Synergistic inhibition of colon cancer cell growth by a combination of atorvastatin and phloretin

Zhou,Mo; Zheng,Jinkai; Bi,Jinfeng; Wu,Xinye; Lyu,Jian; Gao,Kun

doi:10.3892/ol.2017.7480

Synergistic inhibition of colon cancer cell growth by a combination of atorvastatin and phloretin

Authors:
- Mo Zhou
- Jinkai Zheng
- Jinfeng Bi
- Xinye Wu
- Jian Lyu
- Kun Gao
View Affiliations

Affiliations: Institute of Food Science and Technology, CAAS, Key Laboratory of Agro‑Products Processing, Ministry of Agriculture, Beijing 100193, P.R. China
Published online on: November 23, 2017 https://doi.org/10.3892/ol.2017.7480
Pages: 1985-1992

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Atorvastatin (ATST), a drug commonly used to reduce the levels of cholesterol and low‑density lipoproteins, is a prospective agent for the prevention of colorectal cancer in patients with hyperlipidemia. ATST in combination with functional components is a promising strategy for cancer chemoprevention. In the present study, the growth inhibitory effect of ATST combined with phloretin (PT) on SW620 and HCT116 colon cancer cells was investigated. The results of MTT assays indicated that the combination of PT and ATST markedly reduced cell survival in both cell lines compared with PT or ATST treatment administered individually. The interaction indexes between PT and ATST, which were used to analyze their interaction pattern, were computed by the median‑effect equation. The interaction indexes of each PT and ATST concentration pair were <1.0, which indicated a strong synergistic effect between the two compounds. The data obtained by flow cytometry and western blot analysis of cleaved‑poly (ADP‑ribose) polymerase indicated a synergistic effect resulted in apoptosis and cell cycle arrest at the G2/M checkpoint. Furthermore, combined treatment with PT and ATST markedly downregulated the expression of cyclin B and upregulated the expression of phospho‑cdc2 and Myt1, which suggested that the activation of cdc2 was downregulated. This combined treatment strategy enhanced the anti‑cancer activity of ATST at a relatively low dosage and suggested a possible method of preventing colorectal cancer in patients with hyperlipidemia.

View Figures

View References

1	Baena R and Salinas P: Diet and colorectal cancer. Maturitas. 80:258–264. 2015. View Article : Google Scholar : PubMed/NCBI
2	Lippi G, Mattiuzzi C and Cervellin G: Meat consumption and cancer risk: A critical review of published meta-analyses. Crit Rev Oncol Hematol. 97:1–14. 2016. View Article : Google Scholar : PubMed/NCBI
3	Keshk WA, Zineldeen DH, Wasfy RE and El-Khadrawy OH: Fatty acid synthase/oxidized low-density lipoprotein as metabolic oncogenes linking obesity to colon cancer via NF-kappa B in Egyptians. Med Oncol. 31:1922014. View Article : Google Scholar : PubMed/NCBI
4	Davis-Yadley AH, Lipka S, Shen H, Devanney V, Swarup S, Barnowsky A, Silpe J, Mosdale J, Pan Q, Fridlyand S, et al: Ethnic disparities in the risk of colorectal adenomas associated with lipid levels: A retrospective multiethnic study. J Gastrointest Cancer. 46:29–35. 2015. View Article : Google Scholar : PubMed/NCBI
5	Reverter M, Rentero C, Garcia-Melero A, Hoque M, Vilà de Muga S, Alvarez-Guaita A, Conway JR, Wood P, Cairns R, Lykopoulou L, et al: Cholesterol regulates Syntaxin 6 trafficking at trans-Golgi network endosomal boundaries. Cell Rep. 7:883–897. 2014. View Article : Google Scholar : PubMed/NCBI
6	Sheng R, Kim H, Lee H, Xin Y, Chen Y, Tian W, Cui Y, Choi JC, Doh J, Han JK, et al: Cholesterol selectively activates canonical Wnt signalling over non-canonical Wnt signalling. Nat Commun. 5:43932014. View Article : Google Scholar : PubMed/NCBI
7	Nielsen SF, Nordestgaard BG and Bojesen SE: Statin use and reduced cancer-related mortality. N Engl J Med. 367:1792–1802. 2012. View Article : Google Scholar : PubMed/NCBI
8	Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK and Rennert G: Statins and the risk of colorectal cancer. N Engl J Med. 352:2184–2192. 2005. View Article : Google Scholar : PubMed/NCBI
9	Lytras T, Nikolopoulos G and Bonovas S: Statins and the risk of colorectal cancer: An updated systematic review and meta-analysis of 40 studies. World J Gastroenterol. 20:1858–1870. 2014. View Article : Google Scholar : PubMed/NCBI
10	Xiao H and Yang CS: Combination regimen with statins and NSAIDs: A promising strategy for cancer chemoprevention. Int J Cancer. 123:983–990. 2008. View Article : Google Scholar : PubMed/NCBI
11	Xiao H, Zhang Q, Lin Y, Reddy BS and Yang CS: Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells. Int J Cancer. 122:2115–2124. 2008. View Article : Google Scholar : PubMed/NCBI
12	Yang Z, Xiao H, Jin H, Koo PT, Tsang DJ and Yang CS: Synergistic actions of atorvastatin with gamma-tocotrienol and celecoxib against human colon cancer HT29 and HCT116 cells. Int J Cancer. 126:852–863. 2010.PubMed/NCBI
13	Lu G, Xiao H, You H, Lin Y, Jin H, Snagaski B and Yang CS: Synergistic inhibition of lung tumorigenesis by a combination of green tea polyphenols and atorvastatin. Clin Cancer Res. 14:4981–4988. 2008. View Article : Google Scholar : PubMed/NCBI
14	Bazzano LA, Serdula MK and Liu S: Dietary intake of fruits and vegetables and risk of cardiovascular disease. Curr Atheroscler Rep. 5:492–499. 2003. View Article : Google Scholar : PubMed/NCBI
15	Liu RH: Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals. Am J Clin Nutr. 78(3 Suppl): 517S–520S. 2003.PubMed/NCBI
16	Boyer J and Liu RH: Apple phytochemicals and their health benefits. Nutr J. 3:52004. View Article : Google Scholar : PubMed/NCBI
17	Hyson DA: A comprehensive review of apples and apple components and their relationship to human health. Adv Nutr. 2:408–420. 2011. View Article : Google Scholar : PubMed/NCBI
18	Kobori M, Iwashita K, Shinmoto H and Tsushida T: Phloretin-induced apoptosis in B16 melanoma 4A5 cells and HL60 human leukemia cells. Biosci Biotechnol Biochem. 63:719–725. 1999. View Article : Google Scholar : PubMed/NCBI
19	Iwashita K, Kobori M, Yamaki K and Tsushida T: Flavonoids inhibit cell growth and induce apoptosis in B16 melanoma 4A5 cells. Biosci Biotechnol Biochem. 64:1813–1820. 2000. View Article : Google Scholar : PubMed/NCBI
20	Park SY, Kim EJ, Shin HK, Kwon DY, Kim MS, Surh YJ and Park JH: Induction of apoptosis in HT-29 colon cancer cells by phloretin. J Med Food. 10:581–586. 2007. View Article : Google Scholar : PubMed/NCBI
21	Wu CH, Ho YS, Tsai CY, Wang YJ, Tseng H, Wei PL, Lee CH, Liu RS and Lin SY: In vitro and in vivo study of phloretin-induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter. Int J Cancer. 124:2210–2219. 2009. View Article : Google Scholar : PubMed/NCBI
22	Yang KC, Tsai CY, Wang YJ, Wei PL, Lee CH, Chen JH, Wu CH and Ho YS: Apple polyphenol phloretin potentiates the anticancer actions of paclitaxel through induction of apoptosis in human hep G2 cells. Mol Carcinog. 48:420–431. 2009. View Article : Google Scholar : PubMed/NCBI
23	Chou TC and Talalay P: Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI
24	Gazzerro P, Proto MC, Gangemi G, Malfitano AM, Ciaglia E, Pisanti S, Santoro A, Laezza C and Bifulco M: Pharmacological actions of statins: A critical appraisal in the management of cancer. Pharmacol Rev. 64:102–146. 2012. View Article : Google Scholar : PubMed/NCBI
25	Huang EH, Johnson LA, Eaton K, Hynes MJ, Carpentino JE and Higgins PD: Atorvastatin induces apoptosis in vitro and slows growth of tumor xenografts but not polyp formation in MIN mice. Dig Dis Sci. 55:3086–3094. 2010. View Article : Google Scholar : PubMed/NCBI
26	Athyros VG, Tziomalos K, Karagiannis A and Mikhailidis DP: Atorvastatin: Safety and tolerability. Expert Opin Drug Saf. 9:667–674. 2010. View Article : Google Scholar : PubMed/NCBI
27	Gray RT, Loughrey MB, Bankhead P, Cardwell CR, McQuaid S, O'Neill RF, Arthur K, Bingham V, McGready C, Gavin AT, et al: Statin use, candidate mevalonate pathway biomarkers and colon cancer survival in a population-based cohort study. Br J Cancer. 116:1652–1659. 2017. View Article : Google Scholar : PubMed/NCBI
28	Voorneveld PW, Reimers MS, Bastiaannet E, Jacobs RJ, van Eijk R, Zanders MMJ, Herings RMC, van Herk-Sukel MPP, Kodach LL, van Wezel T, et al: Statin use after diagnosis of colon cancer and patient survival. Gastroenterology. 153:470–479.e4. 2017. View Article : Google Scholar : PubMed/NCBI
29	Ishikawa S, Hayashi H, Kinoshita K, Abe M, Kuroki H, Tokunaga R, Tomiyasu S, Tanaka H, Sugita H, Arita T, et al: Statins inhibit tumor progression via an enhancer of zeste homolog 2-mediated epigenetic alteration in colorectal cancer. Int J Cancer. 135:2528–2536. 2014. View Article : Google Scholar : PubMed/NCBI
30	Evan GI and Vousden KH: Proliferation, cell cycle and apoptosis in cancer. Nature. 411:342–348. 2001. View Article : Google Scholar : PubMed/NCBI
31	Fisher D, Krasinska L, Coudreuse D and Novák B: Phosphorylation network dynamics in the control of cell cycle transitions. J Cell Sci. 125:4703–4711. 2012. View Article : Google Scholar : PubMed/NCBI
32	Chow JP and Poon RY: The CDK1 inhibitory kinase MYT1 in DNA damage checkpoint recovery. Oncogene. 32:4778–4788. 2013. View Article : Google Scholar : PubMed/NCBI
33	Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC and Fornace AJ Jr: Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene. 18:2892–2900. 1999. View Article : Google Scholar : PubMed/NCBI
34	Dash BC and El-Deiry WS: Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity. Mol Cell Biol. 25:3364–3387. 2005. View Article : Google Scholar : PubMed/NCBI
35	Lin YC, Lin JH, Chou CW, Chang YF, Yeh SH and Chen CC: Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2. Cancer Res. 68:2375–2383. 2008. View Article : Google Scholar : PubMed/NCBI
36	Mohammed A, Qian L, Janakiram NB, Lightfoot S, Steele VE and Rao CV: Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48Cre/+ LSL-KrasG12D/+ mice. Int J Cancer. 131:1951–1962. 2012. View Article : Google Scholar : PubMed/NCBI
37	Buranrat B, Senggunprai L, Prawan A and Kukongviriyapan V: Simvastatin and atorvastatin as inhibitors of proliferation and inducers of apoptosis in human cholangiocarcinoma cells. Life Sci. 153:41–49. 2016. View Article : Google Scholar : PubMed/NCBI