Advertisement

Involvement of mitophagy-mediated cell death in colon cancer cells by folate-appended methyl-β-cyclodextrin

  • Khaled M. Elamin
  • Yuki Yamashita
  • Keiichi Motoyama
  • Taishi Higashi
  • Hidetoshi Arima
Original Article
  • 147 Downloads

Abstract

In recent years, colorectal cancer has gained great attention among various types of cancers. We previously synthesized folate-appended methyl-β-cyclodextrin (FA-M-β-CyD) as a novel autophagic antitumor agent. In this study, to further elucidate the impact of FA-M-β-CyD as an antitumor agent, we evaluated cytotoxic activity and the antiproliferative effect in colon cancer cells and colorectal cancer model mice, respectively. As a result, FA-M-β-CyD showed potent cytotoxic activity in HCT116 cells, a human colon cancer cell line, through folate receptor-α (FR-α)-mediated cellular uptake. In addition, FA-M-β-CyD elicited autophagosome formation and induced mitophagy in HCT116 cells. Importantly, FA-M-β-CyD drastically reduced the number of tumor polyps in colorectal cancer model mice induced by azoxymethane/dextran sodium sulfate after intravenous injections once a week for 4 weeks. These results suggest that FA-M-β-CyD has the antiproliferative effect in the colorectal cancer, due to the FR-α-mediated endocytosis and mitophagy induction.

Keywords

Folate receptor Methyl-β-cyclodextrin Colon cancer Autophagy Targeting 

Notes

Acknowledgements

This work was partially supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (16K08198), Center for Clinical and Translational Research of Kyushu University, and a Ministry of Health, Labor, and Welfare Grant-in-Aid for Third Term Comprehensive Control Research for Cancer program (24100701).

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest directly relevant to the content of this article.

References

  1. 1.
    Danhier, F., Feron, O., Preat, V.: To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J. Control. Release 148(2), 135–146 (2010). doi: 10.1016/j.jconrel.2010.08.027 CrossRefGoogle Scholar
  2. 2.
    Longley, D.B., Harkin, D.P., Johnston, P.G.: 5-Fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3(5), 330–338 (2003)CrossRefGoogle Scholar
  3. 3.
    Millimouno, F.M., Dong, J., Yang, L., Li, J., Li, X.: Targeting apoptosis pathways in cancer and perspectives with natural compounds from mother nature. Cancer Prev. Res. 7(11), 1081–1107 (2014). doi: 10.1158/1940-6207.CAPR-14-0136 CrossRefGoogle Scholar
  4. 4.
    Stein, A., Bokemeyer, C.: How to select the optimal treatment for first line metastatic colorectal cancer. World J. Gastroenterol. 20(4), 899–907 (2014). doi: 10.3748/wjg.v20.i4.899 CrossRefGoogle Scholar
  5. 5.
    Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F.: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136(5), E359–386 (2015). doi: 10.1002/ijc.29210 CrossRefGoogle Scholar
  6. 6.
    Haggar, F.A., Boushey, R.P.: Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin. Colon Rectal Surg. 22(4), 191–197 (2009). doi: 10.1055/s-0029-1242458 CrossRefGoogle Scholar
  7. 7.
    Amankwatia, E.B., Chakravarty, P., Carey, F.A., Weidlich, S., Steele, R.J., Munro, A.J., Wolf, C.R., Smith, G.: MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms. Br. J. Cancer 112(9), 1480–1490 (2015). doi: 10.1038/bjc.2015.125 CrossRefGoogle Scholar
  8. 8.
    Rajamanickam, S., Agarwal, R.: Natural products and colon cancer: current status and future prospects. Drug Dev. Res. 69(7), 460–471 (2008). doi: 10.1002/ddr.20276 CrossRefGoogle Scholar
  9. 9.
    Mattar, M.C., Lough, D., Pishvaian, M.J., Charabaty, A.: Current management of inflammatory bowel disease and colorectal cancer. Gastrointest. Cancer Res. 4(2), 53–61 (2011)Google Scholar
  10. 10.
    Tanaka, T.: Development of an inflammation-associated colorectal cancer model and its application for research on carcinogenesis and chemoprevention. Int. J. Inflamm. (2012). doi: 10.1155/2012/658786 Google Scholar
  11. 11.
    Coussens, L.M., Werb, Z.: Inflammation and cancer. Nature. 420(6917), 860–867 (2002)CrossRefGoogle Scholar
  12. 12.
    De Robertis, M., Massi, E., Poeta, M.L., Carotti, S., Morini, S., Cecchetelli, L., Signori, E., Fazio, V.M.: The AOM/DSS murine model for the study of colon carcinogenesis: from pathways to diagnosis and therapy studies. J. Carcinog. (2011). doi: 10.4103/1477-3163.78279 Google Scholar
  13. 13.
    Barderas, R., Villar-Vázquez, R., Fernández-Aceñero, M.J., Babel, I., Peláez-García, A., Torres, S., Casal, J.I.: Sporadic colon cancer murine models demonstrate the value of autoantibody detection for preclinical cancer diagnosis. Sci. Rep. 3, 2938 (2013). doi: 10.1038/srep02938 CrossRefGoogle Scholar
  14. 14.
    Kurkov, S.V., Loftsson, T.: Cyclodextrins. Int. J. Pharm. 453(1), 167–180 (2013). doi: 10.1016/j.ijpharm.2012.06.055 CrossRefGoogle Scholar
  15. 15.
    Zhang, J., Ma, P.X.: Cyclodextrin-based supramolecular systems for drug delivery: recent progress and future perspective. Adv. Drug Deliv. Rev. 65(9), 1215–1233 (2013). doi: 10.1016/j.addr.2013.05.001 CrossRefGoogle Scholar
  16. 16.
    Szabó, Z.I., Gáll, R., Gál, Z., Vancea, S., Rédai, E., Fülöp, I., Sipos, E., Donáth-Nagy, G., Noszál, B., Tóth G.: Cyclodextrin complexation improves aqueous solubility of the antiepileptic drug, rufinamide: solution and solid state characterization of compound-cyclodextrin binary systems. J. Incl. Phenom. Macrocycl. Chem. 88, 43–52 (2017). doi: 10.1007/s10847-017-0710-z CrossRefGoogle Scholar
  17. 17.
    Kiss, T., Fenyvesi, F., Bacskay, I., Varadi, J., Fenyvesi, E., Ivanyi, R., Szente, L., Tosaki, A., Vecsernyes, M.: Evaluation of the cytotoxicity of β-cyclodextrin derivatives: evidence for the role of cholesterol extraction. Eur. J. Pharm. Sci. 40(4), 376–380 (2010)CrossRefGoogle Scholar
  18. 18.
    Motoyama, K., Kameyama, K., Onodera, R., Araki, N., Hirayama, F., Uekama, K., Arima, H.: Involvement of PI3K-Akt-Bad pathway in apoptosis induced by 2,6-di-O-methyl-β-cyclodextrin, not 2,6-di-O-methyl-α-cyclodextrin, through cholesterol depletion from lipid rafts on plasma membranes in cells. Eur. J. Pharm. Sci. 38(3), 249–261 (2009). doi: 10.1016/j.ejps.2009.07.010 CrossRefGoogle Scholar
  19. 19.
    Onodera, R., Motoyama, K., Okamatsu, A., Higashi, T., Kariya, R., Okada, S., Arima, H.: Involvement of cholesterol depletion from lipid rafts in apoptosis induced by methyl-β-cyclodextrin. Int. J. Pharm. 452(1–2), 116–123 (2013). doi: 10.1016/j.ijpharm.2013.04.071 CrossRefGoogle Scholar
  20. 20.
    Grosse, P.Y., Bressolle, F., Pinguet, F.: Antiproliferative effect of methyl-β-cyclodextrin in vitro and in human tumour xenografted athymic nude mice. Br. J. Cancer 78(9), 1165–1169 (1998)CrossRefGoogle Scholar
  21. 21.
    Kameyama, K., Motoyama, K., Tanaka, N., Yamashita, Y., Higashi, T., Arima, H.: Induction of mitophagy-mediated antitumor activity with folate-appended methyl-β-cyclodextrin. Int. J. Nanomed. 12, 3433–3446 (2017). doi: 10.2147/IJN.S133482 CrossRefGoogle Scholar
  22. 22.
    Onodera, R., Motoyama, K., Arima, H.: Design and evaluation of folate-appended methyl-β-cyclodextrin as a new antitumor agent. J. Incl. Phenom. Macrocycl. Chem. 70(3–4), 321–326 (2010). doi: 10.1007/s10847-010-9843-z Google Scholar
  23. 23.
    Onodera, R., Motoyama, K., Okamatsu, A., Higashi, T., Arima, H.: Potential use of folate-appended methyl-β-cyclodextrin as an anticancer agent. Sci. Rep. 3, 1104 (2013). doi: 10.1038/srep01104 CrossRefGoogle Scholar
  24. 24.
    Onodera, R., Motoyama, K., Tanaka, N., Ohyama, A., Okamatsu, A., Higashi, T., Kariya, R., Okada, S., Arima, H.: Involvement of autophagy in antitumor activity of folate-appended methyl-β-cyclodextrin. Sci. Rep. 4, 4417 (2014). doi: 10.1038/srep04417 CrossRefGoogle Scholar
  25. 25.
    Kelemen, L.E.: The role of folate receptor α in cancer development, progression and treatment: cause, consequence or innocent bystander? Int. J. Cancer. 119(2), 243–250 (2006). doi: 10.1002/ijc.21712 CrossRefGoogle Scholar
  26. 26.
    Doherty, G.J., McMahon, H.T.: Mechanisms of endocytosis. Annu. Rev. Biochem. 78, 857–902 (2009). doi: 10.1146/annurev.biochem.78.081307.110540 CrossRefGoogle Scholar
  27. 27.
    Sato, K., Tsuchihara, K., Fujii, S., Sugiyama, M., Goya, T., Atomi, Y., Ueno, T., Ochiai, A., Esumi, H.: Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res. 67(20), 9677–9684 (2007). doi: 10.1158/0008-5472.can-07-1462 CrossRefGoogle Scholar
  28. 28.
    Yang, Z.J., Chee, C.E., Huang, S., Sinicrope, F.A.: The role of autophagy in cancer: therapeutic implications. Mol. Cancer Ther. 10(9), 1533–1541 (2011). doi: 10.1158/1535-7163.MCT-11-0047 CrossRefGoogle Scholar
  29. 29.
    Motoyama, K., Onodera, R., Tanaka, N., Kameyama, K., Higashi, T., Kariya, R., Okada, S., Arima, H.: Evaluation of antitumor effects of folate-conjugated methyl-β-cyclodextrin in melanoma. Biol. Pharm. Bull. 38(3), 374–379 (2015). doi: 10.1248/bpb.b14-00531 CrossRefGoogle Scholar
  30. 30.
    Ricci, M.S., Zong, W.-X.: Chemotherapeutic approaches for targeting cell death pathways. Oncologist 11(4), 342–357 (2006). doi: 10.1634/theoncologist.11-4-342 CrossRefGoogle Scholar
  31. 31.
    Cheng, Y., Ren, X., Hait, W.N., Yang, J.M.: Therapeutic targeting of autophagy in disease: biology and pharmacology. Pharmacol. Rev. 65(4), 1162–1197 (2013). doi: 10.1124/pr.112.007120 CrossRefGoogle Scholar
  32. 32.
    Tan, S., Wong, E.: Mitophagy transcriptome: mechanistic insights into polyphenol-mediated mitophagy. Oxid. Med. Cell. Longev. (2017). doi: 10.1155/2017/9028435 Google Scholar
  33. 33.
    Yoshimi, K., Hashimoto, T., Niwa, Y., Hata, K., Serikawa, T., Tanaka, T., Kuramoto, T.: Use of a chemically induced-colon carcinogenesis-prone Apc-mutant rat in a chemotherapeutic bioassay. BMC Cancer 12(1), 1–8 (2012). doi: 10.1186/1471-2407-12-448 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  • Khaled M. Elamin
    • 1
  • Yuki Yamashita
    • 1
    • 2
  • Keiichi Motoyama
    • 1
  • Taishi Higashi
    • 1
  • Hidetoshi Arima
    • 1
    • 2
  1. 1.Department of Physical Pharmaceutics, Graduate School of Pharmaceutical SciencesKumamoto UniversityKumamotoJapan
  2. 2.Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program”Kumamoto UniversityKumamotoJapan

Personalised recommendations