Advertisement

Archives of Pharmacal Research

, Volume 39, Issue 6, pp 825–832 | Cite as

Characterization of the cytotoxic activity of [2]rotaxane (TRO-A0001), a novel supramolecular compound, in cancer cells

  • Yoshihiko Fujita
  • Masahiko Kimura
  • Hiroki Sato
  • Toshikazu Takata
  • Nobufumi Ono
  • Kazuto NishioEmail author
Research Article

Abstract

Rotaxanes comprise a class of interlocked molecules containing a wheel threaded onto an axle with blocking groups on the ends to keep the wheel from sliding off. Here, we show that [2][bis(2-(3,5-dimethylphenylcarbonyloxy)ethyl) ammoniumtrifluoromethanesulfonate]-[dibenzo-24-crown-8] rotaxane (TRO-A0001), a rotaxane compound, exerted a growth inhibitory effect on several human cancer cell lines. An MTT assay revealed an IC50 of 14-830 nM for TRO-A0001 in these cells. Neither the wheel nor the axle part alone inhibited tumor cell growth, suggesting that the complete rotaxane molecule with its unique “intramolecular mobility” is required to inhibit cell growth. Annexin-V/PI staining provided evidence of the induction of apoptosis, which was further confirmed by the observation of poly (ADP-ribose) polymerase cleavage. Furthermore, a cell cycle analysis using flow cytometry showed that TRO-A0001 treatment resulted in G1 arrest in glioblastoma T98G and melanoma G361 cells. An immunoblot analysis revealed that in both cell lines, TRO-A0001 treatment caused the induction of p21/Cip1, thereby down-regulating Cdks 2, 4 and 6 and reducing Cyclins D1 and E. The results presented in this study demonstrate cytotoxicity of the rotaxane compound and its potential as a lead compound for the development of a chemotherapeutic agent against cancer.

Keywords

Rotaxane Supramolecular compound Cancer G1 cell-cycle arrest p21/Cip1 Apoptosis 

Notes

Acknowledgments

This work was supported by the Grant-in-Aid for Scientific Research (C) (Grant No. 25350979) of Ministry of Education, Culture, Sports, Science and Technology of Japan. We thank Kurashimo S. and Kitayama T. for technical support and Marco A. De Velasco for critically reading the manuscript.

Compliance with ethical standards

Conflict of interest

All authors have no conflicts of interest to disclose.

References

  1. Balzani VV, Credi A, Raymo FM, Stoddart JF (2000) Artificial molecular machines. Angew Chem Int Ed 39:3348–3391CrossRefGoogle Scholar
  2. Bao X, Isaacsohn I, Drew AF, Smithrud DB (2006) Determining the intracellular transport mechanism of a cleft-[2]rotaxane. J Am Chem Soc 128:12229–12238CrossRefPubMedGoogle Scholar
  3. Carlson B, Lahusen T, Singh S, Loaiza-Perez A, Worland PJ, Pestell R, Albanese C, Sausville EA, Senderowicz AM (1999) Down-regulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res 59:4634–4641PubMedGoogle Scholar
  4. Chambron JC, Sauvage JP, Mislow K, De Cian A, Fischer J (2001) A [2]catenane and a [2]rotaxane as prototypes of topological and Euclidean molecular “rubber gloves”. Chemistry 7:4085–4096CrossRefPubMedGoogle Scholar
  5. Fujita Y, Islam R, Sakai K, Kaneda H, Kudo K, Tamura D, Aomatsu K, Nagai T, Kimura H, Matsumoto K, de Velasco MA, Arao T, Okawara T, Nishio K (2012) Aza-derivatives of resveratrol are potent macrophage migration inhibitory factor inhibitors. Invest New Drugs 30:1876–1878CrossRefGoogle Scholar
  6. Hara K, Beppu T, Kimura M, Fujita Y, Takata T, Nishio K, Ono N (2013) Influence of novel supramolecular substace, [2]Rotaxane, on the caspase signaling pathway in melanoma and colon cancer cells in vitro. J Pharmacol Sci 122:153–157CrossRefPubMedGoogle Scholar
  7. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62CrossRefPubMedGoogle Scholar
  8. Kihara N, Koike Y, Takata T (2007) Effect of steric Barrier on the shuttling of rotaxane having crown ether wheel. Chem Lett 36:208–209CrossRefGoogle Scholar
  9. Kimura M, Makio K, Hara K, Hiruma W, Fujita Y, Takata T, Nishio K, Ono N (2014) A supramolecular substace, [2]Rotaxane, induces apoptosis in human Molt-3 acute lymphoblastic leukemia cells. Drug Res. doi: 10.1055/s-0034-1395628 Google Scholar
  10. Malik A, Afaq F, Sarfaraz S, Adhami VM, Syed DN, Mukhtar H (2005) Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci USA 102:14813–14818CrossRefPubMedPubMedCentralGoogle Scholar
  11. Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK (2004) Pathology: cancer cells compress intratumour vessels. Nature 427:695CrossRefPubMedGoogle Scholar
  12. Pavletich NP (1999) Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J Mol Biol 287:821–828CrossRefPubMedGoogle Scholar
  13. Shi J, Xu Y, Wang X, Zhang L, Zhu J, Pang T, Bao X (2015) Synthesis and evaluation of a novel Rhodamine B pyrene [2] rotaxane as an intracellular delivery agent for doxorubicin. Org Biomol Chem 13:7517–7529CrossRefPubMedGoogle Scholar
  14. Tanaka K, Arao T, Maegawa M, Matsumoto K, Kaneda H, Kudo K, Fujita Y, Yokote H, Yanagihara K, Yamada Y, Okamoto I, Nakagawa K, Nishio K (2009) SRPX2 is overexpressed in gastric cancer and promotes cellular migration and adhesion. Int J Cancer 124:1072–1080CrossRefPubMedGoogle Scholar
  15. Uemura T, Moritake K, Akiyama Y, Kimura Y, Shingu T, Yamasaki T (2002) Experimental validation of deuterium oxide—mediated antitumoral activity as it relates to apoptosis in murine malignant astrocytoma cells. J Neurosurg 96:900–908CrossRefPubMedGoogle Scholar
  16. Wang X, Smithrud DB (2011) Pt-rotaxanes as cytotoxic agents. Bioorg Med Chem Lett 21:6880–6883CrossRefPubMedGoogle Scholar
  17. Yun JM, Kweon MH, Kwon H, Hwang K, Mukhtar H (2006) Induction of apoptosis and cell cycle arrest by a chalcone panduratin A isolated from Kaempferia pandurata in androgen-independent human prostate cancer cells PC3 and DU145. Carcinogenesis 27:1454–1464CrossRefPubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2016

Authors and Affiliations

  • Yoshihiko Fujita
    • 1
  • Masahiko Kimura
    • 2
  • Hiroki Sato
    • 3
  • Toshikazu Takata
    • 3
  • Nobufumi Ono
    • 4
  • Kazuto Nishio
    • 1
    Email author
  1. 1.Department of Genome BiologyKinki University Faculty of MedicineOsakaJapan
  2. 2.Medicinal-Informatics and Research Unit, Faculty of Pharmaceutical SciencesFukuoka UniversityFukuokaJapan
  3. 3.Department of Organic and Polymeric MaterialsTokyo Institute of TechnologyTokyoJapan
  4. 4.Miki Health Science Research InstituteFukuokaJapan

Personalised recommendations