Skip to main content

Advertisement

SpringerLink
Log in

YSL-12, a novel microtubule-destabilizing agent, exerts potent anti-tumor activity against colon cancer in vitro and in vivo

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Microtubules play a central role in various fundamental cell functions and thus become an attractive target for cancer therapy. A novel compound YSL-12 is a combretastatin A-4 (CA-4) analogue with more stability. We investigated its anti-tumor activity and mechanisms in vitro and in vivo for the first time.

Methods

Cytotoxicity was evaluated by MTT method. In vitro microtubule polymerization assay was performed using a fluorescence-based method by multifunction fluorescence microplate reader. Intracellular microtubule network was detected by immunofluorescence method. Cell cycle analysis and apoptosis were measured by flow cytometry. Metabolic stability was recorded by liquid chromatography–ultraviolet detection and liquid chromatography–mass spectrometry. In vivo anti-tumor activity was assessed using HT-29 colon carcinoma xenografts established in BALB/c nude mice.

Results

YSL-12 displayed nanomolar-level cytotoxicity against various human cancer cell lines. A high selectivity toward normal cells and potent activity toward drug-resistant cells were also observed. YSL-12 was identified as tubulin polymerization inhibitor evidenced by effectively inhibits tubulin polymerization and heavily disrupted microtubule networks in living HT-29 cells. YSL-12 displayed potent disruption effect of pre-established tumor vasculature in vitro. In addition, YSL-12 treatment also caused cell cycle arrest in the G2/M phase and induced cell apoptosis in a dose-dependent manner. In vitro metabolic stability study revealed YSL-12 displayed considerable better stability than CA-4 in liver microsomes. In vivo, YSL-12 delayed tumor growth with 69.4 % growth inhibition.

Conclusions

YSL-12 is a promising microtubule inhibitor that has great potential for the treatment of colon carcinoma in vitro and in vivo and worth being a candidate for further development of cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Wade RH (2009) On and around microtubules: an overview. Mol Biotechnol 43(1073–6085):177–191

    Article  CAS  PubMed  Google Scholar 

  2. Horio T, Murata T (2014) The role of dynamic instability in microtubule organization. Front Plant Sci 5:511. doi:10.3389/fpls.2014.00511

    Article  PubMed  PubMed Central  Google Scholar 

  3. Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4(1474–175X):253–265

    Article  CAS  PubMed  Google Scholar 

  4. Lin CM, Singh SB, Chu PS, Dempcy RO, Schmidt JM, Pettit GR, Hamel E (1988) Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin: a structure-activity study. Mol Pharmacol 34(2):200–208

    CAS  PubMed  Google Scholar 

  5. Stanton RA, Gernert KM, Nettles JH, Aneja R (2011) Drugs that target dynamic microtubules: a new molecular perspective. Med Res Rev 31(3):443–481. doi:10.1002/med.20242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kingston DGI (2009) Tubulin-interactive natural products as anticancer agents. J Nat Prod 72(3):507–515. doi:10.1021/np800568j

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pettit GR, Sb Singh, Hamel E, Lin CM, Alberts DS, Garcia-Kendall D (1989) Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. Experientia 45(2):209–211

    Article  CAS  PubMed  Google Scholar 

  8. Cirla A, Mann J (2003) Combretastatins: from natural products to drug discovery. Nat Prod Rep 20(6):558–564

    Article  CAS  PubMed  Google Scholar 

  9. Bedford SBQ, Charmaine P, Rathbone Daniel L, Slack John A, Griffin Roger J, Stevens Malcolm F G (1996) Synthesis of water-soluble prodrugs of the cytotoxic agent combretastatin A4. Bioorg Med Chem Lett 6:157–160. doi:10.1016/0960-894X(95)00580-M

    Article  CAS  Google Scholar 

  10. Kaur R, Kaur G, Gill RK, Soni R, Bariwal J (2014) Recent developments in tubulin polymerization inhibitors: an overview. Eur J Med Chem 87:89–124. doi:10.1016/j.ejmech.2014.09.051

    Article  CAS  PubMed  Google Scholar 

  11. Woods JA, Hadfield JA, Pettit GR, Fox BW, McGown AT (1995) The interaction with tubulin of a series of stilbenes based on combretastatin A-4. Brit J Cancer 71(4):705–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Magalhães HIF, Bezerra DP, Cavalcanti BC, Wilke DV, Rotta R, Lima DP, Beatriz A, Alves APNN, Bitencourt DFS, Figueiredo IST, Alencar NMN, Costa-Lotufo LV, Moraes MO, Pessoa C (2010) In vitro and in vivo antitumor effects of (4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone. Cancer Chemother Pharmacol 68(1):45–52. doi:10.1007/s00280-010-1446-2

    Article  PubMed  Google Scholar 

  13. Siim BG, Lee AE, Shalal-Zwain S, Pruijn FB, McKeage MJ, Wilson WR (2003) Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Cancer Chemother Pharmacol 51(1):43–52. doi:10.1007/s00280-002-0529-0

    Article  CAS  PubMed  Google Scholar 

  14. Bonne D, Heuséle C, Simon C, Pantaloni D (1985) 4′,6-Diamidino-2-phenylindole, a fluorescent probe for tubulin and microtubules. J Biol Chem 260(5):2819–2825

    CAS  PubMed  Google Scholar 

  15. Diaz JF, Andreu JM (1993) Assembly of purified GDP-tubulin into microtubules induced by taxol and taxotere: reversibility, ligand stoichiometry, and competition. Biochemistry 32(11):2747–2755

    Article  CAS  PubMed  Google Scholar 

  16. Luconi M, Mannelli M (2012) Xenograft models for preclinical drug testing: implications for adrenocortical cancer. Mol Cell Endocrinol 351(1):71–77. doi:10.1016/j.mce.2011.09.043

    Article  CAS  PubMed  Google Scholar 

  17. Chen C-T, Gan Y, Au JLS, Wientjes MG (1998) Androgen-dependent and -independent human prostate xenograft tumors as models for drug activity evaluation. Cancer Res 58(13):2777–2783

    CAS  PubMed  Google Scholar 

  18. Ouyang L, Luo Y, Tian M, Zhang SY, Lu R, Wang JH, Kasimu R, Li X (2014) Plant natural products: from traditional compounds to new emerging drugs in cancer therapy. Cell Prolif 47(6):506–515. doi:10.1111/cpr.12143

    Article  CAS  PubMed  Google Scholar 

  19. Pettit GR, Rhodes MR, Herald DL, Chaplin DJ, Stratford MR, Hamel E, Pettit RK, Chapuis JC, Oliva D (1998) Antineoplastic agents 393. Synthesis of the trans-isomer of combretastatin A-4 prodrug. Anticancer Drug Des 13(8):981–993

    CAS  PubMed  Google Scholar 

  20. Ohsumi K, Hatanaka T, Fujita K, Nakagawa R, Fukuda Y, Nihei Y, Suga Y, Morinaga Y, Akiyama Y, Tsuji T (1998) Syntheses and antitumor activity of cis-restricted combretastatins: 5-Membered heterocyclic analogues. Bioorg Med Chem Lett 8(22):3153–3158. doi:10.1016/S0960-894X(98)00579-4

    Article  CAS  PubMed  Google Scholar 

  21. Qiao F, Zuo D, Shen X, Qi H, Wang H, Zhang W, Wu Y (2012) DAT-230, a novel microtubule inhibitor, exhibits potent anti-tumor activity by inducing G2/M phase arrest, apoptosis in vitro and perfusion decrease in vivo to HT-1080. Cancer Chemother Pharmacol 70(2):259–270. doi:10.1007/s00280-012-1907-x

    Article  CAS  PubMed  Google Scholar 

  22. Romagnoli R, Baraldi PG, Lopez-Cara C, Preti D, Aghazadeh Tabrizi M, Balzarini J, Bassetto M, Brancale A, Fu XH, Gao Y, Li J, Zhang SZ, Hamel E, Bortolozzi R, Basso G, Viola G (2013) Concise synthesis and biological evaluation of 2-Aroyl-5-amino benzo[b]thiophene derivatives as a novel class of potent antimitotic agents. J Med Chem 56(22):9296–9309. doi:10.1021/jm4013938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fojo AT, Menefee M (2005) Microtubule targeting agents: basic mechanisms of multidrug resistance (MDR). Semin Oncol Supplement 7:3–8. doi:10.1053/j.seminoncol.2005.09.010

    Article  Google Scholar 

  24. Perez EA (2009) Microtubule inhibitors: differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol Cancer Ther 8(8):2086–2095

    Article  CAS  PubMed  Google Scholar 

  25. Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4(4):253–265

    Article  CAS  PubMed  Google Scholar 

  26. Löwe J, Li H, Downing KH, Nogales E (2001) Refined structure of αβ-tubulin at 3.5 Å resolution1. J Mol Biol 313(5):1045–1057. doi:10.1006/jmbi.2001.5077

    Article  PubMed  Google Scholar 

  27. Catania KC, Remple FE (2005) Asymptotic prey profitability drives star-nosed moles to the foraging speed limit. Nature 433(7025):519–522. http://www.nature.com/nature/journal/v433/n7025/suppinfo/nature03250_S1.html

  28. Ahmed B, van Eijk LI, Bouma-ter Steege JCA, van der Schaft DWJ, van Esch AM, Joosten-Achjanie SR, Lambin P, Landuyt W, Griffioen AW (2003) Vascular targeting effect of combretastatin A-4 phosphate dominates the inherent angiogenesis inhibitory activity. Int J Cancer 105(1):20–25. doi:10.1002/ijc.11010

    Article  CAS  PubMed  Google Scholar 

  29. Vincent L, Kermani P, Young LM, Cheng J, Zhang F, Shido K, Lam G, Bompais-Vincent H, Zhu Z, Hicklin DJ, Bohlen P, Chaplin DJ, May C, Rafii S (2005) Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling. J Clin Invest 115(11):2992–3006. doi:10.1172/JCI24586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Goldar S, Khaniani MS, Derakhshan SM, Baradaran B (2015) Molecular mechanisms of apoptosis and roles in cancer development and treatment. Asian Pac J Cancer Prev 16(6):2129–2144. doi:10.7314/apjcp.2015.16.6.2129

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (81273518), the financial science and technology special competitive allocation project of Zhanjiang city (2014A01021, 2015A01025) and the Characteristic innovation Program for College of Education Department of Guangdong Province (2014KTSCX084).

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China

      De Cai, Zhiqing Qiu, Liming Xie & Zhixiu Lin

    2. Department of Respiratory Medical, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China

      Weimin Yao

    3. College of Pharmacy, Guangdong Medical University, Zhanjiang, China

      Yuyu Liu

    4. Department of Obstetrics and Gynecology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China

      Haixiang Huang

    5. Department of Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China

      Sihai Liao

    6. Department of Pharmacy, Central People’s Hospital of Zhanjiang, Zhanjiang, China

      Qun Luo

    Authors
    1. De Cai
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Zhiqing Qiu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Weimin Yao
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yuyu Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Haixiang Huang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Sihai Liao
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Qun Luo
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Liming Xie
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Zhixiu Lin
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to De Cai.

    Ethics declarations

    Conflicts of interest

    There are no conflicts of interest.

    Additional information

    De Cai and Zhiqing Qiu have contributed equally to this work.

    Liming Xie and Zhixiu Lin are co-corresponding authors.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Cai, D., Qiu, Z., Yao, W. et al. YSL-12, a novel microtubule-destabilizing agent, exerts potent anti-tumor activity against colon cancer in vitro and in vivo. Cancer Chemother Pharmacol 77, 1217–1229 (2016). https://doi.org/10.1007/s00280-016-3036-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00280-016-3036-4

    Keywords

    Search

    Navigation