A novel resveratrol derivative selectively inhibits the proliferation of colorectal cancer cells with KRAS mutation
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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.
KeywordsResveratrol Colorectal cancer Three-dimensional culture KRAS Oncogene
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).
Compliance with ethical standards
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.
- 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 59:2596–2601PubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Kishi A, Shinka Y, Matsukawa T, Yamada Y, Yamada I (2016) A novel resveratrol derivative. Japan Patent 2016-30739Google Scholar
- 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle Scholar