Experts worldwide ranked by ideXlab platform
Chinthalapally V Rao - One of the best experts on this subject based on the ideXlab platform.
-
abstract 5075 naproxen blocks spontaneous Lung Adenoma progression to adenocarcinoma in kras g12vmice
Cancer Research, 2019Co-Authors: Gaurav Kumar, Venkateshwar Madka, Altaf Mohammed, Anil Singh, Stanley Lightfoot, Craig D Logsdon, Nicole Stratton, Chinthalapally V RaoAbstract:The aim of the present study was to investigate the effects of a non-steroidal anti-inflammatory drug (NSAID), naproxen, on a spontaneous mouse model of Lung adenocarcinoma. Lung cancer is the most frequently diagnosed cancer and the primary cause of cancer-related deaths worldwide. Inflammation plays an important role in the development and progression of Lung and several other cancers. The association between NSAID use and Lung cancer risk suggests a beneficial effect on patients’ Lung cancer progression. Preventing Lung cancer can help to significantly reduce cancer-related mortality. Compared with other NSAIDs, naproxen is relatively safer in terms of cardiovascular risk. Eight-week-old transgenic KrasG12V male and female mice (n=20) or littermate wild-type (n=5) mice were fed (AIN76A) diets containing naproxen (0 ppm or 400 ppm) in modified AIN76-A diet for 28 weeks. At 36 weeks of age, mice were euthanized. Lungs were collected and evaluated for Lung tumor incidence and multiplicity, and were saved in formalin for histopathological identification of Adenoma and adenocarcinoma. By 12 weeks of age, KrasG12V mice developed visible Lung tumors that enlarged in size and progressed to adenocarcinoma by 24-36 weeks of age. Lung tumor incidence was observed in 100% of KrasG12V mice. Dietary administration of naproxen did not show any overt-toxicities. No significant changes were observed in body weight gain or any major organ’s (liver, kidney, and pancreas) gross morphology or weight in mice fed with naproxen compared with mice fed control diet. Due to reduced tumor burden, Lungs of the naproxen-fed mice weighed less (230.6± 12.2 mg, p=0.019) (Mean±SEM) than those of the control group (384.0±68.1 mg). Importantly, mice fed control diet developed 19.8±0.96 total Lung tumors (2.5±0.3 Adenoma, 17.3±0.7 adenocarcinoma). The results suggest that naproxen inhibits total Lung tumor formation by ~52% (9.4±0.85;p Citation Format: Gaurav Kumar, Venkateshwar Madka, Craig Logsdon, Anil Singh, Nicole Stratton, Stanley Lightfoot, Altaf Mohammed, Chinthalapally V. Rao. Naproxen blocks spontaneous Lung Adenoma progression to adenocarcinoma in Kras-G12V mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5075.
-
β escin inhibits nnk induced Lung adenocarcinoma and aldh1a1 and rhoa rock expression in a j mice and growth of h460 human Lung cancer cells
Cancer Prevention Research, 2013Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Chinthalapally V RaoAbstract:Lung cancer is the leading cause of cancer-related deaths. β-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of Lung Adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human Lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, Lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 μmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 β-escin) or 36 weeks (15 control, 5 β-escin) and evaluated for Lung tumor via histopathologic methods. Administration of 500 ppm β-escin significantly suppressed Lung tumor (Adenoma + adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. β-Escin inhibited NNK-induced Lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that Lung tumors from mice exposed to β-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 Lung cancer cells treated with different concentrations of β-escin (0-40 μmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that β-escin inhibits tobacco carcinogen-induced Lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling.
-
abstract lb 182 licofelone inhibits nnk induced Lung adenocarcinoma formation in a j mice by suppressing cox lox and inhibits human Lung cancer cell growth by p21 up regulation
Cancer Research, 2013Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Levy Kopelovich, Chinthalapally V RaoAbstract:Lung cancer is the leading causes of cancer deaths. Inflammation plays an important role in Lung tumor progression; in that eicosanoids levels derived from cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) positively influence the tumor growth. We have evaluated chemopreventive effects of a novel dual LOX/ COX inhibitor, Licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma and adenocarcinoma formation in female A/J mice and its possible mode of action was evaluated using human Lung cancer cell line A549. For bioassay, at 6 weeks of age, mice were randomized and fed control AIN-76A modified diet. At 7 weeks of age (25-mice/group) intended for carcinogen treatment received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after the NNK treatment, groups intended for Licofelone treatment were administered 200 and 400 ppm in diet for either 17 weeks (10 mice/group) and/or 34 weeks (15 mice/group) to assess efficacy against Lung Adenoma and adenocarcinoma. Intervention with 200 or 400 ppm Licofelone significantly suppressed Lung Adenomas by 29% (p . These results suggest that licofelone a dual 5LOX/COX inhibitor inhibits the NNK induced Lung Adenomas and more so by suppressing adenocarcinoma formation in a dose-dependent manner. IHC analysis of Lung tumors from NNK treated mice exposed to licofelone showed a significantly reduced proliferating cell nuclear antigen (PCNA) positive index, increased TUNEL positive cells and p21 expression as compared to Lung adenocarcinomas from NNK treated mice fed with control diet. Treatment with Licofelone significantly suppressed both COX and 5-LOX expression and its metabolite formation in NNK induced Lung tumors and human Lung cancer cell line growth inhibition was associated with p21-upregulation. These findings suggest that dietary Licofelone inhibits tobacco carcinogen-induced Lung Adenoma and adenocarcinoma formation in a dose-dependent manner by modulating COX-2 and 5-LOX activities. {Supported by NIH, NCI grants NO1-CN-53300 and Kerley-Cade Chair} Citation Format: Jagan Mohan Reddy Patlolla, Levy Kopelovich, Li Qian, Laura Biddick, Yuting Zhang, Dhimant Desai, Shantu Amin, Stan Lightfoot, Chinthalapally V. Rao. Licofelone inhibits NNK-induced Lung adenocarcinoma formation in A/J mice by suppressing COX/LOX and inhibits human Lung cancer cell growth by p21 up-regulation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-182. doi:10.1158/1538-7445.AM2013-LB-182
-
abstract lb 176 chemoprevention of nnk induced Lung Adenoma and adenocarcinoma in a j mice by p53 modulating agents cp 31398 and prima 1
Cancer Research, 2012Co-Authors: Chinthalapally V Rao, Dhimant Desai, Shantu Amin, Altaf Mohammed, Li Qian, Yuting Zhang, Jagan M R Patlolla, Misty Brewer, Stan Lightfoot, Levy KopelovichAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Lung cancer is a leading cause of cancer deaths worldwide. p53 Mutations including wild-type p53 nuclear localization due to excessive endogenous electrophilic molecules are highly prevalent in tobacco associated Lung cancers. Here, we report the chemopreventive effects of direct-acting p53 modulating agents, CP-31398 and Prima-1 on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma and adenocarcinoma in female A/J mice. Seven weeks-old mice on a regular AIN-76A diet, received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after NNK treatment, groups of mice (25 mice/group) were fed control AIN-76A or experimental diets containing 50 and 100 ppm CP-31398, or 150 and 300 ppm Prima-1. Mice were sacrificed after 20 weeks (10 mice/group) and/or 36 weeks (15 mice/group) following NNK-treatment and evaluated for Lung Adenomas and adenocarcinomas by histopathological methods. Administration of 50 and 100 ppm CP-31398 significantly suppressed Lung tumor formation by 29% and 39.5% (P<0.01-0.0001), respectively after 20 weeks and 32.2% and 40.1% (P<0.01-0.0001), respectively after 36 weeks. Similarly, 150 and 300 ppm Prima-1 significantly suppressed Lung tumor formation by 22.2% and 34% (P<0.04-0.0001) after 20 weeks and 28.8% and 47.4% (P<0.01-0.0001) after 36 weeks, respectively. Inhibition of NNK-induced Lung adenocarcinoma by either agent was greater than 55-72% (p<0.0001) after 20 weeks and about 40-57% after 36 weeks. These results suggest that restoring/activating wild-type p53 function by small molecules significantly inhibits NNK-induced Lung tumor in A/J mice, most notably delaying progression of Adenomas to adenocarcinoma. IHC analysis of Lung tumors from NNK-treated mice exposed to either CP-31398 or Prima-1 showed a significantly reduced proliferating cell nuclear antigen (PCNA)-positive index, increased accumulation of nuclear wt-p53 including increased p21 and TUNNEL positive cells compared to Lung tumors from NNK-treated mice fed with control diet. Incidentally, neither COX-1 nor iNOS were significantly affected by CP-31398 or Prima -1 in the NNK derived Lung tumors. These results demonstrate, for the first time, the chemopreventive role of p53 modulating agents on tobacco specific carcinogen-induced Lung adenocarcinomas. {Supported by NIH, NCI grants NO1-CN-53300}. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-176. doi:1538-7445.AM2012-LB-176
Yuting Zhang - One of the best experts on this subject based on the ideXlab platform.
-
abstract 2625 simultaneous targeting of odc and 5 lox cox block the tobacco carcinogen induced Lung Adenoma progression to adenocarcinoma in a j mice
Cancer Research, 2016Co-Authors: Gaurav Kumar, Jagan Mohan R Patolla, Venkateshwar Madka, Altaf Mohammed, Li Qian, Yuting Zhang, Laura Biddick, Anil Singh, Allison F Gillaspy, Stanley LightfootAbstract:Increased polyamine synthesis and inflammation have long been associated with intraepithelial neoplasia and their progression to malignant tumor growth, including Lung cancer. Targeting multiple pathways simultaneously with low-dose combinations may be an effective approach to modulate different pathways and their downstream signaling, which may result in an increased efficacy and reduced side effects than a single-agent high dose strategy. The aim of the present study was to investigate the effects of DFMO (ODC inhibitor) and licofelone, a dual 5-LOX-COX inhibitor, individually and in combination, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone NNK-induced Lung Adenoma and progression to adenocarcinoma in female A/J mice. At 6 weeks of age, mice (25 /group) were fed AIN-76A-modified diet, and one week later, Lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 μmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed with either control or experimental diets containing DFMO (1500 or 3000 ppm) or Licofelone (200 or 400 ppm) or combination of low doses of DFMO and Licofelone. Mice were killed after 17 or 34 weeks of drug exposure and tumors were evaluated via histopathology and Lung tumors were assayed for modification of various biomarkers of proliferation and apoptosis. Results suggest that both DFMO and licofelone showed dose-dependent inhibition of NNK-induced Lung Adenoma progression to adenocarcinoma. At high dose DFMO and Licofelone showed 46% and 55% of adenocarcinoma inhibition. Importantly, low dose combination of DFMO and licofelone showed more pronounced effects at both 17 or 34 weeks in inhibiting the total adenocarcinomas (Adenoma and adenocarcinoma progression) by >65% and somewhat in a synergistic manner as compared to individual low doses of DFMO and licofelone. Combination-treated Lung tumors exhibited modulation of ODC pathway key components (Arg1, Oat, Oaz, SRM, SMS, and SAT) along with decreased proliferation (PCNA, cyclin D1 and Cyclin A) and increased expression of p53, p21 and p27 compared to tumors from mice fed with control diet. These data suggest that targeting ODC plus 5-LOX/COX decreases the progression of Adenoma to adenocarcinoma. Furthermore, Adenoma progression delay by combination of DFMO and Licofelone is associated with decreased tumor invasive markers such as MMTPs and EMT markers. In conclusion, targeting two or more pathways is an effective chemopreventive approach for high-risk Lung cancer individual9s particularly former tobacco smokers with Lung hyperplasia and Adenomas. (Supported by Kerley-Cade Chair Endowment and NCI-N01-CN-53300) Citation Format: Gaurav Kumar, Jagan Mohan R. Patolla, Venkateshwar Madka, Altaf Mohammed, Li Qian, Yuting Zhang, Laura Biddick, Anil Singh, Allison Gillaspy, Stanley Lightfoot, Levy Kopelovich, Vernon E. Steele, Chinthalapally V. Rao. Simultaneous targeting of ODC and 5-LOX/COX block the tobacco carcinogen-induced Lung Adenoma progression to adenocarcinoma in A/J mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2625.
-
simultaneous targeting of 5 lox cox and odc block nnk induced Lung Adenoma progression to adenocarcinoma in a j mice
American Journal of Cancer Research, 2016Co-Authors: Gaurav Kumar, Venkateshwar Madka, Altaf Mohammed, Yuting Zhang, Laura Biddick, Anil Singh, Allison F Gillaspy, Stanley Lightfoot, Jagan M R Patlolla, Vernon E SteeleAbstract:Lung cancer is the leading cause of cancer deaths worldwide. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and tumor resistance. To target COX-2, 5-LOX, and ODC simultaneously, we tested the effects of a dual 5-LOX-COX inhibitor, licofelone, and an ODC inhibitor, DFMO, alone and in combination, on NNK-induced Lung tumors in female A/J mice. Seven-week-old mice were treated with NNK (10 μmol/mouse, single dose, i.p.) and randomized to different treatment groups. Three weeks after injection, mice were fed control or experimental diets (DFMO 1500/3000 ppm, licofelone 200/400 ppm, or a low-dose combination of 1500 ppm DFMO and 200 ppm licofelone) for 17 or 34 weeks. Both agents significantly inhibited tumor formation in a dose-dependent manner. As anticipated more Adenomas and adenocarcinomas were observed at 17 and 34 weeks, respectively. Importantly, low dose combination of DFMO and licofelone showed more pronounced effects at 17 or 34 weeks in inhibiting the total tumor formation (~60%, p < 0.0001) and adenocarcinoma (~65%, p < 0.0001) compared to individual high dose of DFMO (~44% and 46%, p < 0.0001) and licofelone (~48% and 55%, p < 0.0001). DFMO and combination-treated mice Lung tumors exhibited modulated ODC pathway components (Oat, Oaz, SRM, SMS, and SAT, p < 0.05) along with decreased proliferation (PCNA, Cyclin D1 and Cyclin A) and increased expression of p53, p21 and p27 compared to mice fed control diet. Both DFMO and licofelone significantly inhibited tumor inflammatory markers. Our findings suggest that a low-dose combined treatment targeting inflammation and polyamine synthesis may provide effective chemoprevention.
-
β escin inhibits nnk induced Lung adenocarcinoma and aldh1a1 and rhoa rock expression in a j mice and growth of h460 human Lung cancer cells
Cancer Prevention Research, 2013Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Chinthalapally V RaoAbstract:Lung cancer is the leading cause of cancer-related deaths. β-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of Lung Adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human Lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, Lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 μmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 β-escin) or 36 weeks (15 control, 5 β-escin) and evaluated for Lung tumor via histopathologic methods. Administration of 500 ppm β-escin significantly suppressed Lung tumor (Adenoma + adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. β-Escin inhibited NNK-induced Lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that Lung tumors from mice exposed to β-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 Lung cancer cells treated with different concentrations of β-escin (0-40 μmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that β-escin inhibits tobacco carcinogen-induced Lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling.
-
abstract lb 182 licofelone inhibits nnk induced Lung adenocarcinoma formation in a j mice by suppressing cox lox and inhibits human Lung cancer cell growth by p21 up regulation
Cancer Research, 2013Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Levy Kopelovich, Chinthalapally V RaoAbstract:Lung cancer is the leading causes of cancer deaths. Inflammation plays an important role in Lung tumor progression; in that eicosanoids levels derived from cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) positively influence the tumor growth. We have evaluated chemopreventive effects of a novel dual LOX/ COX inhibitor, Licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma and adenocarcinoma formation in female A/J mice and its possible mode of action was evaluated using human Lung cancer cell line A549. For bioassay, at 6 weeks of age, mice were randomized and fed control AIN-76A modified diet. At 7 weeks of age (25-mice/group) intended for carcinogen treatment received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after the NNK treatment, groups intended for Licofelone treatment were administered 200 and 400 ppm in diet for either 17 weeks (10 mice/group) and/or 34 weeks (15 mice/group) to assess efficacy against Lung Adenoma and adenocarcinoma. Intervention with 200 or 400 ppm Licofelone significantly suppressed Lung Adenomas by 29% (p . These results suggest that licofelone a dual 5LOX/COX inhibitor inhibits the NNK induced Lung Adenomas and more so by suppressing adenocarcinoma formation in a dose-dependent manner. IHC analysis of Lung tumors from NNK treated mice exposed to licofelone showed a significantly reduced proliferating cell nuclear antigen (PCNA) positive index, increased TUNEL positive cells and p21 expression as compared to Lung adenocarcinomas from NNK treated mice fed with control diet. Treatment with Licofelone significantly suppressed both COX and 5-LOX expression and its metabolite formation in NNK induced Lung tumors and human Lung cancer cell line growth inhibition was associated with p21-upregulation. These findings suggest that dietary Licofelone inhibits tobacco carcinogen-induced Lung Adenoma and adenocarcinoma formation in a dose-dependent manner by modulating COX-2 and 5-LOX activities. {Supported by NIH, NCI grants NO1-CN-53300 and Kerley-Cade Chair} Citation Format: Jagan Mohan Reddy Patlolla, Levy Kopelovich, Li Qian, Laura Biddick, Yuting Zhang, Dhimant Desai, Shantu Amin, Stan Lightfoot, Chinthalapally V. Rao. Licofelone inhibits NNK-induced Lung adenocarcinoma formation in A/J mice by suppressing COX/LOX and inhibits human Lung cancer cell growth by p21 up-regulation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-182. doi:10.1158/1538-7445.AM2013-LB-182
-
abstract lb 176 chemoprevention of nnk induced Lung Adenoma and adenocarcinoma in a j mice by p53 modulating agents cp 31398 and prima 1
Cancer Research, 2012Co-Authors: Chinthalapally V Rao, Dhimant Desai, Shantu Amin, Altaf Mohammed, Li Qian, Yuting Zhang, Jagan M R Patlolla, Misty Brewer, Stan Lightfoot, Levy KopelovichAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Lung cancer is a leading cause of cancer deaths worldwide. p53 Mutations including wild-type p53 nuclear localization due to excessive endogenous electrophilic molecules are highly prevalent in tobacco associated Lung cancers. Here, we report the chemopreventive effects of direct-acting p53 modulating agents, CP-31398 and Prima-1 on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma and adenocarcinoma in female A/J mice. Seven weeks-old mice on a regular AIN-76A diet, received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after NNK treatment, groups of mice (25 mice/group) were fed control AIN-76A or experimental diets containing 50 and 100 ppm CP-31398, or 150 and 300 ppm Prima-1. Mice were sacrificed after 20 weeks (10 mice/group) and/or 36 weeks (15 mice/group) following NNK-treatment and evaluated for Lung Adenomas and adenocarcinomas by histopathological methods. Administration of 50 and 100 ppm CP-31398 significantly suppressed Lung tumor formation by 29% and 39.5% (P<0.01-0.0001), respectively after 20 weeks and 32.2% and 40.1% (P<0.01-0.0001), respectively after 36 weeks. Similarly, 150 and 300 ppm Prima-1 significantly suppressed Lung tumor formation by 22.2% and 34% (P<0.04-0.0001) after 20 weeks and 28.8% and 47.4% (P<0.01-0.0001) after 36 weeks, respectively. Inhibition of NNK-induced Lung adenocarcinoma by either agent was greater than 55-72% (p<0.0001) after 20 weeks and about 40-57% after 36 weeks. These results suggest that restoring/activating wild-type p53 function by small molecules significantly inhibits NNK-induced Lung tumor in A/J mice, most notably delaying progression of Adenomas to adenocarcinoma. IHC analysis of Lung tumors from NNK-treated mice exposed to either CP-31398 or Prima-1 showed a significantly reduced proliferating cell nuclear antigen (PCNA)-positive index, increased accumulation of nuclear wt-p53 including increased p21 and TUNNEL positive cells compared to Lung tumors from NNK-treated mice fed with control diet. Incidentally, neither COX-1 nor iNOS were significantly affected by CP-31398 or Prima -1 in the NNK derived Lung tumors. These results demonstrate, for the first time, the chemopreventive role of p53 modulating agents on tobacco specific carcinogen-induced Lung adenocarcinomas. {Supported by NIH, NCI grants NO1-CN-53300}. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-176. doi:1538-7445.AM2012-LB-176
Jagan M R Patlolla - One of the best experts on this subject based on the ideXlab platform.
-
simultaneous targeting of 5 lox cox and odc block nnk induced Lung Adenoma progression to adenocarcinoma in a j mice
American Journal of Cancer Research, 2016Co-Authors: Gaurav Kumar, Venkateshwar Madka, Altaf Mohammed, Yuting Zhang, Laura Biddick, Anil Singh, Allison F Gillaspy, Stanley Lightfoot, Jagan M R Patlolla, Vernon E SteeleAbstract:Lung cancer is the leading cause of cancer deaths worldwide. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and tumor resistance. To target COX-2, 5-LOX, and ODC simultaneously, we tested the effects of a dual 5-LOX-COX inhibitor, licofelone, and an ODC inhibitor, DFMO, alone and in combination, on NNK-induced Lung tumors in female A/J mice. Seven-week-old mice were treated with NNK (10 μmol/mouse, single dose, i.p.) and randomized to different treatment groups. Three weeks after injection, mice were fed control or experimental diets (DFMO 1500/3000 ppm, licofelone 200/400 ppm, or a low-dose combination of 1500 ppm DFMO and 200 ppm licofelone) for 17 or 34 weeks. Both agents significantly inhibited tumor formation in a dose-dependent manner. As anticipated more Adenomas and adenocarcinomas were observed at 17 and 34 weeks, respectively. Importantly, low dose combination of DFMO and licofelone showed more pronounced effects at 17 or 34 weeks in inhibiting the total tumor formation (~60%, p < 0.0001) and adenocarcinoma (~65%, p < 0.0001) compared to individual high dose of DFMO (~44% and 46%, p < 0.0001) and licofelone (~48% and 55%, p < 0.0001). DFMO and combination-treated mice Lung tumors exhibited modulated ODC pathway components (Oat, Oaz, SRM, SMS, and SAT, p < 0.05) along with decreased proliferation (PCNA, Cyclin D1 and Cyclin A) and increased expression of p53, p21 and p27 compared to mice fed control diet. Both DFMO and licofelone significantly inhibited tumor inflammatory markers. Our findings suggest that a low-dose combined treatment targeting inflammation and polyamine synthesis may provide effective chemoprevention.
-
β escin inhibits nnk induced Lung adenocarcinoma and aldh1a1 and rhoa rock expression in a j mice and growth of h460 human Lung cancer cells
Cancer Prevention Research, 2013Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Chinthalapally V RaoAbstract:Lung cancer is the leading cause of cancer-related deaths. β-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of Lung Adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human Lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, Lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 μmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 β-escin) or 36 weeks (15 control, 5 β-escin) and evaluated for Lung tumor via histopathologic methods. Administration of 500 ppm β-escin significantly suppressed Lung tumor (Adenoma + adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. β-Escin inhibited NNK-induced Lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that Lung tumors from mice exposed to β-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 Lung cancer cells treated with different concentrations of β-escin (0-40 μmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that β-escin inhibits tobacco carcinogen-induced Lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling.
-
abstract lb 182 licofelone inhibits nnk induced Lung adenocarcinoma formation in a j mice by suppressing cox lox and inhibits human Lung cancer cell growth by p21 up regulation
Cancer Research, 2013Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Levy Kopelovich, Chinthalapally V RaoAbstract:Lung cancer is the leading causes of cancer deaths. Inflammation plays an important role in Lung tumor progression; in that eicosanoids levels derived from cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) positively influence the tumor growth. We have evaluated chemopreventive effects of a novel dual LOX/ COX inhibitor, Licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma and adenocarcinoma formation in female A/J mice and its possible mode of action was evaluated using human Lung cancer cell line A549. For bioassay, at 6 weeks of age, mice were randomized and fed control AIN-76A modified diet. At 7 weeks of age (25-mice/group) intended for carcinogen treatment received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after the NNK treatment, groups intended for Licofelone treatment were administered 200 and 400 ppm in diet for either 17 weeks (10 mice/group) and/or 34 weeks (15 mice/group) to assess efficacy against Lung Adenoma and adenocarcinoma. Intervention with 200 or 400 ppm Licofelone significantly suppressed Lung Adenomas by 29% (p . These results suggest that licofelone a dual 5LOX/COX inhibitor inhibits the NNK induced Lung Adenomas and more so by suppressing adenocarcinoma formation in a dose-dependent manner. IHC analysis of Lung tumors from NNK treated mice exposed to licofelone showed a significantly reduced proliferating cell nuclear antigen (PCNA) positive index, increased TUNEL positive cells and p21 expression as compared to Lung adenocarcinomas from NNK treated mice fed with control diet. Treatment with Licofelone significantly suppressed both COX and 5-LOX expression and its metabolite formation in NNK induced Lung tumors and human Lung cancer cell line growth inhibition was associated with p21-upregulation. These findings suggest that dietary Licofelone inhibits tobacco carcinogen-induced Lung Adenoma and adenocarcinoma formation in a dose-dependent manner by modulating COX-2 and 5-LOX activities. {Supported by NIH, NCI grants NO1-CN-53300 and Kerley-Cade Chair} Citation Format: Jagan Mohan Reddy Patlolla, Levy Kopelovich, Li Qian, Laura Biddick, Yuting Zhang, Dhimant Desai, Shantu Amin, Stan Lightfoot, Chinthalapally V. Rao. Licofelone inhibits NNK-induced Lung adenocarcinoma formation in A/J mice by suppressing COX/LOX and inhibits human Lung cancer cell growth by p21 up-regulation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-182. doi:10.1158/1538-7445.AM2013-LB-182
-
abstract lb 176 chemoprevention of nnk induced Lung Adenoma and adenocarcinoma in a j mice by p53 modulating agents cp 31398 and prima 1
Cancer Research, 2012Co-Authors: Chinthalapally V Rao, Dhimant Desai, Shantu Amin, Altaf Mohammed, Li Qian, Yuting Zhang, Jagan M R Patlolla, Misty Brewer, Stan Lightfoot, Levy KopelovichAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Lung cancer is a leading cause of cancer deaths worldwide. p53 Mutations including wild-type p53 nuclear localization due to excessive endogenous electrophilic molecules are highly prevalent in tobacco associated Lung cancers. Here, we report the chemopreventive effects of direct-acting p53 modulating agents, CP-31398 and Prima-1 on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma and adenocarcinoma in female A/J mice. Seven weeks-old mice on a regular AIN-76A diet, received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after NNK treatment, groups of mice (25 mice/group) were fed control AIN-76A or experimental diets containing 50 and 100 ppm CP-31398, or 150 and 300 ppm Prima-1. Mice were sacrificed after 20 weeks (10 mice/group) and/or 36 weeks (15 mice/group) following NNK-treatment and evaluated for Lung Adenomas and adenocarcinomas by histopathological methods. Administration of 50 and 100 ppm CP-31398 significantly suppressed Lung tumor formation by 29% and 39.5% (P<0.01-0.0001), respectively after 20 weeks and 32.2% and 40.1% (P<0.01-0.0001), respectively after 36 weeks. Similarly, 150 and 300 ppm Prima-1 significantly suppressed Lung tumor formation by 22.2% and 34% (P<0.04-0.0001) after 20 weeks and 28.8% and 47.4% (P<0.01-0.0001) after 36 weeks, respectively. Inhibition of NNK-induced Lung adenocarcinoma by either agent was greater than 55-72% (p<0.0001) after 20 weeks and about 40-57% after 36 weeks. These results suggest that restoring/activating wild-type p53 function by small molecules significantly inhibits NNK-induced Lung tumor in A/J mice, most notably delaying progression of Adenomas to adenocarcinoma. IHC analysis of Lung tumors from NNK-treated mice exposed to either CP-31398 or Prima-1 showed a significantly reduced proliferating cell nuclear antigen (PCNA)-positive index, increased accumulation of nuclear wt-p53 including increased p21 and TUNNEL positive cells compared to Lung tumors from NNK-treated mice fed with control diet. Incidentally, neither COX-1 nor iNOS were significantly affected by CP-31398 or Prima -1 in the NNK derived Lung tumors. These results demonstrate, for the first time, the chemopreventive role of p53 modulating agents on tobacco specific carcinogen-induced Lung adenocarcinomas. {Supported by NIH, NCI grants NO1-CN-53300}. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-176. doi:1538-7445.AM2012-LB-176
Shantu Amin - One of the best experts on this subject based on the ideXlab platform.
-
β escin inhibits nnk induced Lung adenocarcinoma and aldh1a1 and rhoa rock expression in a j mice and growth of h460 human Lung cancer cells
Cancer Prevention Research, 2013Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Chinthalapally V RaoAbstract:Lung cancer is the leading cause of cancer-related deaths. β-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of Lung Adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human Lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, Lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 μmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 β-escin) or 36 weeks (15 control, 5 β-escin) and evaluated for Lung tumor via histopathologic methods. Administration of 500 ppm β-escin significantly suppressed Lung tumor (Adenoma + adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. β-Escin inhibited NNK-induced Lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that Lung tumors from mice exposed to β-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 Lung cancer cells treated with different concentrations of β-escin (0-40 μmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that β-escin inhibits tobacco carcinogen-induced Lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling.
-
abstract lb 182 licofelone inhibits nnk induced Lung adenocarcinoma formation in a j mice by suppressing cox lox and inhibits human Lung cancer cell growth by p21 up regulation
Cancer Research, 2013Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Levy Kopelovich, Chinthalapally V RaoAbstract:Lung cancer is the leading causes of cancer deaths. Inflammation plays an important role in Lung tumor progression; in that eicosanoids levels derived from cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) positively influence the tumor growth. We have evaluated chemopreventive effects of a novel dual LOX/ COX inhibitor, Licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma and adenocarcinoma formation in female A/J mice and its possible mode of action was evaluated using human Lung cancer cell line A549. For bioassay, at 6 weeks of age, mice were randomized and fed control AIN-76A modified diet. At 7 weeks of age (25-mice/group) intended for carcinogen treatment received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after the NNK treatment, groups intended for Licofelone treatment were administered 200 and 400 ppm in diet for either 17 weeks (10 mice/group) and/or 34 weeks (15 mice/group) to assess efficacy against Lung Adenoma and adenocarcinoma. Intervention with 200 or 400 ppm Licofelone significantly suppressed Lung Adenomas by 29% (p . These results suggest that licofelone a dual 5LOX/COX inhibitor inhibits the NNK induced Lung Adenomas and more so by suppressing adenocarcinoma formation in a dose-dependent manner. IHC analysis of Lung tumors from NNK treated mice exposed to licofelone showed a significantly reduced proliferating cell nuclear antigen (PCNA) positive index, increased TUNEL positive cells and p21 expression as compared to Lung adenocarcinomas from NNK treated mice fed with control diet. Treatment with Licofelone significantly suppressed both COX and 5-LOX expression and its metabolite formation in NNK induced Lung tumors and human Lung cancer cell line growth inhibition was associated with p21-upregulation. These findings suggest that dietary Licofelone inhibits tobacco carcinogen-induced Lung Adenoma and adenocarcinoma formation in a dose-dependent manner by modulating COX-2 and 5-LOX activities. {Supported by NIH, NCI grants NO1-CN-53300 and Kerley-Cade Chair} Citation Format: Jagan Mohan Reddy Patlolla, Levy Kopelovich, Li Qian, Laura Biddick, Yuting Zhang, Dhimant Desai, Shantu Amin, Stan Lightfoot, Chinthalapally V. Rao. Licofelone inhibits NNK-induced Lung adenocarcinoma formation in A/J mice by suppressing COX/LOX and inhibits human Lung cancer cell growth by p21 up-regulation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-182. doi:10.1158/1538-7445.AM2013-LB-182
-
abstract lb 176 chemoprevention of nnk induced Lung Adenoma and adenocarcinoma in a j mice by p53 modulating agents cp 31398 and prima 1
Cancer Research, 2012Co-Authors: Chinthalapally V Rao, Dhimant Desai, Shantu Amin, Altaf Mohammed, Li Qian, Yuting Zhang, Jagan M R Patlolla, Misty Brewer, Stan Lightfoot, Levy KopelovichAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Lung cancer is a leading cause of cancer deaths worldwide. p53 Mutations including wild-type p53 nuclear localization due to excessive endogenous electrophilic molecules are highly prevalent in tobacco associated Lung cancers. Here, we report the chemopreventive effects of direct-acting p53 modulating agents, CP-31398 and Prima-1 on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma and adenocarcinoma in female A/J mice. Seven weeks-old mice on a regular AIN-76A diet, received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after NNK treatment, groups of mice (25 mice/group) were fed control AIN-76A or experimental diets containing 50 and 100 ppm CP-31398, or 150 and 300 ppm Prima-1. Mice were sacrificed after 20 weeks (10 mice/group) and/or 36 weeks (15 mice/group) following NNK-treatment and evaluated for Lung Adenomas and adenocarcinomas by histopathological methods. Administration of 50 and 100 ppm CP-31398 significantly suppressed Lung tumor formation by 29% and 39.5% (P<0.01-0.0001), respectively after 20 weeks and 32.2% and 40.1% (P<0.01-0.0001), respectively after 36 weeks. Similarly, 150 and 300 ppm Prima-1 significantly suppressed Lung tumor formation by 22.2% and 34% (P<0.04-0.0001) after 20 weeks and 28.8% and 47.4% (P<0.01-0.0001) after 36 weeks, respectively. Inhibition of NNK-induced Lung adenocarcinoma by either agent was greater than 55-72% (p<0.0001) after 20 weeks and about 40-57% after 36 weeks. These results suggest that restoring/activating wild-type p53 function by small molecules significantly inhibits NNK-induced Lung tumor in A/J mice, most notably delaying progression of Adenomas to adenocarcinoma. IHC analysis of Lung tumors from NNK-treated mice exposed to either CP-31398 or Prima-1 showed a significantly reduced proliferating cell nuclear antigen (PCNA)-positive index, increased accumulation of nuclear wt-p53 including increased p21 and TUNNEL positive cells compared to Lung tumors from NNK-treated mice fed with control diet. Incidentally, neither COX-1 nor iNOS were significantly affected by CP-31398 or Prima -1 in the NNK derived Lung tumors. These results demonstrate, for the first time, the chemopreventive role of p53 modulating agents on tobacco specific carcinogen-induced Lung adenocarcinomas. {Supported by NIH, NCI grants NO1-CN-53300}. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-176. doi:1538-7445.AM2012-LB-176
-
elevated 8 hydroxy 2 deoxyguanosine levels in Lung dna of a j mice and f344 rats treated with 4 methylnitrosamino 1 3 pyridyl 1 butanone and inhibition by dietary 1 4 phenylenebis methylene selenocyanate
Carcinogenesis, 1998Co-Authors: Jose Rosa, Bogdan Prokopczyk, Dhimant Desai, Shantu Amin, Karam ElbayoumyAbstract:1,4-Phenylenebis(methylene)selenocyanate (p-XSC) is an effective chemopreventive agent against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma in female A/J mice. While p-XSC can effectively inhibit NNK-induced DNA methylation in female A/J mice and in male F344 rats, its effect on NNK-induced oxidative DNA damage had not been determined. Thus, the effect of p-XSC on the levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in Lung DNA from A/J mice and F344 rats treated with NNK was examined. Mice were given NNK by gavage (0.5 mg/mouse in 0.2 ml corn oil, three times per week for 3 weeks) or by a single i.p. injection (2 mg/mouse in 0.1 ml saline) while maintained on a control diet (AIN-76A) or control diet containing p-XSC at 10 or 15 p.p.m. (as Se) starting 1 week before NNK administration and continuing until termination. Mice were killed 2 h after the last NNK gavage in the multiple administration protocol or 2 h after the single i.p. injection. Treatment with NNK by gavage significantly elevated the levels of 8-OH-dG in Lung DNA of A/J mice from 0.7 +/- 0.1 to 1.6 +/- 0.2 adducts/10(5) 2'-deoxyguanosine (dG) (P < 0.001), while dietary p-XSC (at 10 p.p.m. Se) prevented significant elevation of the levels of this lesion caused by NNK, keeping them at 0.9 +/- 0.1 adducts/10(5) dG (P < 0.003). Injection of NNK in saline also significantly increased the levels of 8-OH-dG in Lung DNA of A/J mice from 1.2 +/- 0.6 to 3.6 +/- 0.8/10(5) dG adducts (P < 0.01), while dietary p-XSC (at 15 p.p.m. Se) kept these levels at 1.9 +/- 0.5 adducts/10(5) dG (P < 0.03). Rats were given a single i.p. injection of NNK (100 mg/kg body wt) in saline while being maintained on control diet (AIN-76A) or control diet containing p-XSC (15 p.p.m. as Se) starting 1 week before NNK administration and continuing until termination. The rats were killed 2 h after injection. Treatment with NNK using this protocol significantly elevated the levels of 8-OH-dG in Lung DNA of F344 rats from 2.6 +/- 0.5 to 3.5 +/- 0.5 adducts/10(5) dG (P < 0.03), while dietary p-XSC (at 15 p.p.m. Se) kept the levels of this lesion at 2.2 +/- 0.6 adducts/10(5) dG (P < 0.01). Our findings suggest that the chemopreventive efficacy of p-XSC against NNK-induced Lung tumorigenesis in A/J mice and F344 rats may be due in part to inhibition of oxidative DNA damage.
Dhimant Desai - One of the best experts on this subject based on the ideXlab platform.
-
β escin inhibits nnk induced Lung adenocarcinoma and aldh1a1 and rhoa rock expression in a j mice and growth of h460 human Lung cancer cells
Cancer Prevention Research, 2013Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Chinthalapally V RaoAbstract:Lung cancer is the leading cause of cancer-related deaths. β-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of Lung Adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human Lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, Lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 μmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 β-escin) or 36 weeks (15 control, 5 β-escin) and evaluated for Lung tumor via histopathologic methods. Administration of 500 ppm β-escin significantly suppressed Lung tumor (Adenoma + adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. β-Escin inhibited NNK-induced Lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that Lung tumors from mice exposed to β-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 Lung cancer cells treated with different concentrations of β-escin (0-40 μmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that β-escin inhibits tobacco carcinogen-induced Lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling.
-
abstract lb 182 licofelone inhibits nnk induced Lung adenocarcinoma formation in a j mice by suppressing cox lox and inhibits human Lung cancer cell growth by p21 up regulation
Cancer Research, 2013Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Levy Kopelovich, Chinthalapally V RaoAbstract:Lung cancer is the leading causes of cancer deaths. Inflammation plays an important role in Lung tumor progression; in that eicosanoids levels derived from cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) positively influence the tumor growth. We have evaluated chemopreventive effects of a novel dual LOX/ COX inhibitor, Licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma and adenocarcinoma formation in female A/J mice and its possible mode of action was evaluated using human Lung cancer cell line A549. For bioassay, at 6 weeks of age, mice were randomized and fed control AIN-76A modified diet. At 7 weeks of age (25-mice/group) intended for carcinogen treatment received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after the NNK treatment, groups intended for Licofelone treatment were administered 200 and 400 ppm in diet for either 17 weeks (10 mice/group) and/or 34 weeks (15 mice/group) to assess efficacy against Lung Adenoma and adenocarcinoma. Intervention with 200 or 400 ppm Licofelone significantly suppressed Lung Adenomas by 29% (p . These results suggest that licofelone a dual 5LOX/COX inhibitor inhibits the NNK induced Lung Adenomas and more so by suppressing adenocarcinoma formation in a dose-dependent manner. IHC analysis of Lung tumors from NNK treated mice exposed to licofelone showed a significantly reduced proliferating cell nuclear antigen (PCNA) positive index, increased TUNEL positive cells and p21 expression as compared to Lung adenocarcinomas from NNK treated mice fed with control diet. Treatment with Licofelone significantly suppressed both COX and 5-LOX expression and its metabolite formation in NNK induced Lung tumors and human Lung cancer cell line growth inhibition was associated with p21-upregulation. These findings suggest that dietary Licofelone inhibits tobacco carcinogen-induced Lung Adenoma and adenocarcinoma formation in a dose-dependent manner by modulating COX-2 and 5-LOX activities. {Supported by NIH, NCI grants NO1-CN-53300 and Kerley-Cade Chair} Citation Format: Jagan Mohan Reddy Patlolla, Levy Kopelovich, Li Qian, Laura Biddick, Yuting Zhang, Dhimant Desai, Shantu Amin, Stan Lightfoot, Chinthalapally V. Rao. Licofelone inhibits NNK-induced Lung adenocarcinoma formation in A/J mice by suppressing COX/LOX and inhibits human Lung cancer cell growth by p21 up-regulation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-182. doi:10.1158/1538-7445.AM2013-LB-182
-
abstract lb 176 chemoprevention of nnk induced Lung Adenoma and adenocarcinoma in a j mice by p53 modulating agents cp 31398 and prima 1
Cancer Research, 2012Co-Authors: Chinthalapally V Rao, Dhimant Desai, Shantu Amin, Altaf Mohammed, Li Qian, Yuting Zhang, Jagan M R Patlolla, Misty Brewer, Stan Lightfoot, Levy KopelovichAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Lung cancer is a leading cause of cancer deaths worldwide. p53 Mutations including wild-type p53 nuclear localization due to excessive endogenous electrophilic molecules are highly prevalent in tobacco associated Lung cancers. Here, we report the chemopreventive effects of direct-acting p53 modulating agents, CP-31398 and Prima-1 on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma and adenocarcinoma in female A/J mice. Seven weeks-old mice on a regular AIN-76A diet, received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after NNK treatment, groups of mice (25 mice/group) were fed control AIN-76A or experimental diets containing 50 and 100 ppm CP-31398, or 150 and 300 ppm Prima-1. Mice were sacrificed after 20 weeks (10 mice/group) and/or 36 weeks (15 mice/group) following NNK-treatment and evaluated for Lung Adenomas and adenocarcinomas by histopathological methods. Administration of 50 and 100 ppm CP-31398 significantly suppressed Lung tumor formation by 29% and 39.5% (P<0.01-0.0001), respectively after 20 weeks and 32.2% and 40.1% (P<0.01-0.0001), respectively after 36 weeks. Similarly, 150 and 300 ppm Prima-1 significantly suppressed Lung tumor formation by 22.2% and 34% (P<0.04-0.0001) after 20 weeks and 28.8% and 47.4% (P<0.01-0.0001) after 36 weeks, respectively. Inhibition of NNK-induced Lung adenocarcinoma by either agent was greater than 55-72% (p<0.0001) after 20 weeks and about 40-57% after 36 weeks. These results suggest that restoring/activating wild-type p53 function by small molecules significantly inhibits NNK-induced Lung tumor in A/J mice, most notably delaying progression of Adenomas to adenocarcinoma. IHC analysis of Lung tumors from NNK-treated mice exposed to either CP-31398 or Prima-1 showed a significantly reduced proliferating cell nuclear antigen (PCNA)-positive index, increased accumulation of nuclear wt-p53 including increased p21 and TUNNEL positive cells compared to Lung tumors from NNK-treated mice fed with control diet. Incidentally, neither COX-1 nor iNOS were significantly affected by CP-31398 or Prima -1 in the NNK derived Lung tumors. These results demonstrate, for the first time, the chemopreventive role of p53 modulating agents on tobacco specific carcinogen-induced Lung adenocarcinomas. {Supported by NIH, NCI grants NO1-CN-53300}. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-176. doi:1538-7445.AM2012-LB-176
-
elevated 8 hydroxy 2 deoxyguanosine levels in Lung dna of a j mice and f344 rats treated with 4 methylnitrosamino 1 3 pyridyl 1 butanone and inhibition by dietary 1 4 phenylenebis methylene selenocyanate
Carcinogenesis, 1998Co-Authors: Jose Rosa, Bogdan Prokopczyk, Dhimant Desai, Shantu Amin, Karam ElbayoumyAbstract:1,4-Phenylenebis(methylene)selenocyanate (p-XSC) is an effective chemopreventive agent against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced Lung Adenoma in female A/J mice. While p-XSC can effectively inhibit NNK-induced DNA methylation in female A/J mice and in male F344 rats, its effect on NNK-induced oxidative DNA damage had not been determined. Thus, the effect of p-XSC on the levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in Lung DNA from A/J mice and F344 rats treated with NNK was examined. Mice were given NNK by gavage (0.5 mg/mouse in 0.2 ml corn oil, three times per week for 3 weeks) or by a single i.p. injection (2 mg/mouse in 0.1 ml saline) while maintained on a control diet (AIN-76A) or control diet containing p-XSC at 10 or 15 p.p.m. (as Se) starting 1 week before NNK administration and continuing until termination. Mice were killed 2 h after the last NNK gavage in the multiple administration protocol or 2 h after the single i.p. injection. Treatment with NNK by gavage significantly elevated the levels of 8-OH-dG in Lung DNA of A/J mice from 0.7 +/- 0.1 to 1.6 +/- 0.2 adducts/10(5) 2'-deoxyguanosine (dG) (P < 0.001), while dietary p-XSC (at 10 p.p.m. Se) prevented significant elevation of the levels of this lesion caused by NNK, keeping them at 0.9 +/- 0.1 adducts/10(5) dG (P < 0.003). Injection of NNK in saline also significantly increased the levels of 8-OH-dG in Lung DNA of A/J mice from 1.2 +/- 0.6 to 3.6 +/- 0.8/10(5) dG adducts (P < 0.01), while dietary p-XSC (at 15 p.p.m. Se) kept these levels at 1.9 +/- 0.5 adducts/10(5) dG (P < 0.03). Rats were given a single i.p. injection of NNK (100 mg/kg body wt) in saline while being maintained on control diet (AIN-76A) or control diet containing p-XSC (15 p.p.m. as Se) starting 1 week before NNK administration and continuing until termination. The rats were killed 2 h after injection. Treatment with NNK using this protocol significantly elevated the levels of 8-OH-dG in Lung DNA of F344 rats from 2.6 +/- 0.5 to 3.5 +/- 0.5 adducts/10(5) dG (P < 0.03), while dietary p-XSC (at 15 p.p.m. Se) kept the levels of this lesion at 2.2 +/- 0.6 adducts/10(5) dG (P < 0.01). Our findings suggest that the chemopreventive efficacy of p-XSC against NNK-induced Lung tumorigenesis in A/J mice and F344 rats may be due in part to inhibition of oxidative DNA damage.
