Nutrition Research and Practice

The Korean Nutrition Society (한국영양학회)
권호 표지
DOI QR코드

DOI QR Code

Combination of oxaliplatin and β-carotene suppresses colorectal cancer by regulating cell cycle, apoptosis, and cancer stemness in vitro

  • Junghyeun Lee (Department of Nutritional Science and Food Management, Ewha Womans University) ;
  • Seung Chul Heo (Department of Surgery, Seoul National University-Seoul Metropolitan Government (SNU-SMG) Boramae Medical Center) ;
  • Yuri Kim (Department of Nutritional Science and Food Management, Ewha Womans University)
  • Received : 2023.08.22
  • Accepted : 2023.12.06
  • Published : 2024.02.01
Download PDF
⟨ Previous Next ⟩

Abstract

BACKGROUND/OBJECTIVES: Colorectal cancer (CRC) is the third most common cancer worldwide with a high recurrence rate. Oxaliplatin (OXA) resistance is one of the major reasons hindering CRC therapy. β-Carotene (BC) is a provitamin A and is known to have antioxidant and anticancer effects. However, the combined effect of OXA and BC has not been investigated. Therefore, this study investigated the anticancer effects and mechanism of the combination of OXA and BC on CRC. MATERIALS/METHODS: In the present study, the effects of the combination of OXA and BC on cell viability, cell cycle arrest, and cancer stemness were investigated using HCT116, HT29, OXA-resistant cells, and human CRC organoids. RESULTS: The combination of OXA and BC enhanced apoptosis, G2/M phase cell cycle arrest, and inhibited cancer cell survival in human CRC resistant cells and CRC organoids without toxicity in normal organoids. Cancer stem cell marker expression and self-replicating capacity were suppressed by combined treatment with OXA and BC. Moreover, this combined treatment upregulated apoptosis and the stem cell-related JAK/STAT signaling pathway. CONCLUSIONS: Our results suggest a novel potential role of BC in reducing resistance to OXA, thereby enhances the anticancer effects of OXA. This enhancement is achieved through the regulation of cell cycle, apoptosis, and stemness in CRC.

Keywords

Acknowledgement

This research was supported by the BK21 FOUR (Fostering Outstanding Universities for Research) funded by the Ministry of Education (MOE, Korea) and National Research Foundation of Korea (NRF-5199990614253, Education Research Center for 4IR-Based Health Care).

References

  1. Jung KW, Won YJ, Kang MJ, Kong HJ, Im JS, Seo HG. Prediction of cancer incidence and mortality in Korea, 2022. Cancer Res Treat 2022;54:345-51. https://doi.org/10.4143/crt.2022.179
  2. Hammond WA, Swaika A, Mody K. Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol 2016;8:57-84. https://doi.org/10.1177/1758834015614530
  3. Nagourney RA, Evans S, Tran PH, Nagourney AJ, Sugarbaker PH. Colorectal cancer cells from patients treated with FOLFOX or CAPOX are resistant to oxaliplatin. Eur J Surg Oncol 2021;47:738-42. https://doi.org/10.1016/j.ejso.2020.09.017
  4. Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003;22:7265-79. https://doi.org/10.1038/sj.onc.1206933
  5. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med 2011;17:313-9. https://doi.org/10.1038/nm.2304
  6. Yang Z, Zhao N, Cui J, Wu H, Xiong J, Peng T. Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210. Cell Oncol (Dordr) 2020;43:123-36. https://doi.org/10.1007/s13402-019-00476-6
  7. Zhang HL, Wang P, Lu MZ, Zhang SD, Zheng L. c-Myc maintains the self-renewal and chemoresistance properties of colon cancer stem cells. Oncol Lett 2019;17:4487-93. https://doi.org/10.3892/ol.2019.10081
  8. Tang S, Yuan X, Song J, Chen Y, Tan X, Li Q. Association analyses of the JAK/STAT signaling pathway with the progression and prognosis of colon cancer. Oncol Lett 2019;17:159-64.
  9. Xiong W, Dong J, Kong S. Dentatin exerts anticancer effects on human colon cancer cell lines via cell cycle arrest, autophagy, inhibition of cell migration and JAK/STAT signalling pathway. J BUON 2019;24:1488-93.
  10. Houssein M, Abi Saab W, Khalil M, Khalife H, Fatfat M. Cell death by gallotannin is associated with inhibition of the JAK/STAT pathway in human colon cancer cells. Curr Ther Res Clin Exp 2020;92:100589.
  11. Taylor PR, Li B, Dawsey SM, Li JY, Yang CS, Guo W, Blot WJ. Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group. Cancer Res 1994;54:2029s-2031s.
  12. Palozza P, Serini S, Maggiano N, Angelini M, Boninsegna A, Di Nicuolo F, Ranelletti FO, Calviello G. Induction of cell cycle arrest and apoptosis in human colon adenocarcinoma cell lines by beta-carotene through downregulation of cyclin A and Bcl-2 family proteins. Carcinogenesis 2002;23:11-8. https://doi.org/10.1093/carcin/23.1.11
  13. Cui Y, Lu Z, Bai L, Shi Z, Zhao WE, Zhao B. Beta-carotene induces apoptosis and up-regulates peroxisome proliferator-activated receptor gamma expression and reactive oxygen species production in MCF-7 cancer cells. Eur J Cancer 2007;43:2590-601. https://doi.org/10.1016/j.ejca.2007.08.015
  14. Lim JY, Kim YS, Kim KM, Min SJ, Kim Y. B-carotene inhibits neuroblastoma tumorigenesis by regulating cell differentiation and cancer cell stemness. Biochem Biophys Res Commun 2014;450:1475-80. https://doi.org/10.1016/j.bbrc.2014.07.021
  15. Zhang X, Zhao WE, Hu L, Zhao L, Huang J. Carotenoids inhibit proliferation and regulate expression of peroxisome proliferators-activated receptor gamma (PPARγ) in K562 cancer cells. Arch Biochem Biophys 2011;512:96-106. https://doi.org/10.1016/j.abb.2011.05.004
  16. Ngoc NB, Lv P, Zhao WE. Suppressive effects of lycopene and β-carotene on the viability of the human esophageal squamous carcinoma cell line EC109. Oncol Lett 2018;15:6727-32.
  17. Lee HA, Park S, Kim Y. Effect of β-carotene on cancer cell stemness and differentiation in SK-N-BE(2)C neuroblastoma cells. Oncol Rep 2013;30:1869-77. https://doi.org/10.3892/or.2013.2643
  18. Lee KE, Kwon M, Kim YS, Kim Y, Chung MG, Heo SC, Kim Y. β-carotene regulates cancer stemness in colon cancer in vivo and in vitro. Nutr Res Pract 2022;16:161-72. https://doi.org/10.4162/nrp.2022.16.2.161
  19. Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc 2006;1:2315-9. https://doi.org/10.1038/nprot.2006.339
  20. Kim E, Shin JH, Seok PR, Kim MS, Yoo SH, Kim Y. Phyllodulcin, a natural functional sweetener, improves diabetic metabolic changes by regulating hepatic lipogenesis, inflammation, oxidative stress, fibrosis, and gluconeogenesis in db/db mice. J Funct Foods 2018;42:1-11. https://doi.org/10.1016/j.jff.2017.12.038
  21. Cristobal A, van den Toorn HWP, van de Wetering M, Clevers H, Heck AJR, Mohammed S. Personalized proteome profiles of healthy and tumor human colon organoids reveal both individual diversity and basic features of colorectal cancer. Cell Reports 2017;18:263-74. https://doi.org/10.1016/j.celrep.2016.12.016
  22. Michels BE, Mosa MH, Grebbin BM, Yepes D, Darvishi T, Hausmann J, Urlaub H, Zeuzem S, Kvasnicka HM, Oellerich T, et al. Human colon organoids reveal distinct physiologic and oncogenic Wnt responses. J Exp Med 2019;216:704-20. https://doi.org/10.1084/jem.20180823
  23. Howells LM, Mitra A, Manson MM. Comparison of oxaliplatin- and curcumin-mediated antiproliferative effects in colorectal cell lines. Int J Cancer 2007;121:175-83. https://doi.org/10.1002/ijc.22645
  24. Palozza P, Serini S, Maggiano N, Tringali G, Navarra P, Ranelletti FO, Calviello G. Beta-carotene downregulates the steady-state and heregulin-alpha-induced COX-2 pathways in colon cancer cells. J Nutr 2005;135:129-36. https://doi.org/10.1093/jn/135.1.129
  25. Upadhyaya KR, Radha KS, Madhyastha HK. Cell cycle regulation and induction of apoptosis by beta-carotene in U937 and HL-60 leukemia cells. J Biochem Mol Biol 2007;40:1009-15.
  26. Sowmya Shree G, Yogendra Prasad K, Arpitha HS, Deepika UR, Nawneet Kumar K, Mondal P, Ganesan P. β-carotene at physiologically attainable concentration induces apoptosis and down-regulates cell survival and antioxidant markers in human breast cancer (MCF-7) cells. Mol Cell Biochem 2017;436:1-12. https://doi.org/10.1007/s11010-017-3071-4
  27. Demols A, Peeters M, Polus M, Marechal R, Gay F, Monsaert E, Hendlisz A, Van Laethem JL. Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: a phase II study. Br J Cancer 2006;94:481-5. https://doi.org/10.1038/sj.bjc.6602966
  28. Kim D, Kim Y, Kim Y. Effects of β-carotene on expression of selected microRNAs, histone acetylation, and DNA methylation in colon cancer stem cells. J Cancer Prev 2019;24:224-32. https://doi.org/10.15430/JCP.2019.24.4.224
  29. Xiong H, Zhang ZG, Tian XQ, Sun DF, Liang QC, Zhang YJ, Lu R, Chen YX, Fang JY. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia 2008;10:287-97. https://doi.org/10.1593/neo.07971
  30. Aggarwal BB, Sethi G, Ahn KS, Sandur SK, Pandey MK, Kunnumakkara AB, Sung B, Ichikawa H. Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci 2006;1091:151-69. https://doi.org/10.1196/annals.1378.063
  31. Yu L, Li J, Xiao M. Picrocrocin exhibits growth inhibitory effects against SKMEL-2 human malignant melanoma cells by targeting JAK/STAT5 signaling pathway, cell cycle arrest and mitochondrial mediated apoptosis. J BUON 2018;23:1163-8.