Indole-3-carbinol inhibits cell proliferation and induces apoptosis in Hep-2 laryngeal cancer cells

Wang,Ya-Qiu; Chen,Chen; Chen,Zhe; Xu,Yong; Wang,Yan; Xiao,Bo-Kui; Chen,Shi-Ming; Tao,Ze-Zhang

doi:10.3892/or.2013.2411

Indole-3-carbinol inhibits cell proliferation and induces apoptosis in Hep-2 laryngeal cancer cells

Authors:
- Ya-Qiu Wang
- Chen Chen
- Zhe Chen
- Yong Xu
- Yan Wang
- Bo-Kui Xiao
- Shi-Ming Chen
- Ze-Zhang Tao
View Affiliations

Affiliations: Department of Otolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, P.R. China
Published online on: April 22, 2013 https://doi.org/10.3892/or.2013.2411
Pages: 227-233

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

Indole-3-carbinol (I3C) is an active component of cruciferous vegetables and markedly inhibits the growth of a variety of tumors. However, its role in laryngeal cancer remains obscure. The aim of the present study was to elucidate the possible mechanisms whereby I3C influences Hep-2 laryngeal cancer cell proliferation and apoptosis. Treatment with I3C dose-dependently and significantly inhibited Hep-2 cell proliferation, and at doses of 100 and 150 µM, I3C induced cell morphological changes and promoted apoptosis. Following treatment of Hep-2 cells with I3C, we found that the protein expression of phosphatidylinositol-3-kinase (PI3K) p110α, PI3K p110β, PI3K class III, p-PDK1, Akt, p-Akt and the downstream signaling proteins p-c-Raf and GSK3-β were significantly downregulated. Additionally, tumor-bearing mouse models were constructed using BALB/c nude mice. The mice were subdivided into groups: pretreated with I3C, or treated with I3C or an untreated control group. After 8 weeks, mice pretreated or treated with IC3 developed smaller tumors compared to the untreated control group, and the protein expression of PI3K p110α, PI3K class III, Akt, p-Akt and the downstream signaling proteins p-c-Raf and GSK3-β in the tumors were significantly downregulated. Furthermore, no harmful side effect were observed in the heart, liver and kidney of the I3C-treated nude mice. In conclusion, I3C inhibited proliferation and induced the apoptosis of laryngeal tumor cells both in vivo and in vitro, and exhibited low toxicity to normal cells. The inhibitory effects noted with I3C treatment may depend on decreased phosphatidylinositol-3 kinase/serine-threonine kinase (PI3K/Akt) expression. This approach may be applied to the clinical treatment of laryngeal tumors and in drug screening.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Michaud DS, Spiegelman D, Clinton SK, Rimm EB, Willett WC and Giovannucci EL: Fruit and vegetable intake and incidence of bladder cancer in a male prospective cohort. J Natl Cancer Inst. 91:605–613. 1999. View Article : Google Scholar : PubMed/NCBI
3	Annema N, Heyworth JS, McNaughton SA, Iacopetta B and Fritschi L: Fruit and vegetable consumption and the risk of proximal colon, distal colon, and rectal cancers in a case-control study in Western Australia. J Am Diet Assoc. 111:1479–1490. 2011. View Article : Google Scholar : PubMed/NCBI
4	Larsson SC, Hakansson N, Näslund I, Bergkvist L and Wolk A: Fruit and vegetable consumption in relation to pancreatic cancer risk: a prospective study. Cancer Epidemiol Biomarkers Prev. 15:301–305. 2006. View Article : Google Scholar : PubMed/NCBI
5	van Poppel G, Verhoeven DT, Verhagen H and Goldbohm RA: Brassica vegetables and cancer prevention. Epidemiology and mechanisms. Adv Exp Med Biol. 472:159–168. 1999.
6	Keck AS and Finley JW: Cruciferous vegetables: cancer protective mechanisms of glucosinolate hydrolysis products and selenium. Integr Cancer Ther. 3:5–12. 2004. View Article : Google Scholar : PubMed/NCBI
7	Shertzer H and Senft A: The micronutrient indole-3-carbinol: implications for disease and chemoprevention. Drug Metabol Drug Interact. 14:159–188. 2011.PubMed/NCBI
8	Chinni SR, Li Y, Upadhyay S, Koppolu PK and Sarkar FH: Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene. 20:2927–2936. 2001. View Article : Google Scholar : PubMed/NCBI
9	Brew CT, Aronchik I, Hsu JC, et al: Indole-3-carbinol activates the ATM signaling pathway independent of DNA damage to stabilize p53 and induce G1 arrest of human mammary epithelial cells. Int J Cancer. 118:857–868. 2006. View Article : Google Scholar : PubMed/NCBI
10	Rahman KM, Aranha O and Sarkar FH: Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells. Nutr Cancer. 45:101–112. 2003. View Article : Google Scholar : PubMed/NCBI
11	Meng Q, Qi M, Chen DZ, et al: Suppression of breast cancer invasion and migration by indole-3-carbinol: associated with up-regulation of BRCA1 and E-cadherin/catenin complexes. J Mol Med. 78:155–165. 2000. View Article : Google Scholar : PubMed/NCBI
12	Aggarwal BB and Ichikawa H: Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 4:1201–1215. 2005. View Article : Google Scholar : PubMed/NCBI
13	Chang F, Lee JT, Navolanic PM, et al: Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia. 17:590–603. 2003. View Article : Google Scholar : PubMed/NCBI
14	Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and González-Barón M: PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30:193–204. 2004.PubMed/NCBI
15	Watanabe S, Sato K, Okazaki Y, Tonogi M, Tanaka Y and Yamane GY: Activation of PI3K-AKT pathway in oral epithelial dysplasia and early cancer of tongue. Bull Tokyo Dent Coll. 50:125–133. 2009. View Article : Google Scholar : PubMed/NCBI
16	Oganesian A, Hendricks JD and Williams DE: Long term dietary indole-3-carbinol inhibits diethylnitrosamine-initiated hepatocarcinogenesis in the infant mouse model. Cancer Lett. 118:87–94. 1997. View Article : Google Scholar
17	Plate AY and Gallaher DD: Effects of indole-3-carbinol and phenethyl isothiocyanate on colon carcinogenesis induced by azoxymethane in rats. Carcinogenesis. 27:287–292. 2006. View Article : Google Scholar : PubMed/NCBI
18	Pappa G, Lichtenberg M, Iori R, Barillari J, Bartsch H and Gerhäuser C: Comparison of growth inhibition profiles and mechanisms of apoptosis induction in human colon cancer cell lines by isothiocyanates and indoles from Brassicaceae. Mutat Res. 599:76–87. 2006. View Article : Google Scholar : PubMed/NCBI
19	Brognard J, Clark AS, Ni Y and Dennis PA: Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res. 61:3986–3997. 2001.PubMed/NCBI
20	Cicenas J: The potential role of Akt phosphorylation in human cancers. Int J Biol Markers. 23:1–9. 2008.PubMed/NCBI
21	Rahman KM, Li Y and Sarkar FH: Inactivation of akt and NF-κB play important roles during indole-3-carbinol-induced apoptosis in breast cancer cells. Nutr Cancer. 48:84–94. 2004.
22	Chen DZ, Qi M, Auborn KJ and Carter TH: Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. J Nutr. 131:3294–3302. 2001.
23	Wu TY, Saw CL, Khor TO, Pung D, Boyanapalli SS and Kong AN: In vivo pharmacodynamics of indole-3-carbinol in the inhibition of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice: involvement of Nrf2 and cell cycle/apoptosis signaling pathways. Mol Carcinog. 51:761–770. 2012. View Article : Google Scholar : PubMed/NCBI
24	Newfield L, Goldsmith A, Bradlow HL and Auborn K: Estrogen metabolism and human papillomavirus-induced tumors of the larynx: chemo-prophylaxis with indole-3-carbinol. Anticancer Res. 13:337–341. 1993.PubMed/NCBI