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Chloroform extract of Citrus unshiu Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells

  • Authors:
    • Ye Seul Choi
    • Jang Mi Han
    • Yue Jai Kang
    • Hye Jin Jung
  • View Affiliations / Copyright

    Affiliations: Department of Life Science and Biochemical Engineering, Sun Moon University, Asan, South Chungcheong 31460, Republic of Korea, Department of Aquatic Life and Medical Sciences, Sun Moon University, Asan, South Chungcheong 31460, Republic of Korea
    Copyright: © Choi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 86
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    Published online on: November 24, 2020
       https://doi.org/10.3892/mmr.2020.11727
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Abstract

Cervical cancer is the second most common cancer among women worldwide. However, chemotherapies for this cancer often cause many side effects and chemoresistance. Citrus unshiu Markovich peel (CECU) has been used as a traditional medicine for the treatment of various diseases in East Asia. Recently, the anticancer activities and mechanisms of action of CECU extract have been reported in a number of different cancer cell types, but no study has evaluated the therapeutic effect of this natural product on cervical cancer cells. In the current study, the anticancer activity and the underlying molecular mechanism of the chloroform extract of CECU was investigated on HeLa human cervical cancer cells. The results showed that CECU effectively inhibited the proliferation and migration of HeLa cells. Treatment of cells with CECU led to cell cycle arrest at the G2/M phase and activation of extrinsic and intrinsic apoptotic pathways. Furthermore, the proliferation inhibitory effect of CECU was due to the inactivation of AKT and ERK signaling, upregulation of p53 and p21, and downregulation of cyclin B1 and cyclin D1, but not reactive oxygen species (ROS) generation. Furthermore, CECU inhibited the stem‑like features of HeLa cells by downregulating key cancer stemness biomarkers. Therefore, CECU may be an effective complementary and alternative medicine for the prevention and treatment of cervical cancer.
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1 

Schiffman M, Castle PE, Jeronimo J, Rodriguez AC and Wacholder S: Human papillomavirus and cervical cancer. Lancet. 370:890–907. 2007. View Article : Google Scholar

2 

Liontos M, Kyriazoglou A, Dimitriadis I, Dimopoulos MA and Bamias A: Systemic therapy in cervical cancer: 30 years in review. Crit Rev Oncol Hematol. 137:9–17. 2019. View Article : Google Scholar

3 

Pfeffer CM and Singh AT: Apoptosis: A target for anticancer therapy. Int J Mol Sci. 19:E4482018. View Article : Google Scholar

4 

Otto T and Sicinski P: Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 17:93–115. 2017. View Article : Google Scholar

5 

Hu Z, Ding W, Zhu D, Yu L, Jiang X, Wang X, Zhang C, Wang L, Ji T, Liu D, et al: TALEN-mediated targeting of HPV oncogenes ameliorates HPV-related cervical malignancy. J Clin Invest. 125:425–436. 2015. View Article : Google Scholar

6 

Arroyo M, Bagchi S and Raychaudhuri P: Association of the human papillomavirus type 16 E7 protein with the S-phase-specific E2F-cyclin A complex. Mol Cell Biol. 13:6537–6546. 1993. View Article : Google Scholar

7 

Ayob AZ and Ramasamy TS: Cancer stem cells as key drivers of tumour progression. J Biomed Sci. 25:202018. View Article : Google Scholar

8 

Feng D, Peng C, Li C, Zhou Y, Li M, Ling B, Wei H and Tian Z: Identification and characterization of cancer stem-like cells from primary carcinoma of the cervix uteri. Oncol Rep. 22:1129–1134. 2009.

9 

Cooke SL, Temple J, Macarthur S, Zahra MA, Tan LT, Crawford RA, Ng CK, Jimenez-Linan M, Sala E and Brenton JD: Intra-tumour genetic heterogeneity and poor chemoradiotherapy response in cervical cancer. Br J Cancer. 104:361–368. 2011. View Article : Google Scholar

10 

Ortiz-Sánchez E, Santiago-López L, Cruz-Domínguez VB, Toledo-Guzmán ME, Hernández-Cueto D, Muñiz-Hernández S, Garrido E, Cantú De León D and García-Carrancá A: Characterization of cervical cancer stem cell-like cells: Phenotyping, stemness, and human papilloma virus co-receptor expression. Oncotarget. 7:31943–31954. 2016. View Article : Google Scholar

11 

Huang R and Rofstad EK: Cancer stem cells (CSCs), cervical CSCs and targeted therapies. Oncotarget. 8:35351–35367. 2017. View Article : Google Scholar

12 

Lichota A and Gwozdzinski K: Anticancer activity of natural compounds from plant and marine environment. Int J Mol Sci. 19:E35332018. View Article : Google Scholar

13 

Roy M, Mukherjee A, Sarkar R, Mukherjee S and Biswas J: In search of natural remediation for cervical cancer. Anticancer Agents Med Chem. 15:57–65. 2015. View Article : Google Scholar

14 

Yang CH and Horwitz SB: Taxol®: The first microtubule stabilizing agent. Int J Mol Sci. 18:17332017. View Article : Google Scholar

15 

McCreight LJ, Bailey CJ and Pearson ER: Metformin and the gastrointestinal tract. Diabetologia. 59:426–435. 2016. View Article : Google Scholar

16 

Kanaze FI, Bounartzi MI, Georgarakis M and Niopas I: Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects. Eur J Clin Nutr. 61:472–477. 2007. View Article : Google Scholar

17 

Min KY, Kim HJ, Lee KA, Kim KT and Paik HD: Antimicrobial activity of acid-hydrolyzed Citrus unshiu peel extract in milk. J Dairy Sci. 97:1955–1960. 2014. View Article : Google Scholar

18 

Oh YC, Cho WK, Jeong YH, Im GY, Yang MC, Hwang YH and Ma JY: Anti-inflammatory effect of Citrus Unshiu peel in LPS-stimulated RAW 264.7 macrophage cells. Am J Chin Med. 40:611–629. 2012. View Article : Google Scholar

19 

Ahn KI, Choi EO, Kwon DH, HwangBo H, Kim MY, Kim HJ, Ji SY, Hong SH, Jeong JW, Park C, et al: Induction of apoptosis by ethanol extract of Citrus unshiu Markovich peel in human bladder cancer T24 cells through ROS-mediated inactivation of the PI3K/Akt pathway. Biosci Trends. 11:565–573. 2017. View Article : Google Scholar

20 

Kim MY, Choi EO, HwangBo H, Kwon DH, Ahn KI, Kim HJ, Ji SY, Hong SH, Jeong JW, Kim GY, et al: Reactive oxygen species-dependent apoptosis induction by water extract of Citrus unshiu peel in MDA-MB-231 human breast carcinoma cells. Nutr Res Pract. 12:129–134. 2018. View Article : Google Scholar

21 

Kim MY, Bo HH, Choi EO, Kwon DH, Kim HJ, Ahn KI, Ji SY, Jeong JW, Park SH, Hong SH, et al: Induction of apoptosis by Citrus unshiu peel in human breast cancer MCF-7 cells: Involvement of ROS-dependent activation of AMPK. Biol Pharm Bull. 41:713–721. 2018. View Article : Google Scholar

22 

Li AN, Li S, Zhang YJ, Xu XR, Chen YM and Li HB: Resources and biological activities of natural polyphenols. Nutrients. 6:6020–6047. 2014. View Article : Google Scholar

23 

Li S, Ma YM, Zheng PS and Zhang P: GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2. J Exp Clin Cancer Res. 37:802018. View Article : Google Scholar

24 

Al Bitar S and Gali-Muhtasib H: The role of the cyclin dependent kinase inhibitor p21cip1/waf1 in targeting cancer: Molecular mechanisms and novel therapeutics. Cancers (Basel). 11:E14752019. View Article : Google Scholar

25 

Fulda S and Debatin KM: Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 25:4798–4811. 2006. View Article : Google Scholar

26 

Llambi F and Green DR: Apoptosis and oncogenesis: Give and take in the BCL-2 family. Curr Opin Genet Dev. 21:12–20. 2011. View Article : Google Scholar

27 

Redza-Dutordoir M and Averill-Bates DA: Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta. 1863:2977–2992. 2016. View Article : Google Scholar

28 

Shin HJ, Han JM, Choi YS and Jung HJ: Pterostilbene suppresses both cancer cells and cancer stem-like cells in cervical cancer with superior bioavailability to resveratrol. Molecules. 25:E2282020. View Article : Google Scholar

29 

Jung N, Kwon HJ and Jung HJ: Downregulation of mitochondrial UQCRB inhibits cancer stem cell-like properties in glioblastoma. Int J Oncol. 52:241–251. 2018.

30 

Vafaee K, Dehghani S, Tahmasvand R, Saeed Abadi F, Irian S and Salimi M: Potent antitumor property of Allium bakhtiaricum extracts. BMC Complement Altern Med. 19:1162019. View Article : Google Scholar

31 

Yan Z, Feng J, Peng J, Lai Z, Zhang L, Jin Y, Yang H, Chen W and Lin J: Chloroform extract of Hedyotis diffusa Willd inhibits viability of human colorectal cancer cells via suppression of AKT and ERK signaling pathways. Oncol Lett. 14:7923–7930. 2017.

32 

Panche AN, Diwan AD and Chandra SR: Flavonoids: An overview. J Nutr Sci. 5:e472016. View Article : Google Scholar

33 

Parhiz H, Roohbakhsh A, Soltani F, Rezaee R and Iranshahi M: Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: An updated review of their molecular mechanisms and experimental models. Phytother Res. 29:323–331. 2015. View Article : Google Scholar

34 

Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, Zhang G, Wang X, Dong Z, Chen F, et al: Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 5:82020. View Article : Google Scholar

35 

Bielecka ZF, Maliszewska-Olejniczak K, Safir IJ, Szczylik C and Czarnecka AM: Three-dimensional cell culture model utilization in cancer stem cell research. Biol Rev Camb Philos Soc. 92:1505–1520. 2017. View Article : Google Scholar

36 

Liu XF, Yang WT, Xu R, Liu JT and Zheng PS: Cervical cancer cells with positive Sox2 expression exhibit the properties of cancer stem cells. PLoS One. 9:e870922014. View Article : Google Scholar

37 

Wang YD, Cai N, Wu XL, Cao HZ, Xie LL and Zheng PS: OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway. Cell Death Dis. 4:e7602013. View Article : Google Scholar

38 

Javed S, Sharma BK, Sood S, Sharma S, Bagga R, Bhattacharyya S, Rayat CS, Dhaliwal L and Srinivasan R: Significance of CD133 positive cells in four novel HPV-16 positive cervical cancer-derived cell lines and biopsies of invasive cervical cancer. BMC Cancer. 18:3572018. View Article : Google Scholar

39 

Krebsbach PH and Villa-Diaz LG: The role of integrin α6 (CD49f) in stem cells: More than a conserved biomarker. Stem Cells Dev. 26:1090–1099. 2017. View Article : Google Scholar

40 

Organista-Nava J, Gómez-Gómez Y, Garibay-Cerdenares OL, Leyva-Vázquez MA and Illades-Aguiar B: Cervical cancer stem cell-associated genes: Prognostic implications in cervical cancer. Oncol Lett. 18:7–14. 2019.

41 

Tomita H, Tanaka K, Tanaka T and Hara A: Aldehyde dehydrogenase 1A1 in stem cells and cancer. Oncotarget. 7:11018–11032. 2016. View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Choi Y, Han J, Kang Y and Jung H: Chloroform extract of <em>Citrus unshiu</em> Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells. Mol Med Rep 23: 86, 2021.
APA
Choi, Y., Han, J., Kang, Y., & Jung, H. (2021). Chloroform extract of <em>Citrus unshiu</em> Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells. Molecular Medicine Reports, 23, 86. https://doi.org/10.3892/mmr.2020.11727
MLA
Choi, Y., Han, J., Kang, Y., Jung, H."Chloroform extract of <em>Citrus unshiu</em> Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells". Molecular Medicine Reports 23.1 (2021): 86.
Chicago
Choi, Y., Han, J., Kang, Y., Jung, H."Chloroform extract of <em>Citrus unshiu</em> Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells". Molecular Medicine Reports 23, no. 1 (2021): 86. https://doi.org/10.3892/mmr.2020.11727
Copy and paste a formatted citation
x
Spandidos Publications style
Choi Y, Han J, Kang Y and Jung H: Chloroform extract of <em>Citrus unshiu</em> Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells. Mol Med Rep 23: 86, 2021.
APA
Choi, Y., Han, J., Kang, Y., & Jung, H. (2021). Chloroform extract of <em>Citrus unshiu</em> Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells. Molecular Medicine Reports, 23, 86. https://doi.org/10.3892/mmr.2020.11727
MLA
Choi, Y., Han, J., Kang, Y., Jung, H."Chloroform extract of <em>Citrus unshiu</em> Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells". Molecular Medicine Reports 23.1 (2021): 86.
Chicago
Choi, Y., Han, J., Kang, Y., Jung, H."Chloroform extract of <em>Citrus unshiu</em> Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells". Molecular Medicine Reports 23, no. 1 (2021): 86. https://doi.org/10.3892/mmr.2020.11727
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