Skip to main content

Advertisement

Springer Nature Link
Log in

The synergistic anticancer effects of ReoT3D, CPT-11, and BBI608 on murine colorectal cancer cells

  • Research article
  • Published:
DARU Journal of Pharmaceutical Sciences Aims and scope Submit manuscript

Abstract

Background

Many types of oncolytic viruses (OVs) were enrolled in clinical trials. Recently, an OV named Talimogene laherparepvec approved for the treatment of melanoma. This achievement highlighted the clinical application of OVs. Scientists focus on using these anticancer agents in combination with the current or/and new anticancer chemotherapeutics. They aim to increase the oncolytic effect of a new approach for the treatment of cancer cells.

Objectives

The present study aimed to assess the anticancer impacts of ReoT3D, irinotecan (CPT-11), and napabucasin (BBI608) against murine colorectal cancer cells (CT26). They are assessed alone and in combination with each other.

Methods

Here, oncolytic reovirus was propagated and titrated. Then MTT assay was carried out to assess the toxicity of this OV and chemotherapeutics effect on CT26 cells. The anticancer effects of ReoT3D, CPT-11, and BBI608, alone and simultaneously, on CT26 cell line, were assessed by the induction of apoptosis, cell cycle arrest, colony-forming, migration, and real-time PCR experiments.

Results

Alone treatment with ReoT3D, CPT-11, and BBI608 led to effectively inducing of apoptosis, cell cycle arrest, and apoptotic genes expression level and significantly reduce of colony-forming, migration, and anti-apoptotic genes expression rate. Importantly, the maximum anticancer effect against CT26 cell line was seen upon combination ReoT3D, CPT-11, and BBI608 treatment.

Conclusion

The present study highlights that combination of ReoT3D, CPT-11, and BBI560 showed synergistic anticancer activity against CT26 cell line. This modality might be considered as a new approach against colorectal cancer (CRC) in the in vivo and clinical trial investigations.

Graphical abstract

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

Data availability

Available upon the request.

Code availability

Not applicable.

References

  1. Cabasag CJ, Arnold M, Butler J, Inoue M, Trabert B, Webb PM, et al. The influence of birth cohort and calendar period on global trends in ovarian cancer incidence. Int J Cancer. 2020;146(3):749–58.

    CAS  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RG, Barzi A, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–93.

    PubMed  Google Scholar 

  3. Geng F, Wang Z, Yin H, Yu J, Cao B. Molecular targeted drugs and treatment of colorectal cancer: recent progress and future perspectives. Cancer Biother Radiopharm. 2017;32(5):149–60.

    CAS  PubMed  Google Scholar 

  4. Lawler SE, Speranza M-C, Cho C-F, Chiocca EA. Oncolytic viruses in cancer treatment: a review. JAMA Oncol. 2017;3(6):841–9.

    PubMed  Google Scholar 

  5. Food U, Administration D. FDA approves first-of-its-kind product for the treatment of melanoma. Silver Spring, MD 2015:611–619.

  6. Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014;2(4):295–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Goodarzi Z, Soleimanjahi H, Arefian E, Saberfar E. The effect of bovine rotavirus and its nonstructural protein 4 on ER stress-mediated apoptosis in HeLa and HT-29 cells. Tumour Biol. 2016;37(3):3155–61.

    CAS  PubMed  Google Scholar 

  8. Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: a new era of cancer treatment at dawn. Cancer Sci. 2016;107(10):1373–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Thirukkumaran C, Shi Z-Q, Thirukkumaran P, Luider J, Kopciuk K, Spurrell J, et al. PUMA and NF-kB are cell signaling predictors of reovirus oncolysis of breast cancer. PLoS One. 2017;12(1):e0168233.

    PubMed  PubMed Central  Google Scholar 

  10. Phillips MB, Stuart JD, Stewart RMR, Berry JT, Mainou BA, Boehme KW. Current understanding of reovirus oncolysis mechanisms. Oncolytic Virother. 2018;7:53–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Marcato P, Shmulevitz M, Lee PW. Connecting reovirus oncolysis and Ras signaling. Cell Cycle. 2005;4(4):556.

    CAS  PubMed  Google Scholar 

  12. Drerup JM, Liu Y, Padron AS, Murthy K, Hurez V, Zhang B, et al. Immunotherapy for ovarian cancer. Curr Treat Options in Oncol. 2015;16(1):1.

    Google Scholar 

  13. Smakman N, van den Wollenberg DJ, Rinkes IHB, Hoeben RC, Kranenburg O. Sensitization to apoptosis underlies KrasD12-dependent oncolysis of murine C26 colorectal carcinoma cells by reovirus T3D. J Virol. 2005;79(23):14981–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhao X, Chester C, Rajasekaran N, He Z, Kohrt HE. Strategic combinations: the future of oncolytic virotherapy with reovirus. Mol Cancer Ther. 2016;15(5):767–73.

    CAS  PubMed  Google Scholar 

  15. Villalona-Calero MA, Lam E, Otterson GA, Zhao W, Timmons M, Subramaniam D, et al. Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non–small cell lung cancer patients with K RAS-activated tumors. Cancer. 2016;122(6):875–83.

    CAS  PubMed  Google Scholar 

  16. Phan M, Watson MF, Alain T, Diallo J-S. Oncolytic viruses on drugs: achieving higher therapeutic efficacy. ACS Infect Dis. 2018;4(10):1448–67.

    CAS  PubMed  Google Scholar 

  17. Xu Y, Villalona-Calero M. Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol. 2002;13(12):1841–51.

    CAS  PubMed  Google Scholar 

  18. Prewett MC, Hooper AT, Bassi R, Ellis LM, Waksal HW, Hicklin DJ. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res. 2002;8(5):994–1003.

    CAS  PubMed  Google Scholar 

  19. Hubbard JM, Grothey A. Napabucasin: an update on the first-in-class cancer stemness inhibitor. Drugs. 2017;77(10):1091–103.

    CAS  PubMed  Google Scholar 

  20. Banijamali RS, Soleimanjahi H, Soudi S, Karimi H, Abdoli A, Seyed KS, et al. Kinetics of Oncolytic Reovirus T3D replication and growth pattern in Mesenchymal stem cells. Cell J. 2020;22(3):283–92.

    PubMed  Google Scholar 

  21. Smith RE, Zweerink H, Joklik WK. Polypeptide components of virions, top component and cores of reovirus type 3. Virology. 1969;39(4):791–810.

    CAS  PubMed  Google Scholar 

  22. Van Engeland M, Nieland LJ, Ramaekers FC, Schutte B, Reutelingsperger CP. Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry. 1998;31(1):1–9.

    PubMed  Google Scholar 

  23. Zhang G, Gurtu V, Kain SR, Yan G. Early detection of apoptosis using a fluorescent conjugate of annexin V. Biotechniques. 1997;23(3):525–31.

    CAS  PubMed  Google Scholar 

  24. Comins C, Heinemann L, Harrington K, Melcher A, De Bono J, Pandha H. Reovirus: viral therapy for cancer ‘as nature intended’. Clin Oncol. 2008;20(7):548–54.

    CAS  Google Scholar 

  25. Liu L-X, Zhang W-H, Jiang H-C. Current treatment for liver metastases from colorectal cancer. World J Gastroenterol. 2003;9(2):193–200.

    PubMed  PubMed Central  Google Scholar 

  26. Pandha HS, Heinemann L, Simpson GR, Melcher A, Prestwich R, Errington F, et al. Synergistic effects of oncolytic reovirus and cisplatin chemotherapy in murine malignant melanoma. Clin Cancer Res. 2009;15(19):6158–66.

    CAS  PubMed  Google Scholar 

  27. Maitra R, Seetharam R, Tesfa L, Augustine TA, Klampfer L, Coffey MC, et al. Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan. Oncotarget. 2014;5(9):2807–19.

    PubMed  PubMed Central  Google Scholar 

  28. Igase M, Hwang CC, Kambayashi S, Kubo M, Coffey M, Miyama TS, et al. Oncolytic reovirus synergizes with chemotherapeutic agents to promote cell death in canine mammary gland tumor. Can J Vet Res. 2016;80(1):21–31.

    PubMed  PubMed Central  Google Scholar 

  29. Mahalingam D, Goel S, Aparo S, Patel Arora S, Noronha N, Tran H, et al. A phase II study of pelareorep (REOLYSIN®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma. Cancers. 2018;10(6):160.

    PubMed Central  Google Scholar 

  30. Comins C, Spicer J, Protheroe A, Roulstone V, Twigger K, White CM, et al. REO-10: a phase I study of intravenous reovirus and docetaxel in patients with advanced cancer. Clin Cancer Res. 2010;16(22):5564–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Mahalingam D, Wilkinson GA, Eng KH, Fields P, Raber P, Moseley JL, et al. Pembrolizumab in combination with the Oncolytic virus Pelareorep and chemotherapy in patients with advanced pancreatic adenocarcinoma: a phase Ib study. Clin Cancer Res. 2020;26(1):71–81.

    CAS  PubMed  Google Scholar 

  32. Seetharam RN, Coffey MC, Klampfer L, Mariadason J, Goel S. The addition of Reolysin, an oncolytic reovirus, to irinotecan shows synergistic anticancer activity in colorectal cancer cell lines. AACR; 2010.

  33. Bahrami A, Amerizadeh F, ShahidSales S, Khazaei M, Ghayour-Mobarhan M, Sadeghnia HR, et al. Therapeutic potential of targeting Wnt/β-catenin pathway in treatment of colorectal cancer: rational and progress. J Cell Biochem. 2017;118(8):1979–83.

    CAS  PubMed  Google Scholar 

  34. Fuchs C, Mitchell EP, Hoff PM. Irinotecan in the treatment of colorectal cancer. Cancer Treat Rev. 2006;32(7):491–503.

    CAS  PubMed  Google Scholar 

  35. Beckham JD, Tuttle KD, Tyler KL. Caspase-3 activation is required for reovirus-induced encephalitis in vivo. J Neuro-Oncol. 2010;16(4):306–17.

    CAS  Google Scholar 

  36. Berger AK, Danthi P. Reovirus activates a caspase-independent cell death pathway. MBio. 2013;4(3):e00178–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Banijamali RS, Soleimanjahi H, Soudi S, Karimi H, Abdoli A, Khorrami SMS, et al. Kinetics of Oncolytic Reovirus T3D replication and growth pattern in Mesenchymal stem cells. Cell J. 2020;22(3):283–92.

    PubMed  Google Scholar 

  38. Tian J, Zhang X, Wu H, Liu C, Li Z, Hu X, et al. Blocking the PI3K/AKT pathway enhances mammalian reovirus replication by repressing IFN-stimulated genes. Front Microbiol. 2015;6:886.

    PubMed  PubMed Central  Google Scholar 

  39. Zhang Y, Jin Z, Zhou H, Ou X, Xu Y, Li H, et al. Suppression of prostate cancer progression by cancer cell stemness inhibitor napabucasin. Cancer Med. 2016;5(6):1251–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Siddiquee KAZ, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 2008;18(2):254–67.

    PubMed Central  Google Scholar 

  41. Bhonde M, Hanski M, Notter M, Gillissen B, Daniel P, Zeitz M, et al. Equivalent effect of DNA damage-induced apoptotic cell death or long-term cell cycle arrest on colon carcinoma cell proliferation and tumour growth. Oncogene. 2006;25(2):165–75.

    CAS  PubMed  Google Scholar 

  42. Bi S, Chen K, Feng L, Fu G, Yang Q, Deng M, et al. Napabucasin (BBI608) eliminate AML cells in vitro and in vivo via inhibition of Stat3 pathway and induction of DNA damage. Eur J Pharmacol. 2019;855:252–61.

    CAS  PubMed  Google Scholar 

  43. Poggioli GJ, Keefer C, Connolly JL, Dermody TS, Tyler KL. Reovirus-induced G2/M cell cycle arrest requires ς1s and occurs in the absence of apoptosis. J Virol. 2000;74(20):9562–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Twigger K, Vidal L, White CL, De Bono JS, Bhide S, Coffey M, et al. Enhanced in vitro and in vivo cytotoxicity of combined reovirus and radiotherapy. Clin Cancer Res. 2008;14(3):912–23.

    CAS  PubMed  Google Scholar 

  45. Kajstura M, Halicka HD, Pryjma J, Darzynkiewicz Z. Discontinuous fragmentation of nuclear DNA during apoptosis revealed by discrete “sub-G1” peaks on DNA content histograms. Cytometry Part A. 2007;71(3):125–31.

    Google Scholar 

Download references

Acknowledgements

We thank deputy of research, Tarbiat Modares University and National Institute for Medical Research Development (NIMAD) for financial supports.

Funding

This work was funded by of Tarbiat Modares University, Faculty of Medical Sciences (grant number: Med-76,015) and partially funded by National Institute for Medical Research Development (NIMAD) (grant number: 957970).

Author information

Authors and Affiliations

  1. Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Abouzar Babaei & Hoorieh Soleimanjahi

  2. Department of Hematology and cell therapy, Tarbiat Modares University, Tehran, Iran

    Masoud Soleimani

  3. Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran

    Ehsan Arefian

Authors
  1. Abouzar Babaei
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Hoorieh Soleimanjahi
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Masoud Soleimani
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Ehsan Arefian
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

AB has done all experiments, data collection & analysis and also wrote the original draft of the manuscript. HS has designed the work plan, supervised the whole study and edited the original draft. MS and EA were advisers for the present study that has done bioinformatics works and designed primers for the molecular experiment. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hoorieh Soleimanjahi.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Babaei, A., Soleimanjahi, H., Soleimani, M. et al. The synergistic anticancer effects of ReoT3D, CPT-11, and BBI608 on murine colorectal cancer cells. DARU J Pharm Sci 28, 555–565 (2020). https://doi.org/10.1007/s40199-020-00361-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40199-020-00361-w

Keywords

Profiles

  1. Abouzar Babaei View author profile
  2. Ehsan Arefian View author profile