3'-hydroxy-3,4,5,4'-tetramethoxystilbene, the Metabolite of Resveratrol Analogue DMU-212, Inhibits Ovarian Cancer Cell Growth in Vitro and in a Mice Xenograft Model

Overview

Journal Sci Rep

Specialty Science

Date 2016 Sep 3

PMID 27585955

Citations 14

Authors

Hanna Piotrowska-Kempisty

Marcin Rucinski

Sylwia Borys

Malgorzata Kucinska

Mariusz Kaczmarek

Piotr Zawierucha

Marcin Wierzchowski

Dawid Lazewski

Marek Murias

Jadwiga Jodynis-Liebert

Affiliations

Soon will be listed here.

Abstract

In screening studies, the cytotoxic activity of four metabolites of resveratrol analogue 3,4,5,4'-tetramethoxystilbene (DMU-212) against A-2780 and SKOV-3 ovarian cancer cells was investigated. The most active metabolite, 3'-hydroxy-3,4,5,4'-tetramethoxystilbene (DMU-214), was chosen for further studies. The cytotoxicity of DMU-214 was shown to be higher than that of the parent compound, DMU-212, in both cell lines tested. Since DMU-212 was supposed to undergo metabolic activation through its conversion to DMU-214, an attempt was made to elucidate the mechanism of its anti-proliferative activity. We found that in SKOV-3 cells lacking p53, DMU-214 induced receptor-mediated apoptosis. In A-2780 cell line with expression of wild-type p53, DMU-214 modulated the expression pattern of p53-target genes driving intrinsic and extrinsic apoptosis pathways, as well as DNA repair and damage prevention. Regardless of the up-regulation of p48, p53R2, sestrins and Gaad45 genes involved in cancer cell DNA repair, we demonstrated the stronger anti-proliferative and pro-apoptotic effects of DMU-214 in A-2780 cells when compared to those in SKOV-3. Hence we verified DMU-214 activity in the xenograft model using SCID mice injected with A-2780 cells. The strong anti-proliferative activity of DMU-214 in the in vivo model allowed to suggest the tested compound as a potential therapeutic in ovarian cancer treatment.

Citing Articles

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References

Piotrowska H, Myszkowski K, Abraszek J, Kwiatkowska-Borowczyk E, Amarowicz R, Murias M . DMU-212 inhibits tumor growth in xenograft model of human ovarian cancer. Biomed Pharmacother. 2014; 68(4):397-400. DOI: 10.1016/j.biopha.2014.02.001. View

Menges C, Altomare D, Testa J . FAS-associated factor 1 (FAF1): diverse functions and implications for oncogenesis. Cell Cycle. 2009; 8(16):2528-34. PMC: 2739729. DOI: 10.4161/cc.8.16.9280. View

Lv T, Wang G . Antiproliferation potential of withaferin A on human osteosarcoma cells via the inhibition of G2/M checkpoint proteins. Exp Ther Med. 2015; 10(1):323-329. PMC: 4487066. DOI: 10.3892/etm.2015.2480. View

Androutsopoulos V, Fragiadaki I, Tosca A . Activation of ERK1/2 is required for the antimitotic activity of the resveratrol analogue 3,4,5,4'-tetramethoxystilbene (DMU-212) in human melanoma cells. Exp Dermatol. 2015; 24(8):632-4. DOI: 10.1111/exd.12721. View

Piotrowska H, Myszkowski K, Amarowicz R, Murias M, Kulcenty K, Wierzchowski M . Different susceptibility of colon cancer DLD-1 and LOVO cell lines to apoptosis induced by DMU-212, a synthetic resveratrol analogue. Toxicol In Vitro. 2013; 27(8):2127-34. DOI: 10.1016/j.tiv.2013.09.012. View

Meng E, Hanna A, Samant R, Shevde L . The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer. Cancers (Basel). 2015; 7(3):1333-48. PMC: 4586772. DOI: 10.3390/cancers7030839. View

Roberti M, Pizzirani D, Simoni D, Rondanin R, Baruchello R, Bonora C . Synthesis and biological evaluation of resveratrol and analogues as apoptosis-inducing agents. J Med Chem. 2003; 46(16):3546-54. DOI: 10.1021/jm030785u. View

Sale S, Verschoyle R, Boocock D, Jones D, Wilsher N, Ruparelia K . 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. 2004; 90(3):736-44. PMC: 2409587. DOI: 10.1038/sj.bjc.6601568. View

Eo S, Kim J, Kim S . Induction of G₂/M Arrest by Berberine via Activation of PI3K/Akt and p38 in Human Chondrosarcoma Cell Line. Oncol Res. 2015; 22(3):147-57. PMC: 7838453. DOI: 10.3727/096504015X14298122915583. View

10.

Yellepeddi V, Kumar A, Maher D, Chauhan S, Vangara K, Palakurthi S . Biotinylated PAMAM dendrimers for intracellular delivery of cisplatin to ovarian cancer: role of SMVT. Anticancer Res. 2011; 31(3):897-906. View

11.

Yang X, Li X, Ren J . From French Paradox to cancer treatment: anti-cancer activities and mechanisms of resveratrol. Anticancer Agents Med Chem. 2014; 14(6):806-25. DOI: 10.2174/1871520614666140521121722. View

12.

Piotrowska H, Myszkowski K, Ziolkowska A, Kulcenty K, Wierzchowski M, Kaczmarek M . Resveratrol analogue 3,4,4',5-tetramethoxystilbene inhibits growth, arrests cell cycle and induces apoptosis in ovarian SKOV-3 and A-2780 cancer cells. Toxicol Appl Pharmacol. 2012; 263(1):53-60. DOI: 10.1016/j.taap.2012.05.023. View

13.

Lee J, Ahn J, Kim T, Lee J, Choi J . Mutant p53 promotes ovarian cancer cell adhesion to mesothelial cells via integrin β4 and Akt signals. Sci Rep. 2015; 5:12642. PMC: 4649895. DOI: 10.1038/srep12642. View

14.

Gadducci A, Lanfredini N, Sergiampietri C . Antiangiogenic agents in gynecological cancer: State of art and perspectives of clinical research. Crit Rev Oncol Hematol. 2015; 96(1):113-28. DOI: 10.1016/j.critrevonc.2015.05.009. View

15.

Sale S, Tunstall R, Ruparelia K, Potter G, Steward W, Gescher A . 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. 2005; 115(2):194-201. DOI: 10.1002/ijc.20884. View

16.

Smoliga J, Blanchard O . Enhancing the delivery of resveratrol in humans: if low bioavailability is the problem, what is the solution?. Molecules. 2014; 19(11):17154-72. PMC: 6270951. DOI: 10.3390/molecules191117154. View

17.

Piotrowska H, Kucinska M, Murias M . Biological activity of piceatannol: leaving the shadow of resveratrol. Mutat Res. 2011; 750(1):60-82. DOI: 10.1016/j.mrrev.2011.11.001. View

18.

An Y, Nie F, Wang Z, Zhang D . Preparation and characterization of realgar nanoparticles and their inhibitory effect on rat glioma cells. Int J Nanomedicine. 2012; 6:3187-94. PMC: 3254263. DOI: 10.2147/IJN.S26237. View

19.

Lee S, Nam K, Hoe Y, Min H, Kim E, Ko H . Synthesis and evaluation of cytotoxicity of stilbene analogues. Arch Pharm Res. 2003; 26(4):253-7. DOI: 10.1007/BF02976951. View

20.

Androutsopoulos V, Ruparelia K, Papakyriakou A, Filippakis H, Tsatsakis A, Spandidos D . Anticancer effects of the metabolic products of the resveratrol analogue, DMU-212: structural requirements for potency. Eur J Med Chem. 2011; 46(6):2586-95. DOI: 10.1016/j.ejmech.2011.03.049. View