Antitumor and apoptosis-inducing effects of α-mangostin extracted from the pericarp of the mangosteen fruit (Garcinia mangostana L.)in YD-15 tongue mucoepidermoid carcinoma cells

Lee,Hae  Nim; Jang,Hye  Yeon; Kim,Hyeong  Jin; Shin,Seong  Ah; Choo,Gang  Sik; Park,Young  Seok; Kim,Sang  Ki; Jung,Ji  Youn

doi:10.3892/ijmm.2016.2517

Antitumor and apoptosis-inducing effects of α-mangostin extracted from the pericarp of the mangosteen fruit (Garcinia mangostana L.)in YD-15 tongue mucoepidermoid carcinoma cells

Authors:
- Hae Nim Lee
- Hye Yeon Jang
- Hyeong Jin Kim
- Seong Ah Shin
- Gang Sik Choo
- Young Seok Park
- Sang Ki Kim
- Ji Youn Jung
View Affiliations

Affiliations: Department of Companion and Laboratory Animal Science, Kongju National University, Yesan-eup, Yesan-gun, Chungnam 340-702, Republic of Korea
Published online on: March 4, 2016 https://doi.org/10.3892/ijmm.2016.2517
Pages: 939-948
Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

α-mangostin is a dietary xanthone which has been shown to have antioxidant, anti-allergic, antiviral, antibacterial, anti-inflammatory and anticancer effects in various types of human cancer cells. In the present study, we aimed to elucidate the molecular mechanisms responsible for the apoptosis-inducing effects of α-mangostin on YD-15 tongue mucoepidermoid carcinoma cells. The results from MTT assays revealed that cell proliferation significantly decreased in a dose-dependent manner in the cells treated with α-mangostin. DAPI staining illustrated that chromatin condensation in the cells treated with 15 µM α-mangostin was far greater than that in the untreated cells. Flow cytometric analysis indicated that α-mangostin suppressed YD-15 cell viability by inducing apoptosis and promoting cell cycle arrest in the sub-G1 phase. Western blot analysis of various signaling molecules revealed that α-mangostin targeted the extracellular signal‑regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signaling pathways through the inhibition of ERK1/2 and p38 phosphorylation in a dose‑dependent manner. α-mangostin also increased the levels of Bax (pro-apoptotic), cleaved caspase-3, cleaved caspase-9 and cleaved-poly(ADP-ribose) polymerase (PARP), whereas the levels of the anti-apoptotic factors, Bcl-2 and c-myc, decreased in a dose-dependent manner. The anticancer effects of α-mangostin were also investigated in a tumor xenograft mouse model. The α-mangostin-treated nude mice bearing YD-15 tumor xenografts exhibited a significantly reduced tumor volume and tumor weight due to the potent promoting effects of α-mangostin on cancer cell apoptosis, as determined by TUNEL assay. Immunohistochemical analysis revealed that the level of cleaved caspase-3 increased, whereas the Ki-67, p-ERK1/2 and p-p38 levels decreased in the α-mangostin‑treated mice. Taken together, the findings of our study indicate that α-mangostin induces the apoptosis of YD-15 tongue carcinoma cells through the ERK1/2 and p38 MAPK signaling pathways.

View Figures

View References

1	Jung KW, Won YJ, Kong HJ, Oh CM, Cho HS, Lee DH and Lee KH: Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2012. Cancer Res Treat. 47:127–141. 2015. View Article : Google Scholar : PubMed/NCBI
2	Neville BW and Day TA: Oral cancer and precancerous lesions. CA Cancer J Clin. 52:195–215. 2002. View Article : Google Scholar : PubMed/NCBI
3	Silverman S: Early diagnosis of oral cancer. Cancer. 62:1796–1799. 1998. View Article : Google Scholar
4	Kim MY, Kim CS, Lee SH, Kim JW and Jang HJ: A clinicostatistical analysis of oral cancer patients for recent 8 years. J Korean Assoc Oral Maxillofac Surg. 33:660–668. 2007.
5	Lee EJ, Kim MJ and Myoung H: Change of the invasiveness with selective Cox-2 inhibition in an oral squamous cell carcinoma cell Line, KB: preliminary in vitro study. J Korean Assoc Oral Maxillofac Surg. 33:103–108. 2007.
6	Mahabusarakam W, Wiriyachitra P and Taylor WC: Chemical constituents of Garcinia mangostana. J Nat Prod. 50:474–478. 1987. View Article : Google Scholar
7	Jung HA, Su BN, Keller WJ, Mehta RG and Kinghorn AD: Antioxidant xanthones from the pericarp of Garcinia mangostana (Mangosteen). J Agric Food Chem. 54:2077–2082. 2006. View Article : Google Scholar : PubMed/NCBI
8	Akao Y, Nakagawa Y, Iinuma M and Nozawa Y: Anti-cancer effects of xanthones from pericarps of mangosteen. Int J Mol Sci. 9:355–370. 2008. View Article : Google Scholar
9	Iinuma M, Tosa H, Tanaka T, Asai F, Kobayashi Y, Shimano R and Miyauchi K: Antibacterial activity of xanthones from guttiferaeous plants against methicillin-resistant Staphylococcus aureus. J Pharm Pharmacol. 48:861–865. 1996. View Article : Google Scholar : PubMed/NCBI
10	Sundaram BM, Gopalakrishnan C, Subramanian S, Shankaranarayanan D and Kameswaran L: Antimicrobial activities of Garcinia mangostana. Planta Med. 48:59–60. 1983. View Article : Google Scholar : PubMed/NCBI
11	Chen LG, Yang LL and Wang CC: Anti-inflammatory activity of mangostins from Garcinia mangostana. Food Chem Toxicol. 46:688–693. 2008. View Article : Google Scholar
12	Shan T, Ma Q, Guo K, Liu J, Li W, Wang F and Wu E: Xanthones from mangosteen extracts as natural chemopreventive agents: potential anticancer drugs. Curr Mol Med. 11:666–677. 2011. View Article : Google Scholar : PubMed/NCBI
13	Jiang DJ, Dai Z and Li YJ: Pharmacological effects of xanthones as cardiovascular protective agents. Cardiovasc Drug Rev. 22:91–102. 2004. View Article : Google Scholar : PubMed/NCBI
14	Nakatani K, Yamakuni T, Kondo N, Arakawa T, Oosawa K, Shimura S, Inoue H and Ohizumi Y: γ-Mangostin inhibits inhibitor-kappaB kinase activity and decreases lipopolysaccharide-induced cyclooxygenase-2 gene expression in C6 rat glioma cells. Mol Pharmacol. 66:667–674. 2004. View Article : Google Scholar : PubMed/NCBI
15	Pedraza-Chaverri J, Cárdenas-Rodríguez N, Orozco-Ibarra M and Pérez-Rojas JM: Medicinal properties of mangosteen (Garcinia mangostana). Food Chem Toxicol. 46:3227–3239. 2008. View Article : Google Scholar : PubMed/NCBI
16	Hsieh SC, Huang MH, Cheng CW, Hung JH, Yang SF and Hsieh YH: α-Mangostin induces mitochondrial dependent apoptosis in human hepatoma SK-Hep-1 cells through inhibition of p38 MAPK pathway. Apoptosis. 18:1548–1560. 2013. View Article : Google Scholar : PubMed/NCBI
17	Johnson JJ, Petiwala SM, Syed DN, Rasmussen JT, Adhami VM, Siddiqui IA, Kohl AM and Mukhtar H: α-Mangostin, a xanthone from mangosteen fruit, promotes cell cycle arrest in prostate cancer and decreases xenograft tumor growth. Carcinogenesis. 33:413–419. 2012. View Article : Google Scholar :
18	Watanapokasin R, Jarinthanan F, Nakamura Y, Sawasjirakij N, Jaratrungtawee A and Suksamrarn S: Effects of α-mangostin on apoptosis induction of human colon cancer. World J Gastroenterol. 17:2086–2095. 2011. View Article : Google Scholar : PubMed/NCBI
19	Shibata MA, Iinuma M, Morimoto J, Kurose H, Akamatsu K, Okuno Y, Akao Y and Otsuki Y: α-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn) reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation. BMC Med. 9:692011. View Article : Google Scholar
20	Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 270:1326–1331. 1995. View Article : Google Scholar : PubMed/NCBI
21	Surh YJ, Hurh YJ, Kang JY, Lee E, Kong G and Lee SJ: Resveratrol, an antioxidant present in red wine, induces apoptosis in human promyelocytic leukemia (HL-60) cells. Cancer Lett. 140:1–10. 1999. View Article : Google Scholar : PubMed/NCBI
22	Aisa Y, Miyakawa Y, Nakazato T, Shibata H, Saito K, Ikeda Y and Kizaki M: Fucoidan induces apoptosis of human HS-sultan cells accompanied by activation of caspase-3 and down-regulation of ERK pathways. Am J Hematol. 78:7–14. 2005. View Article : Google Scholar
23	Lazzè MC, Savio M, Pizzala R, Cazzalini O, Perucca P, Scovassi AI, Stivala LA and Bianchi L: Anthocyanins induce cell cycle perturbations and apoptosis in different human cell lines. Carcinogenesis. 25:1427–1433. 2004. View Article : Google Scholar : PubMed/NCBI
24	Shim HY, Park JH, Paik HD, Nah SY, Kim DSHL and Han YS: Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondria-mediated death signaling and SAPK/JNK1/2-c-Jun activation. Mol Cells. 24:95–104. 2007.PubMed/NCBI
25	Talib WH and Mahasneh AM: Antiproliferative activity of plant extracts used against cancer in traditional medicine. Sci Pharm. 78:33–45. 2010. View Article : Google Scholar : PubMed/NCBI
26	Li P, Tian W and Ma X: Alpha-mangostin inhibits intracellular fatty acid synthase and induces apoptosis in breast cancer cells. Mol Cancer. 13:1382014. View Article : Google Scholar : PubMed/NCBI
27	Evan GI and Vousden KH: Proliferation, cell cycle and apoptosis in cancer. Nature. 411:342–348. 2001. View Article : Google Scholar : PubMed/NCBI
28	Korystov YN, Mosin VA, Shaposhnikova VV, Levitman MK, Kudryavtsev AA, Kruglyak EB, Sterlina TS, Vik-torov AV and Drinyaev VA: A comparative study of effects of aversectin C abamectin and ivermectin on apoptosis of rat thymo-cytes induced by radiation and dexamethasone. Acta Vet Brno. 68:23–29. 1999. View Article : Google Scholar
29	Badran A, Iwasaki H, Inoue H and Ueda T: Atypical nuclear apoptosis downstream to caspase-3 activation in ara-C treated CCRF-CEM cells. Int J Oncol. 22:517–522. 2003.PubMed/NCBI
30	Willis S, Day CL, Hinds MG and Huang DC: The Bcl-2-regulated apoptotic pathway. J Cell Sci. 116:4053–4056. 2003. View Article : Google Scholar : PubMed/NCBI
31	Chiarugi V, Magnelli L, Cinelli M and Basi G: Apoptosis and the cell cycle. Cell Mol Biol Res. 40:603–612. 1994.PubMed/NCBI
32	Donovan M and Cotter TG: Control of mitochondrial integrity by Bcl-2 family members and caspase-independent cell death. Biochim Biophys Acta. 1644:133–147. 2004. View Article : Google Scholar : PubMed/NCBI
33	Bao Q and Shi Y: Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ. 14:56–65. 2007. View Article : Google Scholar
34	Galluzzi L, Kepp O, Trojel-Hansen C and Kroemer G: Mitochondrial control of cellular life, stress, and death. Circ Res. 111:1198–1207. 2012. View Article : Google Scholar : PubMed/NCBI
35	Chuang SM, Wang IC and Yang JL: Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmium. Carcinogenesis. 21:1423–1432. 2000. View Article : Google Scholar : PubMed/NCBI
36	Bassi R, Heads R, Marber MS and Clark JE: Targeting p38-MAPK in the ischaemic heart: kill or cure? Curr Opin Pharmacol. 8:141–146. 2008. View Article : Google Scholar : PubMed/NCBI
37	Hatano K, Yamaguchi S, Nimura K, Murakami K, Nagahara A, Fujita K, Uemura M, Nakai Y, Tsuchiya M, Nakayama M, et al: Residual prostate cancer cells after docetaxel therapy increase the tumorigenic potential via constitutive signaling of CXCR4, ERK1/2 and c-Myc. Mol Cancer Res. 11:1088–1100. 2013. View Article : Google Scholar : PubMed/NCBI
38	Sears R, Nuckolls F, Haura E, Taya Y, Tamai K and Nevins JR: Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 14:2501–2514. 2000. View Article : Google Scholar : PubMed/NCBI
39	Krajarng A, Nakamura Y, Suksamrarn S and Watanapokasin R: α-Mangostin induces apoptosis in human chondrosarcoma cells through downregulation of ERK/JNK and Akt signaling pathway. J Agric Food Chem. 59:5746–5754. 2011. View Article : Google Scholar : PubMed/NCBI
40	Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U and Stein H: Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 133:1710–1715. 1984.PubMed/NCBI