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Cancer Chemotherapy and Pharmacology

Erschienen in:

01.12.2008 | Original Article

Resveratrol analog trans 3,4,5,4′-tetramethoxystilbene (DMU-212) mediates anti-tumor effects via mechanism different from that of resveratrol

verfasst von: Zengshuan Ma, Ommoleila Molavi, Azita Haddadi, Raymond Lai, Robert A. Gossage, Afsaneh Lavasanifar

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2008

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Abstract

Purpose

Resveratrol is a well-known chemopreventive and chemotherapeutic agent. Among all of the resveratrol analogs synthesized, 3,4,5,4′-tetramethoxystilbene (DMU-212) shows high activity and selectivity against various cancer cell types. The objective of this study is to investigate why DMU-212 has higher anti-tumor activity than resveratrol.

Methods

The effects of DMU-212 and resveratrol on cell viability, cell cycle, Stat3 activation, and microtubule dynamic were investigated and compared using MTT assay, cell cycle analysis, Western blot, tubulin polymerization assay, respectively, in MDA-MB-435 and MCF-7 human breast cancer cells.

Results

Compared to resveratrol, DMU-212 exerted a significantly higher growth inhibition in both cell lines. Further studies demonstrated that DMU-212 acted via different mechanisms from resveratrol. First, DMU-212 induced predominantly G2/M arrest whereas resveratrol induced G0/G1 arrest in both cell lines. Correlating with these findings, resveratrol induced more dramatic changes in the expression of Cyclin D1 compared to DMU-212. Second, DMU-212 induced apoptosis and reduced the expression of multiple anti-apoptotic proteins more appreciably than resveratrol. Third, while both agents inhibited Stat3 phosphorylation, treatments of DMU-212 but not resveratrol led to a significant increase in tubulin polymerization. The higher sensitivity to DMU-122 in MDA-MB-435 correlated with the more prominent effects seen in these parameters in this cell line, as compared to MCF7.

Conclusion

Compared to resveratrol, the novel stilbene derivative, DMU-212, had higher anti-tumor effects, which are likely owing to its modulation of multiple cellular targets.

Signorelli P, Ghidoni R (2005) Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 16:449–466PubMedCrossRef

Aggarwal BB, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71:1397–1421PubMedCrossRef

de la Lastra CA, Villegas I (2005) Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res 49:405–430CrossRef

Jazirehi AR, Bonavida B (2004) Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin’s lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis. Mol Cancer Ther 3:71–84PubMed

Kotha A, Sekharam M, Cilenti L, Siddiquee K, Khaled A, Zervos AS, Carter B, Turkson J, Jove R (2006) Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein. Mol Cancer Ther 5:621–629PubMedCrossRef

Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, Nair AS, Shishodia S, Aggarwal BB (2007) Resveratrol inhibits proliferation, induces apoptosis and overcomes chemoresistance through downregulation of STAT3 and nuclear factor-{kappa}B-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood 109:2293–2302PubMedCrossRef

Garvin S, Ollinger K, Dabrosin C (2006) Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Lett 231:113–122PubMedCrossRef

Hsieh TC, Wang Z, Hamby CV, Wu JM (2005) Inhibition of melanoma cell proliferation by resveratrol is correlated with upregulation of quinone reductase 2 and p53. Biochem Biophys Res Commun 334:223–230PubMedCrossRef

Trincheri NF, Nicotra G, Follo C, Castino R, Isidoro C (2007) Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D. Carcinogenesis 28:922–931PubMedCrossRef

10.

Notas G, Nifli AP, Kampa M, Vercauteren J, Kouroumalis E, Castanas E (2006) Resveratrol exerts its antiproliferative effect on HepG2 hepatocellular carcinoma cells, by inducing cell cycle arrest, and NOS activation. Biochim Biophys Acta 1760:1657–1666PubMed

11.

Lu J, Ho CH, Ghai G, Chen KY (2001) Resveratrol analog, 3,4,5,4′-tetrahydroxystilbene, differentially induces pro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts. Carcinogenesis 22:321–328PubMedCrossRef

12.

Sale S, Verschoyle RD, Boocock D, Jones DJ, Wilsher N, Ruparelia KC, Potter GA, Farmer PB, Steward WP, Gescher AJ (2004) Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4′-tetramethoxystilbene. Br J Cancer 90:736–744PubMedCrossRef

13.

Sale S, Tunstall RG, Ruparelia KC, Potter GA, Steward WP, Gescher AJ (2005) Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4′-tetramethoxystilbene (DMU-212) on adenoma development in the Apc(Min+) mouse and cyclooxygenase-2 in human-derived colon cancer cells. Int J Cancer 115:194–201PubMedCrossRef

14.

Gosslau A, Chen M, Ho CT, Chen KY (2005) A methoxy derivative of resveratrol analogue selectively induced activation of the mitochondrial apoptotic pathway in transformed fibroblasts. Br J Cancer 92:513–521PubMed

15.

Real PJ, Sierra A, De Juan A, Segovia JC, Lopez-Vega JM, Fernandez-Luna JL (2002) Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene 21:7611–7618PubMedCrossRef

16.

Turkson J, Jove R (2000) STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19:6613–6626PubMedCrossRef

17.

Cross GG, Eisnor CR, Gossage RA, Jenkins HA (2006) Oxazoline chemistry Part 12. A metal-mediated synthesis of DMU-212: X-ray diffraction studies of an important anti-cancer agent. Tetrahedron Lett 47:2245–2247CrossRef

18.

Giannakakou P, Sackett DL, Kang YK, Zhan Z, Buters JT, Fojo T, Poruchynsky MS (1997) Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem 272:17118–17125PubMedCrossRef

19.

Yang S, Zhou Q, Yang X (2007) Caspase-3 status is a determinant of the differential responses to genistein between MDA-MB-231 and MCF-7 breast cancer cells. Biochim Biophys Acta 1773:903–911PubMedCrossRef

20.

Wung BS, Hsu MC, Wu CC, Hsieh CW (2005) Resveratrol suppresses IL-6-induced ICAM-1 gene expression in endothelial cells: effects on the inhibition of STAT3 phosphorylation. Life Sci 78:389–397PubMedCrossRef

21.

Sun J, Blaskovich MA, Jove R, Livingston SK, Coppola D, Sebti SM (2005) Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity. Oncogene 24:3236–3245PubMedCrossRef

22.

Pettit GR, Grealish MP, Jung MK, Hamel E, Pettit RK, Chapuis JC, Schmidt JM (2002) Antineoplastic agents. 465. Structural modification of resveratrol: sodium resverastatin phosphate. J Med Chem 45:2534–2542PubMedCrossRef

23.

Schneider Y, Chabert P, Stutzmann J, Coelho D, Fougerousse A, Gosse F, Launay JF, Brouillard R, Raul F (2003) Resveratrol analog (Z)-3,5,4′-trimethoxystilbene is a potent anti-mitotic drug inhibiting tubulin polymerization. Int J Cancer 107:189–196PubMedCrossRef

24.

Lindahl T, Satoh MS, Poirier GG, Klungland A (1995) Post-translational modification of poly (ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem Sci 20:405–411PubMedCrossRef

25.

Coqueret O (2002) Linking cyclins to transcriptional control. Gene 299:35–55PubMedCrossRef

26.

Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatikakis I, Rassidakis GZ, Zhang W, Fujio Y, Kunisada K, Hamilton SR, Amin HM (2005) Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol 167:969–980PubMed

27.

Mamidipudi V, Zhang J, Lee KC, Cartwright CA (2004) RACK1 regulates G1/S progression by suppressing Src kinase activity. Mol Cell Biol 24:6788–6798PubMedCrossRef

28.

Wang LG, Liu XM, Kreis W, Budman DR (1999) The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review. Cancer Chemother Pharmacol 44:355–361PubMedCrossRef

29.

Bhalla KN (2003) Microtubule-targeted anticancer agents and apoptosis. Oncogene 22:9075–9086PubMedCrossRef

30.

Rubin CI, Atweh GF (2004) The role of stathmin in the regulation of the cell cycle. Cell Biochem 93:242–250CrossRef

31.

Rowinsky EK (1997) The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents. Annu Rev Med 48:353–374PubMedCrossRef

32.

Hadfield JA, Ducki S, Hirst N, McGown AT (2003) Tubulin and microtubules as targets for anticancer drugs. Prog Cell Cycle Res 5:309–325PubMed

33.

Bhat KM, Setaluri V (2007) Microtubule-associated proteins as targets in cancer chemotherapy. Clin Cancer Res 13:2849–2854PubMedCrossRef

34.

Kim S, Min SY, Lee SK, Cho WJ (2003) Comparative molecular field analysis study of stilbene derivatives active against A549 lung carcinoma. Chem Pharm Bull (Tokyo) 51:516–521CrossRef

35.

Park H, Aiyar SE, Fan P, Wang J, Yue W, Okouneva T, Cox C, Jordan MA, Demers L, Cho H, Kim S, Song RX, Santen RJ (2007) Effects of tetramethoxystilbene on hormone-resistant breast cancer cells: biological and biochemical mechanisms of action. Cancer Res 67:5717–5726PubMedCrossRef

36.

Ganansia-Leymarie V, Bischoff P, Bergerat JP, Holl V (2003) Signal transduction pathways of taxanes-induced apoptosis. Curr Med Chem Anticancer Agents 3:291–306PubMedCrossRef

37.

Drew L, Fine RL, Do TN, Douglas GP, Petrylak DP (2002) The novel antimicrotubule agent cryptophycin 52 (LY355703) induces apoptosis via multiple pathways in human prostate cancer cells. Clin Cancer Res 8:3922–3932PubMed

38.

Ng DC, Lin BH, Lim CP, Huang G, Zhang T, Poli V, Cao X (2006) Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin. J Cell Biol 172:245–257PubMedCrossRef

Titel: Resveratrol analog trans 3,4,5,4′-tetramethoxystilbene (DMU-212) mediates anti-tumor effects via mechanism different from that of resveratrol
verfasst von: Zengshuan Ma
Ommoleila Molavi
Azita Haddadi
Raymond Lai
Robert A. Gossage
Afsaneh Lavasanifar
Publikationsdatum: 01.12.2008
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2008
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-008-0704-z

Springer Medizin

Resveratrol analog trans 3,4,5,4′-tetramethoxystilbene (DMU-212) mediates anti-tumor effects via mechanism different from that of resveratrol