A novel oxiranylchromenone derivative, MHY336, induces apoptosis and cell cycle arrest via a p53- and p21-dependent pathway in HCT116 human colon cancer cells

Lee,Sun Hwa; Kang,Yong Jung; Kim,Dong Hwan; Sung,Bokyung; Kang,Jin Ah; Chun,Pusoon; Yoon,Jeong-Hyun; Moon,Hyung Ryong; Kim,Hyung Sik; Chung,Hae Young; Kim,Nam Deuk

doi:10.3892/ijo.2013.2226

A novel oxiranylchromenone derivative, MHY336, induces apoptosis and cell cycle arrest via a p53- and p21-dependent pathway in HCT116 human colon cancer cells

Authors:
- Sun Hwa Lee
- Yong Jung Kang
- Dong Hwan Kim
- Bokyung Sung
- Jin Ah Kang
- Pusoon Chun
- Jeong-Hyun Yoon
- Hyung Ryong Moon
- Hyung Sik Kim
- Hae Young Chung
- Nam Deuk Kim
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Affiliations: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea, College of Pharmacy, Inje University, Gimhae, Gyeongnam 621-749, Republic of Korea, Division of Toxicology, College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
Published online on: December 23, 2013 https://doi.org/10.3892/ijo.2013.2226
Pages: 943-949

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Abstract

In this study, we compared cytotoxicity, cell cycle distribution, and apoptosis on MHY336 treatment in three human colorectal carcinoma HCT116 cells: p53+/+ (p53‑wt), p53-/- (p53-null), and p21-/- (p21-null), as well as investigated the roles of p53 and p21 in cell death. Using these three isogenic variants, the roles of p53 and p21 in the cellular response to treatment with MHY336, a novel topoisomerase IIα inhibitor, were investigated. Our results showed that MHY336 treatment increased the expression of p53 over time in cells with wild-type p53 status. This elevated levels of p53 is associated with increased DNA fragmentation, and cleavage of poly(ADP-ribose) polymerase, consistent with increased sensitivity of these cells to apoptotic stimuli. However, p53-null and p21-null cells were more resistant to the antiproliferative and apoptotic effects of MHY336 than p53-wt cells. The same result was achieved by knocking down p53 and p21 with siRNA in p53-wt cells, indicating that p53 and p21 play a crucial role in MHY336-induced cell cycle arrest and apoptosis. Taken together, these results suggest that MHY336 could be a potential candidate to be used in chemoprevention and/or treatment of colon cancer.

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1.	Merika E, Saif MW, Katz A, Syrigos K and Morse M: Review. Colon cancer vaccines: an update. In Vivo. 24:607–628. 2010.PubMed/NCBI
2.	Cunningham D, Atkin W, Lenz HJ, et al: Colorectal cancer. Lancet. 375:1030–1047. 2010. View Article : Google Scholar
3.	Jung KW, Won YJ, Kong HJ, Oh CM, Seo HG and Lee JS: Prediction of cancer incidence and mortality in Korea, 2013. Cancer Res Treat. 45:15–21. 2013. View Article : Google Scholar : PubMed/NCBI
4.	Luu C, Arrington AK, Schoellhammer HF, Singh G and Kim J: Targeted therapies in colorectal cancer: surgical considerations. J Gastrointest Oncol. 4:328–336. 2013.PubMed/NCBI
5.	Lopez-Lazaro M, Willmore E and Austin CA: The dietary flavonoids myricetin and fisetin act as dual inhibitors of DNA topoisomerases I and II in cells. Mutat Res. 696:41–47. 2010. View Article : Google Scholar : PubMed/NCBI
6.	Cao G, Sofic E and Prior RL: Antioxidant and prooxidant behavior of flavonoids: structure-activity relationships. Free Radic Biol Med. 22:749–760. 1997. View Article : Google Scholar : PubMed/NCBI
7.	Constantinou A, Mehta R, Runyan C, Rao K, Vaughan A and Moon R: Flavonoids as DNA topoisomerase antagonists and poisons: structure-activity relationships. J Nat Prod. 58:217–225. 1995. View Article : Google Scholar : PubMed/NCBI
8.	Patra N, De U, Kang JA, et al: A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells. Eur J Pharmacol. 658:98–107. 2011. View Article : Google Scholar : PubMed/NCBI
9.	Jeong JH, Kang SS, Park KK, Chang HW, Magae J and Chang YC: p53-independent induction of G1 arrest and p21^WAF1/CIP1 expression by ascofuranone, an isoprenoid antibiotic, through downregulation of c-Myc. Mol Cancer Ther. 9:2102–2113. 2010.PubMed/NCBI
10.	Oliner JD, Kinzler KW, Meltzer PS, George DL and Vogelstein B: Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 358:80–83. 1992. View Article : Google Scholar : PubMed/NCBI
11.	Kastan MB, Zhan Q, el-Deiry WS, et al: A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 71:587–597. 1992. View Article : Google Scholar : PubMed/NCBI
12.	Miyashita T and Reed JC: Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 80:293–299. 1995. View Article : Google Scholar : PubMed/NCBI
13.	Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ: The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 75:805–816. 1993. View Article : Google Scholar : PubMed/NCBI
14.	Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R and Beach D: p21 is a universal inhibitor of cyclin kinases. Nature. 366:701–704. 1993. View Article : Google Scholar : PubMed/NCBI
15.	Waldman T, Kinzler KW and Vogelstein B: p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res. 55:5187–5190. 1995.PubMed/NCBI
16.	Agrawal S, Agarwal ML, Chatterjee-Kishore M, Stark GR and Chisolm GM: Stat1-dependent, p53-independent expression of p21 (waf1) modulates oxysterol-induced apoptosis. Mol Cell Biol. 22:1981–1992. 2002. View Article : Google Scholar : PubMed/NCBI
17.	Aneja R, Ghaleb AM, Zhou J, Yang VW and Joshi HC: p53 and p21 determine the sensitivity of noscapine-induced apoptosis in colon cancer cells. Cancer Res. 67:3862–3870. 2007. View Article : Google Scholar : PubMed/NCBI
18.	Haldar S, Negrini M, Monne M, Sabbioni S and Croce CM: Downregulation of bcl-2 by p53 in breast cancer cells. Cancer Res. 54:2095–2097. 1994.PubMed/NCBI
19.	Wang XW and Harris CC: p53 tumor-suppressor gene: clues to molecular carcinogenesis. J Cell Physiol. 173:247–255. 1997. View Article : Google Scholar : PubMed/NCBI
20.	Niculescu AB III, Chen X, Smeets M, Hengst L, Prives C and Reed SI: Effects of p21 (Cip1/Waf1) at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication. Mol Cell Biol. 18:629–643. 1998.PubMed/NCBI
21.	Baus F, Gire V, Fisher D, Piette J and Dulic V: Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts. EMBO J. 22:3992–4002. 2003. View Article : Google Scholar : PubMed/NCBI
22.	el-Deiry WS, Tokino T, Velculescu VE, et al: WAF1, a potential mediator of p53 tumor suppression. Cell. 75:817–825. 1993. View Article : Google Scholar : PubMed/NCBI
23.	Gartel AL and Tyner AL: Transcriptional regulation of the p21(WAF1/CIP1) gene. Exp Cell Res. 246:280–289. 1999. View Article : Google Scholar : PubMed/NCBI
24.	Haupt S, Berger M, Goldberg Z and Haupt Y: Apoptosis - the p53 network. J Cell Sci. 116:4077–4085. 2003. View Article : Google Scholar : PubMed/NCBI
25.	Sandri MI, Isaacs RJ, Ongkeko WM, et al: p53 regulates the minimal promoter of the human topoisomerase IIalpha gene. Nucleic Acids Res. 24:4464–4470. 1996. View Article : Google Scholar : PubMed/NCBI
26.	Wang Q, Zambetti GP and Suttle DP: Inhibition of DNA topoisomerase II alpha gene expression by the p53 tumor suppressor. Mol Cell Biol. 17:389–397. 1997.PubMed/NCBI
27.	Valkov NI and Sullivan DM: Tumor p53 status and response to topoisomerase II inhibitors. Drug Resist Updat. 6:27–39. 2003. View Article : Google Scholar : PubMed/NCBI
28.	Yang SY, Sales KM, Fuller B, Seifalian AM and Winslet MC: Apoptosis and colorectal cancer: implications for therapy. Trends Mol Med. 15:225–233. 2009. View Article : Google Scholar : PubMed/NCBI
29.	Peter ME: The flip side of FLIP. Biochem J. 382:e1–e3. 2004. View Article : Google Scholar : PubMed/NCBI
30.	Ashkenazi A: Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev. 19:325–331. 2008. View Article : Google Scholar : PubMed/NCBI
31.	Cory S and Adams JM: The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2:647–656. 2002. View Article : Google Scholar : PubMed/NCBI
32.	Kuwana T, Mackey MR, Perkins G, et al: Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell. 111:331–342. 2002. View Article : Google Scholar : PubMed/NCBI
33.	Oliver L and Vallette FM: The role of caspases in cell death and differentiation. Drug Resist Updat. 8:163–170. 2005. View Article : Google Scholar : PubMed/NCBI
34.	Iannolo G, Conticello C, Memeo L and De Maria R: Apoptosis in normal and cancer stem cells. Crit Rev Oncol Hematol. 66:42–51. 2008. View Article : Google Scholar : PubMed/NCBI