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Title: 15-Deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPAR{gamma} pathways

Abstract

Highlights: {yields} A topoisomerase-I inhibitor, camptothecin, exhibited synergistically toxicity with 15d-PGJ{sub 2}. {yields} The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. {yields} A PPAR{gamma} antagonist did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. {yields} The treatment of camptothecin combined with 15d-PGJ{sub 2} activated caspase-3 more than the separate treatment. -- Abstract: Renal cell carcinoma (RCC) is chemoresistant cancer. Although several clinical trials were conducted to explore effective medications, the chemoresistance of RCC has not yet been conquered. An endogenous ligand for peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}), 15-deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} (15d-PGJ{sub 2}), induces apoptosis in RCC. Here, we examined synergistic effects of several carcinostatics on the anti-tumor activity of 15d-PGJ{sub 2} in Caki-2 cell line by MTT assay. A topoisomerase-I inhibitor, camptothecin (CPT), exhibited synergistically toxicity with 15d-PGJ{sub 2}, but neither 5-fluorouracil nor cisplatin did. The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. The synergistic effect of topoisomerase-I and II inhibitors was not also detected. A PPAR{gamma} antagonist, GW9662, did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. The treatment of CPT combined with 15d-PGJ{sub 2} activated caspase-3 more than the separatemore » treatment. These results suggest that 15d-PGJ{sub 2} exhibited the anti-tumor activity synergistically with CPT independent of topoisomerase-II and PPAR{gamma}.« less

Authors:
 [1];  [2];  [1];  [2];  [1];  [2];  [1]
  1. Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 2-1, Kami-ohno 7-Chome, Himeji, Hyogo 670-8524 (Japan)
  2. Faculty of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien-kyuban-cho, Nishinomiya, Hyogo 663-8179 (Japan)
Publication Date:
OSTI Identifier:
22204997
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 410; Journal Issue: 3; Other Information: Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CARCINOMAS; CLINICAL TRIALS; INHIBITION; KIDNEYS; LIGANDS; PROSTAGLANDINS; RECEPTORS; TOXICITY; URACILS

Citation Formats

Yamamoto, Yasuhiro, Fujita, Megumi, Koma, Hiromi, Yamamori, Motohiro, Nakamura, Tsutomu, Okamura, Noboru, and Yagami, Tatsurou, E-mail: yagami@himeji-du.ac.jp. 15-Deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPAR{gamma} pathways. United States: N. p., 2011. Web. doi:10.1016/J.BBRC.2011.06.026.
Yamamoto, Yasuhiro, Fujita, Megumi, Koma, Hiromi, Yamamori, Motohiro, Nakamura, Tsutomu, Okamura, Noboru, & Yagami, Tatsurou, E-mail: yagami@himeji-du.ac.jp. 15-Deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPAR{gamma} pathways. United States. doi:10.1016/J.BBRC.2011.06.026.
Yamamoto, Yasuhiro, Fujita, Megumi, Koma, Hiromi, Yamamori, Motohiro, Nakamura, Tsutomu, Okamura, Noboru, and Yagami, Tatsurou, E-mail: yagami@himeji-du.ac.jp. Fri . "15-Deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPAR{gamma} pathways". United States. doi:10.1016/J.BBRC.2011.06.026.
@article{osti_22204997,
title = {15-Deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPAR{gamma} pathways},
author = {Yamamoto, Yasuhiro and Fujita, Megumi and Koma, Hiromi and Yamamori, Motohiro and Nakamura, Tsutomu and Okamura, Noboru and Yagami, Tatsurou, E-mail: yagami@himeji-du.ac.jp},
abstractNote = {Highlights: {yields} A topoisomerase-I inhibitor, camptothecin, exhibited synergistically toxicity with 15d-PGJ{sub 2}. {yields} The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. {yields} A PPAR{gamma} antagonist did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. {yields} The treatment of camptothecin combined with 15d-PGJ{sub 2} activated caspase-3 more than the separate treatment. -- Abstract: Renal cell carcinoma (RCC) is chemoresistant cancer. Although several clinical trials were conducted to explore effective medications, the chemoresistance of RCC has not yet been conquered. An endogenous ligand for peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}), 15-deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} (15d-PGJ{sub 2}), induces apoptosis in RCC. Here, we examined synergistic effects of several carcinostatics on the anti-tumor activity of 15d-PGJ{sub 2} in Caki-2 cell line by MTT assay. A topoisomerase-I inhibitor, camptothecin (CPT), exhibited synergistically toxicity with 15d-PGJ{sub 2}, but neither 5-fluorouracil nor cisplatin did. The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. The synergistic effect of topoisomerase-I and II inhibitors was not also detected. A PPAR{gamma} antagonist, GW9662, did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. The treatment of CPT combined with 15d-PGJ{sub 2} activated caspase-3 more than the separate treatment. These results suggest that 15d-PGJ{sub 2} exhibited the anti-tumor activity synergistically with CPT independent of topoisomerase-II and PPAR{gamma}.},
doi = {10.1016/J.BBRC.2011.06.026},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 410,
place = {United States},
year = {Fri Jul 08 00:00:00 EDT 2011},
month = {Fri Jul 08 00:00:00 EDT 2011}
}
  • The chemokine receptor CXCR4 plays a key role in the metastasis of colorectal cancer and its growth at metastatic sites. Here, we have investigated the mechanisms by which CXCR4 on cancer cells might be regulated by eicosanoids present within the colorectal tumor microenvironment. We show that prostaglandins PGE{sub 2}, PGA{sub 2}, PGD{sub 2}, PGJ{sub 2} and 15dPGJ{sub 2} each down-regulates CXCR4 receptor expression on human colorectal carcinoma cells to differing degrees. The most potent of these were PGD{sub 2} and its metabolites PGJ{sub 2} and 15dPGJ{sub 2}. Down-regulation was most rapid with the end-product 15dPGJ{sub 2} and was accompanied bymore » a marked reduction in CXCR4 mRNA. 15dPGJ{sub 2} is known to be a ligand for the nuclear receptor PPAR{gamma}. Down-regulation of CXCR4 was also observed with the PPAR{gamma} agonist rosiglitazone, while 15dPGJ{sub 2}-induced CXCR4 down-regulation was substantially diminished by the PPAR{gamma} antagonists GW9662 and T0070907. These data support the involvement of PPAR{gamma}. However, the 15dPGJ{sub 2} analogue CAY10410, which can act on PPAR{gamma} but which lacks the intrinsic cyclopentenone structure found in 15dPGJ{sub 2}, down-regulated CXCR4 substantially less potently than 15dPGJ{sub 2}. The cyclopentenone grouping is known to inhibit the activity of NF{kappa}B. Consistent with an additional role for NF{kappa}B, we found that the cyclopentenone prostaglandin PGA{sub 2} and cyclopentenone itself could also down-regulate CXCR4. Immunolocalization studies showed that the cellular context was sufficient to trigger a focal nuclear pattern of NF{kappa}B p50 and that 15dPGJ{sub 2} interfered with this p50 nuclear localization. These data suggest that 15dPGJ{sub 2} can down-regulate CXCR4 on cancer cells through both PPAR{gamma} and NF{kappa}B. 15dPGJ{sub 2}, present within the tumor microenvironment, may act to down-regulate CXCR4 and impact upon the overall process of tumor expansion.« less
  • Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) ligands have been shown to possess anti-proliferative effects in many types of cancer. In clear cell renal cell carcinoma (CCRCC), the targets involved in these effects are not known. In this study, we demonstrated that, in CCRCC cell lines, the endogenous PPAR{gamma} ligand 15-deoxy-{Delta}12,14-prostaglandin J2 (15dPGJ2) induces the expression, both at the mRNA and the protein levels, of the HtrA3 gene. This gene belongs to the High-Temperature Requirement Factor A family of serine proteases that repress signaling by TGF-{beta} family members and inhibit cell migration. Rosiglitazone or ciglitazone, synthetic PPAR{gamma} agonists, did not induce HtrA3more » expression, and the PPAR{gamma} antagonist GW9662 did not prevent 15dPGJ2 induction, suggesting that the up-regulation of HtrA3 by 15dPGJ2 is independent of PPAR{gamma}. The MEK/ERK inhibitor PD98059 dramatically repressed HtrA3 induction. Altogether, these data indicate that 15dPGJ2 is able to stimulate the expression of HtrA3 through an indirect mechanism involving the MEK/ERK pathway but independent of PPAR{gamma}. Our results provide a better understanding of the mechanisms involved in the regulation of HtrA3, a potential tumor suppressor gene.« less
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