Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 1, pp 179–189 | Cite as

Steroidal dimer by001 inhibits proliferation and migration of esophageal cancer cells via multiple mechanisms

  • Sai-Qi Wang
  • Kai-Rui Zhou
  • Xiao-Li Shi
  • Hui-Fang Lv
  • Liang-Yu Bie
  • Wei-Jie Zhao
  • Xiao-Bing ChenEmail author
Original Article



To investigate the potential inhibitory effects of structurally novel steroidal dimer by001 in esophageal cancer in vitro.


The cytotoxicity of by001 on esophageal, gastric, neuroblastoma and prostate cancer cells was examined MTT assay and colony formation assay. By001 induced apoptosis and production of intracellular reactive oxygen species on esophageal cancer cells Ec109, TE-1 and human normal gastric epithelial cells GES-1 was detected by flow cytometry. The effect of by001 on mitochondrial membrane potential was detected by fluorescence microscope through JC-1 staining. The level of intracellular reactive oxygen species was measured by fluorescence microscope and flow cytometry via DCFH-DA staining. The effect of by001 on members of Bcl-2 family, Fas, LC3, PARP and caspases was determined by Western blot. The effect of by001 on migration was measured by

transwell assay.


By001 effectively inhibited proliferation of esophageal, gastric, neuroblastoma and prostate cancer cells in a time- and concentration-dependent manner in vitro. By001 reduced the number and the size of colonies at low micromolar concentrations, elevated cellular ROS levels and caused mitochondrial dysfunction in esophageal cancer cells. Molecular mechanistic studies showed that by001 triggered apoptosis through regulating members of Bcl-2 family and Fas.


These findings suggested that by001 may inhibited proliferation of esophageal cancer cells through mitochondria and death receptor-mediated apoptotic pathways, autophagy induction, as well as suppressed migration of esophageal cancer cells.


Steroidal dimer Steroidal N-heterocycles Anti-proliferative activity Migration Esophageal cancer 



This study was supported by the Natural Science Foundation of China (Grant number 81472714) and the Key Medical Technologies Research and Development Program of Henan Provence (Grant number 201502027).

Compliance with ethical standards

Conflict of interest

Author Sai-Qi Wang declares that she has no conflict of interest. Author Kai-Rui Zhou declares that she has no conflict of interest. Author Xiao-Li Shi declares that she has no conflict of interest. Author Hui-Fang Lv declares that she has no conflict of interest. Author Liang-Yu Bie declares that he has no conflict of interest. Author Wei-Jie Zhao declares that he has no conflict of interest. Author Xiao-Bing Chen declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Gupta A, Kumar BS, Negi AS (2013) Current status on development of steroids as anticancer agents. J Steroid Biochem Mol Biol 13(1):242–270. CrossRefGoogle Scholar
  2. 2.
    Salvador JA, Carvalho JF, Neves MA, Silvestre SM, Leitao AJ, Silva MM, Sa EMM (2013) Anticancer steroids: linking natural and semi-synthetic compounds. Nat Prod Rep 30(2):324–374. CrossRefGoogle Scholar
  3. 3.
    Gupta P, Panda G (2014) Asymmetric assembly of steroidal tetracyclic skeletons. Eur J Org Chem 2014(36):8004–8019. CrossRefGoogle Scholar
  4. 4.
    Singh R, Panda G (2013) An overview of synthetic approaches for heterocyclic steroids. Tetrahedron 69(14):2853–2884. CrossRefGoogle Scholar
  5. 5.
    Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE (2013) Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368(2):138–148. CrossRefGoogle Scholar
  6. 6.
    Njar VC, Brodie AM (2015) Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer. J Med Chem 58(5):2077–2087. CrossRefGoogle Scholar
  7. 7.
    Purushottamachar P, Godbole AM, Gediya LK, Martin MS, Vasaitis TS, Kwegyir-Afful AK, Ramalingam S, Ates-Alagoz Z, Njar VC (2013) Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer. J Med Chem 56(12):4880–4898. CrossRefGoogle Scholar
  8. 8.
    Moser BR (2008) Review of cytotoxic cephalostatins and ritterazines: isolation and synthesis. J Nat Prod 71(3):487–491. CrossRefGoogle Scholar
  9. 9.
    Li Y, Dias JR (1997) Dimeric and oligomeric steroids. Chem Rev 97(1):283–304. CrossRefGoogle Scholar
  10. 10.
    Nahar L, Sarker SD, Turner AB (2007) A review on synthetic and natural steroid dimers: 1997–2006. Curr Med Chem 14(12):1349–1370. CrossRefGoogle Scholar
  11. 11.
    Krstic NM, Matic IZ, Juranic ZD, Novakovic IT, Sladic DM (2014) Steroid dimers-in vitro cytotoxic and antimicrobial activities. J Steroid Biochem Mol Biol 143(9):365–375. CrossRefGoogle Scholar
  12. 12.
    Yu B, Shi XJ, Zheng YF, Fang Y, Zhang E, Yu DQ, Liu HM (2013) A novel [1,2,4] triazolo [1,5-a] pyrimidine-based phenyl-linked steroid dimer: synthesis and its cytotoxic activity. Eur J Med Chem 69(15):323–330. CrossRefGoogle Scholar
  13. 13.
    Yu B, Shi XJ, Qi PP, Yu DQ, Liu HM (2014) Design, synthesis and biological evaluation of novel steroidal spiro-oxindoles as potent antiproliferative agents. J Steroid Biochem Mol Biol 141(1):121–134. CrossRefGoogle Scholar
  14. 14.
    Yu B, Qi PP, Shi XJ, Shan LH, Yu DQ, Liu HM (2014) Discovery of novel steroidal pyran–oxindole hybrids as cytotoxic agents. Steroids 88(5):44–52. CrossRefGoogle Scholar
  15. 15.
    Yu B, Qi PP, Shi XJ, Huang R, Guo H, Zheng YC, Yu DQ, Liu HM (2016) Efficient synthesis of new antiproliferative steroidal hybrids using the molecular hybridization approach. Eur J Med Chem 117:241–255. CrossRefGoogle Scholar
  16. 16.
    Huang LH, Zheng YF, Lu YZ, Song CJ, Wang YG, Yu B, Liu HM (2012) Synthesis and biological evaluation of novel steroidal[17,16-d][1,2,4]triazolo[1,5-a]pyrimidines. Steroids 77(6):710–715. CrossRefGoogle Scholar
  17. 17.
    Yu B, Sun XN, Shi XJ, Qi PP, Fang Y, Zhang E, Yu DQ, Liu HM (2013) Stereoselective synthesis of novel antiproliferative steroidal (E, E) dienamides through a cascade aldol/cyclization process. Steroids 78(11):1134–1140. CrossRefGoogle Scholar
  18. 18.
    Yu B, Zhang E, Sun XN, Ren JL, Fang Y, Zhang BL, Yu DQ, Liu HM (2013) Facile synthesis of novel D-ring modified steroidal dienamides via rearrangement of 2H-pyrans. Steroids 78(5):494–499. CrossRefGoogle Scholar
  19. 19.
    Zhang BL, Zhang E, Pang LP, Song LX, Li YF, Yu B, Liu HM (2013) Design and synthesis of novel D-ring fused steroidal heterocycles. Steroids 78(12–13):1200–1208. CrossRefGoogle Scholar
  20. 20.
    Zhang YL, Li YF, Shi YK, Yu B, Zhang GC, Qi PP, Fu DJ, Shan LH, Liu HM (2015) Efficient three-component one-pot synthesis of steroidal polysubstituted anilines. Steroids 104:1–7. CrossRefGoogle Scholar
  21. 21.
    Yu B, Sun X, Shi X, Qi P, Zheng Y, Yu D, Liu H (2015) Efficient synthesis of novel antiproliferative steroidal spirooxindoles via the [3 + 2] cycloaddition reactions of azomethine ylides. Steroids 102:92–100. CrossRefGoogle Scholar
  22. 22.
    Wang SQ, Wang C, Chang LM, Zhou KR, Wang JW, Ke Y, Yang DX, Shi HG, Wang R, Shi XL, Ma LY, Liu HM (2016) Geridonin and paclitaxel act synergistically to inhibit the proliferation of gastric cancer cells through ROS-mediated regulation of the PTEN/PI3K/Akt pathway. Oncotarget 7(45):72990–73002. Google Scholar
  23. 23.
    Wang SQ, Wang C, Wang JW, Yang DX, Wang R, Wang CJ, Li HJ, Shi HG, Ke Y, Liu HM (2017) Geridonin, a novel derivative of oridonin, inhibits proliferation of MGC 803 cells both in vitro and in vivo through elevating the intracellular ROS. J Pharm Pharmacol 69(2):213–221. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou UniversityHenan Cancer HospitalZhengzhouChina
  2. 2.School of Pharmaceutical Sciences and Collaborative Innovation Center of New Drug Research and Safety Evaluation, Key Laboratory of Henan Province for Drug Quality and EvaluationZhengzhou UniversityZhengzhouChina
  3. 3.Department of PharmacyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
  4. 4.Department of General SurgeryThe Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer HospitalZhengzhouChina

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