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Antitumor activity of a novel series of α-aryloxy-α-methylhydrocinnamic acid derivatives as PPAR gamma agonists against a panel of human cancer cell lines

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Summary

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have shown benefit in treating diabetes mellitus, atherosclerosis and cancer. However, widespread use of thiazolidinediones (TZDs), the clinically used synthetic PPARγ agonists, has been limited by adverse cardiovascular effects. Consequently, numerous novel non-TZD compounds were synthesized and antidiabetic efficacy was evaluated to identify PPARγ agonists for potential clinical use. On the other hand, many studies have documented that the antitumor activity of PPARγ agonists is PPARγ independent. Here we hypothesized that there might exist some compounds with less PPARγ agonistic activity or antidiabetic efficacy but potent antitumor activity. In this study, we evaluated the PPARγ agonistic and antitumor activity of several newly synthesized α-aryloxy-α-methylhydrocinnamic acid derivatives as PPARγ agonists in a panel of human cancer cell lines, which showed promising antitumor activity without appreciable PPARγ agonistic activity. The results of MTT assay revealed that cell viability was inhibited in a dose dependent manner with IC50 17.1–55.1 μM for all the novel compounds and rosiglitazone (17.2–165 μM). They induced cell cycle arrest and apoptosis tested by Flow Cytometry. In conclusion, our findings demonstrate that these compounds have potent in vitro cytotoxicity, the possible mechanism of which is through induction of apoptosis and cell cycle arrest

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References

  1. Berger J, Moller DE (2002) The mechanisms of action of PPARs. Annu Rev Med 53:409–435 doi:10.1146/annurev.med.53.082901.104018

    Article  CAS  PubMed  Google Scholar 

  2. Willson TM, Lambert MH, Kliewer SA (2001) Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 70:341–367 doi:10.1146/annurev.biochem.70.1.341

    Article  CAS  PubMed  Google Scholar 

  3. Chou FS, Wang PS, Kulp S, Pinzone JJ (2007) Effects of thiazolidinediones on differentiation, proliferation, and apoptosis. Mol Cancer Res 5:523–530 doi:10.1158/1541-7786.MCR-06-0278

    Article  CAS  PubMed  Google Scholar 

  4. Lin MS, Chen WC, Bai X, Wang YD (2007) Activation of peroxisome proliferator-activated receptor gamma inhibits cell growth via apoptosis and arrest of the cell cycle in human colorectal cancer. J Dig Dis 8:82–88 doi:10.1111/j.1443-9573.2007.00290.x

    Article  CAS  PubMed  Google Scholar 

  5. Guo YT, Leng XS, Li T, Zhao JM, Lin XH (2004) Peroxisome proliferator-activated receptor gamma ligands suppress liver carcinogenesis induced by diethylnitrosamine in rats. World J Gastroenterol 10:3419–3423

    CAS  PubMed  Google Scholar 

  6. Borbath I, Leclercq I, Moulin P, Sempoux C, Horsmans Y (2007) The PPARgamma agonist pioglitazone inhibits early neoplastic occurrence in the rat liver. Eur J Cancer 43:1755–1763 doi:10.1016/j.ejca.2007.05.005

    Article  CAS  PubMed  Google Scholar 

  7. Kubota T, Koshizuka K, Williamson EA, Asou H, Said JW, Holden S et al (1998) Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res 58:3344–3352

    CAS  PubMed  Google Scholar 

  8. Kebebew E, Peng M, Reiff E, Treseler P, Woeber KA, Clark OH et al (2006) A phase II trial of rosiglitazone in patients with thyroglobulin-positive and radioiodine-negative differentiated thyroid cancer. Surgery 140:960–966 discussion 966–967 doi:10.1016/j.surg.2006.07.038

    Article  PubMed  Google Scholar 

  9. Mueller E, Smith M, Sarraf P, Kroll T, Aiyer A, Kaufman DS et al (2000) Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci USA 97:10990–10995 doi:10.1073/pnas.180329197

    Article  CAS  PubMed  Google Scholar 

  10. Grommes C, Landreth GE, Heneka MT (2004) Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol 5:419–429 doi:10.1016/S1470-2045(04)01509-8

    Article  CAS  PubMed  Google Scholar 

  11. Freudlsperger C, Thies A, Pfuller U, Schumacher U (2007) The proteasome inhibitor bortezomib augments anti-proliferative effects of mistletoe lectin-I and the PPAR-gamma agonist rosiglitazone in human melanoma cells. Anticancer Res 27:207–213

    CAS  PubMed  Google Scholar 

  12. Vogt T, Hafner C, Bross K, Bataille F, Jauch KW, Berand A et al (2003) Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors. Cancer 98:2251–2256 doi:10.1002/cncr.11775

    Article  CAS  PubMed  Google Scholar 

  13. Diamond GA, Kaul S (2007) Rosiglitazone and cardiovascular risk. N Engl J Med 357:938–939 author reply 939–940

    CAS  PubMed  Google Scholar 

  14. Nathan DM (2007) Rosiglitazone and cardiotoxicity–weighing the evidence. N Engl J Med 357:64–66 doi:10.1056/NEJMe078117

    Article  CAS  PubMed  Google Scholar 

  15. Psaty BM, Furberg CD (2007) The record on rosiglitazone and the risk of myocardial infarction. N Engl J Med 357:67–69 doi:10.1056/NEJMe078116

    Article  CAS  PubMed  Google Scholar 

  16. Devasthale PV, Chen S, Jeon Y, Qu F, Shao C, Wang W et al (2005) Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5- methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine [Muraglitazar/BMS-298585], a novel peroxisome proliferator-activated receptor alpha/gamma dual agonist with efficacious glucose and lipid-lowering activities. J Med Chem 48:2248–2250 doi:10.1021/jm0496436

    Article  CAS  PubMed  Google Scholar 

  17. Ahn JH, Shin MS, Jung SH, Kang SK, Kim KR, Rhee SD et al (2006) Indenone derivatives: a novel template for peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. J Med Chem 49:4781–4784 doi:10.1021/jm060389m

    Article  CAS  PubMed  Google Scholar 

  18. Kim KR, Lee JH, Kim SJ, Rhee SD, Jung WH, Yang SD et al (2006) KR-62980: a novel peroxisome proliferator-activated receptor gamma agonist with weak adipogenic effects. Biochem Pharmacol 72:446–454 doi:10.1016/j.bcp.2006.05.005

    Article  CAS  PubMed  Google Scholar 

  19. Ray DM, Akbiyik F, Phipps RP (2006) The peroxisome proliferator-activated receptor gamma (PPARgamma) ligands 15-deoxy-Delta12,14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARgamma-independent mechanisms. J Immunol 177:5068–5076

    CAS  PubMed  Google Scholar 

  20. Papineni S, Chintharlapalli S, Safe S (2008) Methyl 2-Cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate is a peroxisome proliferator-activated receptor-gamma agonist that induces receptor-independent apoptosis in LNCaP prostate cancer cells. Mol Pharmacol 73:553–565 doi:10.1124/mol.107.041285

    Article  CAS  PubMed  Google Scholar 

  21. Chintharlapalli S, Papineni S, Safe S (2007) 1,1-bis(3′-indolyl)-1-(p-substitutedphenyl)methanes inhibit growth, induce apoptosis, and decrease the androgen receptor in LNCaP prostate cancer cells through peroxisome proliferator-activated receptor gamma-independent pathways. Mol Pharmacol 71:558–569 doi:10.1124/mol.106.028696

    Article  CAS  PubMed  Google Scholar 

  22. Ray DM, Morse KM, Hilchey SP, Garcia TM, Felgar RE, Maggirwar SB et al (2006) The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces apoptosis of human diffuse large B-cell lymphoma cells through a peroxisome proliferator-activated receptor gamma-independent pathway. Exp Hematol 34:1202–1211 doi:10.1016/j.exphem.2006.04.026

    Article  CAS  PubMed  Google Scholar 

  23. Han S, Zheng Y, Roman J (2007) Rosiglitazone, an agonist of PPARgamma, inhibits non-small cell carcinoma cell proliferation in part through activation of tumor sclerosis complex-2. PPAR Res 2007:29632 doi:10.1155/2007/29632

    PubMed  Google Scholar 

  24. Keshamouni VG, Arenberg DA, Reddy RC, Newstead MJ, Anthwal S, Standiford TJ (2005) PPAR-gamma activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer. Neoplasia 7:294–301 doi:10.1593/neo.04601

    Article  CAS  PubMed  Google Scholar 

  25. Xiong X, Fu L, Wang L, Cai H, Li L, Jiang H et al (2008) Antitumor activity of a novel EGFR tyrosine kinase inhibitor against human lung carcinoma in vitro and in vivo. Invest New Drugs, online first

  26. Kim KY, Ahn JH, Cheon HG (2007) Apoptotic action of peroxisome proliferator-activated receptor-gamma activation in human non small-cell lung cancer is mediated via proline oxidase-induced reactive oxygen species formation. Mol Pharmacol 72:674–685 doi:10.1124/mol.107.035584

    Article  CAS  PubMed  Google Scholar 

  27. Han S, Roman J (2007) Peroxisome proliferator-activated receptor gamma: a novel target for cancer therapeutics? Anticancer Drugs 18:237–244 doi:10.1097/CAD.0b013e328011e67d

    Article  CAS  PubMed  Google Scholar 

  28. Schoonjans K, Staels B, Auwerx J (1996) The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1302:93–109

    CAS  PubMed  Google Scholar 

  29. Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457–2471 doi:10.1056/NEJMoa072761

    Article  CAS  PubMed  Google Scholar 

  30. Theocharis S, Margeli A, Vielh P, Kouraklis G (2004) Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators. Cancer Treat Rev 30:545–554 doi:10.1016/j.ctrv.2004.04.004

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the National 863 Plan in High Technology Progress (2002AA2Z3130, 2007AA02Z3Z1), and Shanghai Leading Academic Discipline Project (Project Number: B902). We thank members of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences for design and synthesis of the novel compounds. We thank Dr Hualiang Jiang for helpful discussions.

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Authors and Affiliations

  1. Nephrology institute of PLA, Department of Internal Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People’s Republic of China

    Xishan Xiong, Lili Fu, Bing Dai, Jieqiong Liu, Jieshuang Jia, Lin Li, Li Wang & Changlin Mei

  2. Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China

    Yangliang Ye, Jing Tang & Jianhua Shen

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  1. Xishan Xiong
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  2. Yangliang Ye
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  3. Lili Fu
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  8. Lin Li
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  9. Li Wang
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  10. Jianhua Shen
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  11. Changlin Mei
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Correspondence to Jianhua Shen or Changlin Mei.

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Xishan Xiong and Yangliang Ye contributed equally to this work.

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Xiong, X., Ye, Y., Fu, L. et al. Antitumor activity of a novel series of α-aryloxy-α-methylhydrocinnamic acid derivatives as PPAR gamma agonists against a panel of human cancer cell lines. Invest New Drugs 27, 223–232 (2009). https://doi.org/10.1007/s10637-008-9161-0

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