Treatment of etoposide combined with 15-deoxy‑∆12,14‑prostaglandin J2 exerted synergistic antitumor effects against renal cell carcinoma via peroxisome proliferator‑activated receptor‑γ‑independent pathways

Yamamoto,Yasuhiro; Koma,Hiromi; Hiramatsu,Hiroki; Abe,Misa; Murakami,Kazunori; Ohya,Asako; Yagami,Tatsurou

doi:10.3892/mco.2013.234

Treatment of etoposide combined with 15-deoxy‑∆12,14‑prostaglandin J2 exerted synergistic antitumor effects against renal cell carcinoma via peroxisome proliferator‑activated receptor‑γ‑independent pathways

Authors:
- Yasuhiro Yamamoto
- Hiromi Koma
- Hiroki Hiramatsu
- Misa Abe
- Kazunori Murakami
- Asako Ohya
- Tatsurou Yagami
View Affiliations

Affiliations: Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo 670‑8524, Japan
Published online on: December 24, 2013 https://doi.org/10.3892/mco.2013.234
Pages: 292-296

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Renal cell carcinoma (RCC) is characterized by diverse clinical manifestations, few early warning signs and a resistance to radiotherapy and chemotherapy. Although several clinical trials have investigated potential effective therapeutic strategies for RCC, the chemoresistance of RCC has not yet been overcome. An endogenous ligand for the peroxisome proliferator‑activated receptor‑γ (PPARγ), 15‑deoxy‑Δ12,14‑prostaglandin J2 (15d‑PGJ2), was shown to induce apoptosis in RCC. The aim of the present study was to investigate the synergistic effects of carcinostatics on the antitumor activity of 15d‑PGJ2 in the Caki‑2 human RCC cell line with the MTT assay. Our results demonstrated that the topoisomerase‑II inhibitor etoposide (VP‑16) exhibited cytotoxic effects synergistically with 15d‑PGJ2. Furthermore, the presence of the PPARγ antagonist GW9662 did not protect Caki‑2 cells against 15d‑PGJ2‑induced cytotoxicity. Additionally, it was observed that the combined treatment of VP‑16 and 15d‑PGJ2 activated caspase‑3 more efficiently compared to each treatment alone. Therefore, the combined treatment with 15d‑PGJ2 and VP‑16 exhibited synergistic antitumor activity independently of PPARγ.

View Figures

View References

1	Motzer RJ, Bander NH and Nanus DM: Renal-cell carcinoma. N Engl J Med. 335:865–875. 1996. View Article : Google Scholar
2	Costa LJ and Drabkin HA: Renal cell carcinoma: new developments in molecular biology and potential for targeted therapies. Oncologist. 12:1404–1415. 2007. View Article : Google Scholar : PubMed/NCBI
3	Mickisch GH: Gene therapy on renal-cell carcinoma: magic bullet or tragic insanity? World J Urol. 13:178–185. 1995. View Article : Google Scholar : PubMed/NCBI
4	Chen XL, Cao LQ, She MR, Wang Q, Huang XH and Fu XH: Gli-1 siRNA induced apoptosis in Huh7 cells. World J Gastroenterol. 14:582–589. 2008. View Article : Google Scholar : PubMed/NCBI
5	Jin KL, Park JY, Noh EJ, et al: The effect of combined treatment with cisplatin and histone deacetylase inhibitors on HeLa cells. J Gynecol Oncol. 21:262–268. 2010. View Article : Google Scholar : PubMed/NCBI
6	Motzer RJ and Russo P: Systemic therapy for renal cell carcinoma. J Urol. 163:408–417. 2000. View Article : Google Scholar : PubMed/NCBI
7	Aso Y, Tazaki H, Umeda T and Marumo K: Treatment of renal cell carcinoma with systemic administration of intermediate doses of recombinant human interleukin-2 alone. Recombinant Human Interleukin-2 (S-6820) Research Group on Renal Cell Carcinoma. Prog Clin Biol Res. 303:681–688. 1989.
8	Hayashi T, Miyagawa Y, Tsujimura A, Nonomura N, Minami M and Okuyama A: A case of renal cell carcinoma with multiple lung metastases refractory to interferon-α showing complete remission by interleukin-2 monotherapy. Int J Urol. 13:805–808. 2006.PubMed/NCBI
9	Logan JE, Rampersaud EN, Sonn GA, et al: Systemic therapy for metastatic renal cell carcinoma: a review and update. Rev Urol. 14:65–78. 2012.PubMed/NCBI
10	Yamamoto Y, Fujita M, Koma H, et al: 15-Deoxy-Δ^12,14-prostaglandin J₂enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPARγ pathways. Biochem Biophys Res Commun. 410:563–567. 2011.
11	Inoue K, Kawahito Y, Tsubouchi Y, et al: Expression of peroxisome proliferator-activated receptor gamma in renal cell carcinoma and growth inhibition by its agonists. Biochem Biophys Res Commun. 287:727–732. 2001. View Article : Google Scholar : PubMed/NCBI
12	Ward JE, Gould H, Harris T, Bonacci JV and Stewart AG: PPARγ ligands, 15-deoxy-Δ^12,14-prostaglandin J₂and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms. Br J Pharmacol. 141:517–525. 2004.
13	Suzuki K and Uyeda M: Inhibitory properties of antitumor prostaglandins against topoisomerases. Biosci Biotechnol Biochem. 66:1706–1712. 2002. View Article : Google Scholar : PubMed/NCBI
14	Yagami T, Ueda K, Asakura K, et al: Novel binding sites of 15-deoxy-Δ^12,14-prostaglandin J₂in plasma membranes from primary rat cortical neurons. Exp Cell Res. 291:212–227. 2003.
15	Yamamoto Y, Takase K, Kishino J, et al: Proteomic identification of protein targets for 15-deoxy-Δ^12,14-prostaglandin J₂in neuronal plasma membrane. PLoS One. 6:e175522011.
16	Zhang YQ, Tang XQ, Sun L, et al: Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating peroxisome proliferator-activated receptor γ. World J Gastroenterol. 13:1534–1540. 2007.PubMed/NCBI
17	Hamaguchi N, Hamada H, Miyoshi S, et al: In vitro and in vivo therapeutic efficacy of the PPARγ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth. Cancer Sci. 101:1955–1964. 2010.
18	Tikoo K, Kumar P and Gupta J: Rosiglitazone synergizes anticancer activity of cisplatin and reduces its nephrotoxicity in 7,12-dimethyl benz{a}anthracene (DMBA) induced breast cancer rats. BMC Cancer. 9:1072009.PubMed/NCBI
19	Kanbe E, Abe A, Towatari M, Kawabe T, Saito H and Emi N: DR1-like element in human topoisomerase IIα gene involved in enhancement of etoposide-induced apoptosis by PPARγ ligand. Exp Hematol. 31:300–308. 2003.PubMed/NCBI
20	Yuan J, Takahashi A, Masumori N, et al: Ligands for peroxisome proliferator-activated receptor gamma have potent antitumor effect against human renal cell carcinoma. Urology. 65:594–599. 2005. View Article : Google Scholar : PubMed/NCBI
21	Yoshimura R, Matsuyama M, Hase T, et al: The effect of peroxisome proliferator-activated receptor-γ ligand on urological cancer cells. Int J Mol Med. 12:861–865. 2003.
22	Khelifa T and Beck WT: Merbarone, a catalytic inhibitor of DNA topoisomerase II, induces apoptosis in CEM cells through activation of ICE/CED-3-like protease. Mol Pharmacol. 55:548–556. 1999.PubMed/NCBI
23	Brockman JA, Gupta RA and Dubois RN: Activation of PPARγ leads to inhibition of anchorage-independent growth of human colorectal cancer cells. Gastroenterology. 115:1049–1055. 1998.
24	Chen YX, Zhong XY, Qin YF, Bing W and He LZ: 15d-PGJ₂inhibits cell growth and induces apoptosis of MCG-803 human gastric cancer cell line. World J Gastroenterol. 9:2149–2153. 2003.
25	Clay CE, Atsumi GI, High KP and Chilton FH: Early de novo gene expression is required for 15-deoxy-Δ^12,14-prostaglandin J₂-induced apoptosis in breast cancer cells. J Biol Chem. 276:47131–47135. 2001.
26	Li L, Tao J, Davaille J, et al: 15-deoxy-Δ^12,14-prostaglandin J₂induces apoptosis of human hepatic myofibroblasts. A pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors. J Biol Chem. 276:38152–38158. 2001.
27	McClay EF, Winski PJ, Jones JA, Jennerette J III and Gattoni-Celli S: Δ¹²-Prostaglandin-J₂is cytotoxic in human malignancies and synergizes with both cisplatin and radiation. Cancer Res. 56:3866–3869. 1996.
28	Huang X, Okafuji M, Traganos F, Luther E, Holden E and Darzynkiewicz Z: Assessment of histone H2AX phosphorylation induced by DNA topoisomerase I and II inhibitors topotecan and mitoxantrone and by the DNA cross-linking agent cisplatin. Cytometry A. 58:99–110. 2004. View Article : Google Scholar : PubMed/NCBI
29	Aldini G, Carini M, Vistoli G, et al: Identification of actin as a 15-deoxy-Δ^12,14-prostaglandin J₂target in neuroblastoma cells: mass spectrometric, computational, and functional approaches to investigate the effect on cytoskeletal derangement. Biochemistry. 46:2707–2718. 2007.
30	Mizutani H, Tada-Oikawa S, Hiraku Y, Oikawa S, Kojima M and Kawanishi S: Mechanism of apoptosis induced by a new topoisomerase inhibitor through the generation of hydrogen peroxide. J Biol Chem. 277:30684–30689. 2002. View Article : Google Scholar