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A novel resveratrol derivative selectively inhibits the proliferation of colorectal cancer cells with KRAS mutation

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Abstract

Resveratrol is a polyphenolic compound in many edible foods including grapes, peanuts, and berries. Several studies have revealed the beneficial effects of resveratrol against various diseases such as heart disease, diabetes, obesity, neurological disorders, and cancer. A recent study showed that resveratrol inhibits the proliferation of HCT116 human colorectal cancer cells in three-dimensional culture (3DC) via induction of luminal apoptosis in HCT116 cell spheroids. In this study, we showed that a novel compound, caffeic acid-adducted resveratrol, has a stronger inhibitory effect on the growth of HCT116 cell spheroids in 3DC than resveratrol. It showed almost the same inhibitory efficacy as 5-fluorouracil, a conventional anticancer drug. We further showed that the resveratrol derivative did not affect the growth of HKe3 cell spheroids derived from HCT116 cells by disruption of the activating mutant KRAS gene. These results suggest that the resveratrol derivative inhibits the growth of HCT116 cell spheroids via inhibition of an oncogenic KRAS-mediated signaling pathway.

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References

  1. Mukherjee S, Dudley JI, Das DK (2010) Dose-dependency of resveratrol in providing health benefits. Dose Response 8:478–500. doi:10.2203/dose-response.09-015.Mukherjee

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Signorelli P, Ghidoni R (2005) Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 16:449–466. doi:10.1016/j.jnutbio.2005.01.017

    Article  CAS  PubMed  Google Scholar 

  3. Carrizzo A, Forte M, Damato A, Trimarco V, Salzano F, Bartolo M, Maciag A, Puca AA, Vecchione C (2013) Antioxidant effects of resveratrol in cardiovascular, cerebral and metabolic diseases. Food Chem Toxicol 61:215–226. doi:10.1016/j.fct.2013.07.021

    Article  CAS  PubMed  Google Scholar 

  4. Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220

    Article  CAS  Google Scholar 

  5. Fouad MA, Agha AM, Merzabani MM, Shouman SA (2013) Resveratrol inhibits proliferation, angiogenesis and induces apoptosis in colon cancer cells: calorie restriction is the force to the cytotoxicity. Hum Exp Toxicol 32:1067–1080. doi:10.1177/0960327113475679

    Article  CAS  PubMed  Google Scholar 

  6. Carter LG, D’Orazio JA, Pearson KJ (2014) Resveratrol and cancer: focus on in vivo evidence. Endocr Relat Cancer 21:R209–R225. doi:10.1530/ERC-13-0171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sherr CJ, McCormick F (2002) The RB and p53 pathways in cancer. Cancer Cell 2:103–112

    Article  CAS  Google Scholar 

  8. Mnjoyan ZH, Fujise K (2003) Profound negative regulatory effects by resveratrol on vascular smooth muscle cells: a role of p53-p21(WAF1/CIP1) pathway. Biochem Biophys Res Commun 311:546–552

    Article  CAS  Google Scholar 

  9. Hsieh TC, Juan G, Darzynkiewicz Z, Wu JM (1999) Resveratrol increases nitric oxide synthase, induces accumulation of p53 and p21(WAF1/CIP1), and suppresses cultured bovine pulmonary artery endothelial cell proliferation by perturbing progression through S and G2. Cancer Res 59:2596–2601

    CAS  PubMed  Google Scholar 

  10. Narayanan BA, Narayanan NK, Re GG, Nixon DW (2003) Differential expression of genes induced by resveratrol in LNCaP cells: p53-mediated molecular targets. Int J Cancer 104:204–212. doi:10.1002/ijc.10932

    Article  CAS  PubMed  Google Scholar 

  11. Fulda S, Debatin KM (2004) Sensitization for anticancer drug-induced apoptosis by the chemopreventive agent resveratrol. Oncogene 23:6702–6711. doi:10.1038/sj.onc.1207630

    Article  CAS  PubMed  Google Scholar 

  12. McDonald SA, Preston SL, Lovell MJ, Wright NA, Jankowski JA (2006) Mechanisms of disease: from stem cells to colorectal cancer. Nat Clin Pract Gastroenterol Hepatol 3:267–274. doi:10.1038/ncpgasthep0473

    Article  CAS  PubMed  Google Scholar 

  13. Tsunoda T, Takashima Y, Fujimoto T, Koyanagi M, Yoshida Y, Doi K, Tanaka Y, Kuroki M, Sasazuki T, Shirasawa S (2010) Three-dimensionally specific inhibition of DNA repair-related genes by activated KRAS in colon crypt model. Neoplasia 12:397–404

    Article  CAS  Google Scholar 

  14. Shirasawa S, Furuse M, Yokoyama N, Sasazuki T (1993) Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 260:85–88

    Article  CAS  Google Scholar 

  15. Tsunoda T, Ota T, Fujimoto T, Doi K, Tanaka Y, Yoshida Y, Ogawa M, Matsuzaki H, Hamabashiri M, Tyson DR, Kuroki M, Miyamoto S, Shirasawa S (2012) Inhibition of phosphodiesterase-4 (PDE4) activity triggers luminal apoptosis and AKT dephosphorylation in a 3-D colonic-crypt model. Mol Cancer 11:46. doi:10.1186/1476-4598-11-46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295–308. doi:10.1038/nrc2109

    Article  CAS  PubMed  Google Scholar 

  17. Tsunoda T, Ishikura S, Doi K, Matsuzaki H, Iwaihara Y, Shirasawa S (2014) Resveratrol induces luminal apoptosis of human colorectal cancer HCT116 cells in three-dimensional culture. Anticancer Res 34:4551–4555

    CAS  PubMed  Google Scholar 

  18. Tsunoda T, Ishikura S, Doi K, Iwaihara Y, Hidesima H, Luo H, Hirose Y, Shirasawa S (2015) Establishment of a three-dimensional floating cell culture system for screening drugs targeting KRAS-mediated signaling molecules. Anticancer Res 35:4453–4459

    CAS  PubMed  Google Scholar 

  19. Kishi A, Shinka Y, Matsukawa T, Yamada Y, Yamada I (2016) A novel resveratrol derivative. Japan Patent 2016-30739

  20. Mikula-Pietrasik J, Sosinska P, Murias M, Wierzchowski M, Brewinska-Olchowik M, Piwocka K, Szpurek D, Ksiazek K (2015) High potency of a novel resveratrol derivative, 3,3′,4,4′-tetrahydroxy-trans-stilbene, against ovarian cancer is associated with an oxidative stress-mediated imbalance between DNA damage accumulation and repair. Oxid Med Cell Longev 2015:135691. doi:10.1155/2015/135691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hata Y, Etoh T, Inomata M, Shiraishi N, Nishizono A, Kitano S (2008) Efficacy of oncolytic reovirus against human breast cancer cells. Oncol Rep 19:1395–1398

    CAS  PubMed  Google Scholar 

  22. Rosendahl AH, Perks CM, Zeng L, Markkula A, Simonsson M, Rose C, Ingvar C, Holly JM, Jernstrom H (2015) Caffeine and caffeic acid inhibit growth and modify estrogen receptor and insulin-like growth factor I receptor levels in human breast cancer. Clin Cancer Res 21:1877–1887. doi:10.1158/1078-0432.CCR-14-1748

    Article  CAS  PubMed  Google Scholar 

  23. Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, Ke H, Rehmann H, Taussig R, Brown AL, Kim MK, Beaven MA, Burgin AB, Manganiello V, Chung JH (2012) Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148:421–433. doi:10.1016/j.cell.2012.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Keishi Tamura, Hiroaki Fukushima, Ayaka Oki, and Taishi Nawata for technical assistance and our laboratory members for helpful discussions. This work was supported by JSPS KAKENHI Grant Number 17K07184 (to YK) and the Naito Foundation (to YK).

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Correspondence to Yojiro Kotake.

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The resveratrol derivative (UHA6052) used in this study was provided by UHA Mikakuto Co., Ltd. Taiji Matsukawa and Satoshi Doi are employees of UHA Mikakuto Co., Ltd.

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Okamoto, H., Matsukawa, T., Doi, S. et al. A novel resveratrol derivative selectively inhibits the proliferation of colorectal cancer cells with KRAS mutation. Mol Cell Biochem 442, 39–45 (2018). https://doi.org/10.1007/s11010-017-3191-x

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  • DOI: https://doi.org/10.1007/s11010-017-3191-x

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