Skip to main content

Advertisement

SpringerLink
Log in

Tumor-targeting Salmonella typhimurium A1-R overcomes nab-paclitaxel resistance in a cervical cancer PDOX mouse model

  • Gynecologic Oncology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Cervical cancer is a recalcitrant disease. To help overcome this problem, we previously established a patient-derived orthotopic xenograft (PDOX) model of cervical cancer. In the previous study, we found the tumor to be resistant to nab-paclitaxal (nab-PTX). We also previously developed the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R). The aim of the present study was to investigate the efficacy of S. typhimurium A1-R to overcome nab-PTX resistance in the cervical cancer PDOX model.

Methods

Cervical-cancer tumor fragments were implanted orthotopically into the neck of the uterus of nude mice. The cervical-cancer PDOX models were randomized into the following four groups after the tumor volume reached 60 mm3: G1: untreated group; G2: nab-PTX (i.v., 10 mg/kg, biweekly, 3 weeks); G3: Salmonella typhimurium A1-R (i.v., 5 × 107 CFU/body, weekly, 3 weeks); G4: nab-PTX combined with Salmonella typhimurium A1-R (nab-PTX, 10 mg/kg, i.v., biweekly, 3 weeks; S. typhimurium A1-R, 5 × 107 CFU/body, i.v., weekly, 3 weeks). Each group comprised eight mice. All mice were sacrificed on day 22. Tumor volume was measured on day 0 and day 22. Body weight was measured twice a week.

Results

Nab-PTX and Salmonella typhimurium A1-R did not show significant efficacy as monotherapy compared to the control group (P = 0.564 and P = 0.120, respectively). In contrast, nab-PTX combined with Salmonella typhimurium A1-R significantly suppressed tumor growth compared to the untreated control group and nab-PTX group (P < 0.001 and P = 0.026, respectively).

Conclusions

Salmonella typhimurium A1-R has potential future clinical application to overcome drug resistance in cervical cancer.

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

Similar content being viewed by others

References

  1. Wang CW, Wu TI, Yu CT et al (2009) Usefulness of p16 for differentiating primary pulmonary squamous cell carcinoma from cervical squamous cell carcinoma metastatic to the lung. Am J Clin Pathol 131:715–722

    Article  PubMed  Google Scholar 

  2. Hashimoto K, Yonemori K, Katsumata N et al (2011) Use of squamous cell carcinoma antigen as a biomarker of chemotherapy response in patients with metastatic cervical carcinoma. Eur J Obstet Gynecol Reprod Biol 159:394–398

    Article  CAS  PubMed  Google Scholar 

  3. Tewari KS, Sill MW, Long HJ et al (2014) Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370:734–743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Minion LE, Chase DM, Farley JH, Willmott LJ, Monk BJ (2016) Safety and efficacy of salvage nano-particle albumin bound paclitaxel in recurrent cervical cancer: a feasibility study. Gynecol Oncol Res Pract 3:4

    Article  PubMed  PubMed Central  Google Scholar 

  5. Monk BJ, Pandite LN (2011) Survival data from a phase II, open-label study of pazopanib or lapatinib monotherapy in patients with advanced and recurrent cervical cancer. J Clin Oncol 29:4845

    Article  PubMed  Google Scholar 

  6. Symonds RP, Gourley C, Davidson S et al (2015) Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol 16:1515–1524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li Y, Zeng J, Huang M, An J, Bai P, Wu L, Zhang R (2017) A phase 2 study of nanoparticle albumin-bound paclitaxel plus nedaplatin for patients with advanced, recurrent, or metastatic cervical carcinoma. Cancer 123(3):420–425

    Article  CAS  PubMed  Google Scholar 

  8. Boardman CH, Brady WE, Dizon DS, Kunos CA, Moore KN, Zanotti KM, Matthews C, Cosin JA, Aghajanian C, Fracasso PM (2018) A phase I evaluation of extended field radiation therapy with concomitant cisplatin chemotherapy followed by paclitaxel and carboplatin chemotherapy in women with cervical carcinoma metastatic to the para-aortic lymph nodes: an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. https://doi.org/10.1016/j.ygyno.2018.08.006

    Article  PubMed  PubMed Central  Google Scholar 

  9. Murakami T, Murata T, Kawaguchi K et al (2017) Cervical cancer patient-derived orthotopic xenograft (PDOX) is sensitive to cisplatinum and resistant to Nab-paclitaxel. Anticancer Res 37:61–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fu X, Le P, Hoffman RM (1993) A metastatic-orthotopic transplant nude mouse model of human patient breast cancer. Anticancer Res 13:901–904

    CAS  PubMed  Google Scholar 

  11. Fu X, Hoffman RM (1993) Human ovarian carcinoma metastatic models constructed in nude mice by orthotopic transplantation of histologically-intact patient specimens. Anticancer Res 13:283–286

    CAS  PubMed  Google Scholar 

  12. Wang X, Fu X, Hoffman RM (1992) A new patient-like metastatic model of human lung cancer constructed orthotopically with intact tissue via thoracotomy in immunodeficient mice. Int J Cancer 51:992–995

    Article  CAS  PubMed  Google Scholar 

  13. Murakami T, Kiyuna T, Kawaguchi K et al (2017) The irony of highly effective bacterial therapy of a patient-derived orthotopic xenograft (PDOX) model of Ewing's sarcoma, which was blocked by Ewing himself 80 years ago. Cell Cycle 16:1046–1052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fu X, Besterman JM, Monosov A et al (1991) Models of human metastatic colon cancer in nude mice orthotopically constructed by using histologically intact patient specimens. Proc Natl Acad Sci USA 88:9345–9349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Metildi CA, Kaushal S, Luiken GA et al (2014) Fluorescently-labeled chimeric anti-CEA antibody improves detection and resection of human colon cancer in a patient-derived orthotopic xenograft (PDOX) nude mouse model. J Surg Oncol 109:451–458

    Article  CAS  PubMed  Google Scholar 

  16. Furukawa T, Kubota T, Watanabe M et al (1993) Orthotopic transplantation of histologically intact clinical specimens of stomach cancer to nude mice: correlation of metastatic sites in mouse and individual patient donors. Int J Cancer 53:608–612

    Article  CAS  PubMed  Google Scholar 

  17. Fu X, Guadagni F, Hoffman RM (1992) A metastatic nude-mouse model of human pancreatic cancer constructed orthotopically with histologically intact patient specimens. Proc Natl Acad Sci USA 89:5645–5649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hiroshima Y, Zhang Y, Murakami T et al (2014) Efficacy of tumor targeting Salmonella typhimurium A1-R in combination with antiangiogenesis therapy on a pancreatic cancer patient-derived orthotopic xenograph (PDOX) and cell line mouse models. Oncotarget 5:12346–12357

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hiroshima Y, Maawy AA, Katz MH et al (2015) Selective efficacy of zoledronic acid on metastasis in a patient-derived orthotopicxenograph (PDOX) nude-mouse model of human pancreatic cancer. J Surg Oncol 111:311–315

    Article  CAS  PubMed  Google Scholar 

  20. Yamamoto M, Zhao M, Hiroshima Y et al (2016) Efficacy of tumor targeting Salmonella typhimurium A1-R on a melanoma patient derived orthotopic xenograft (PDOX) nude-mouse model. PLoS One 11:e0160882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kawaguchi K, Igarashi K, Murakami T et al (2017) Salmonella typhimurium A1-R targeting of a chemotherapy resistant BRAF-V600E melanoma in a patient-derived orthotopic xenograft (PDOX) model is enhanced in combination with either vemurafenib or temozlomide. Cell Cycle 16:1288–1294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kawaguchi K, Igarashi K, Murakami T et al (2017) Tumor-targeting Salmonella typhimurium A1-R sensitizes melanoma with a BRAF-V600E mutation to vemurafenib in a patient-derived orthotopic xenograft (PDOX) nude mouse model. J Cell Biochem 118:2314–2319

    Article  CAS  PubMed  Google Scholar 

  23. Murakami T, DeLong J, Eilber FC et al (2016) Tumor-targeting Salmonella typhimurium A1-R in combination with doxorubicin eradicate soft tissue sarcoma in a patient-derived orthotopic xenograft PDOX model. Oncotarget 7:12783–12790

    PubMed  PubMed Central  Google Scholar 

  24. Igarashi K, Kawaguchi K, Murakami T et al (2017) High efficacy of pazopanib on an undifferentiated spindle-cell sarcoma resistant to first-line therapy is identified with a patient-derived orthotopic xenograft (PDOX) nude mouse model. J Cell Biochem 118:2739–2743

    Article  CAS  PubMed  Google Scholar 

  25. Igarashi K, Kawaguchi K, Kiyuna T et al (2017) Temozolomide combined with irinotecan caused regression in an adult pleomorphic rhabdomyosarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 8:75874–75880

    PubMed  PubMed Central  Google Scholar 

  26. Igarashi K, Kawaguchi K, Murakami T et al (2017) Intra-arterial administration of tumor-targeting Salmonella typhimurium A1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model. Cell Cycle 16:1164–1170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kawaguchi K, Igarashi K, Murakami T et al (2017) Combination of gemcitabine and docetaxel regresses both gastric leiomyosarcoma proliferation and invasion in an imageable patient-derived orthotopic xenograft (iPDOX) model. Cell Cycle 16:1063–1069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kiyuna T, Murakami T, Tome Y et al (2016) High efficacy of tumor-targeting Salmonella typhimurium A1-R on a doxorubicin- and dactolisib-resistant follicular dendritic-cell sarcoma in a patient-derived orthotopic xenograft PDOX nude mouse model. Oncotarget 7:33046–33054

    Article  PubMed  PubMed Central  Google Scholar 

  29. Hoffman RM (2015) Patient-derived orthotopic xenografts: better mimic of metastasis than subcutaneous xenografts. Nat Rev Cancer 15:451–452

    Article  CAS  PubMed  Google Scholar 

  30. Hoffman RM (2016) Bacterial therapy of cancer: methods and protocols. In: Walker JM (ed) Methods in molecular biology 1409. Humana Press, New York

    Google Scholar 

  31. Hiroshima Y, Zhang Y, Zhao M et al (2015) Tumor-targeting Salmonella typhimurium A1-R in combination with trastuzumab eradicates HER-2-positive cervical cancer cells in patient derived mouse models. PLoS One 10:e0120358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48:452–458

    Article  CAS  PubMed  Google Scholar 

  33. Wang CZ, Kazmierczak RA, Eisenstark A (2016) Strains, mechanism, and perspective: Salmonella-based cancer therapy. Int J Microbiol 2016:5678702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liang K, Liu Q, Li P, Luo H, Wang H, Kong Q (2019) Genetically engineered Salmonella typhimurium: recent advances in cancer therapy. Cancer Lett 448:168–181

    Article  CAS  PubMed  Google Scholar 

  35. Yoon W, Park YC, Kim J, Chae YS, Byeon JH, Min SH, Park S, Yoo Y, Park YK, Kim BM (2017) Application of genetically engineered Salmonella typhimurium for interferon-gamma-induced therapy against melanoma. Eur J Cancer 70:48–61

    Article  CAS  PubMed  Google Scholar 

  36. Zhao M, Yang M, Li XM et al (2005) Tumor-targeting bacterial therapy with amino acid auxotrophs of GFP-expressing Salmonella typhimurium. Proc Natl Acad Sci USA 102:755–760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nagakura C, Hayashi K, Zhao M, Yamauchi K (2009) Efficacy of a genetically-modified Salmonella typhimurium in an orthotopic human pancreatic cancer in nude mice. Anticancer Res 29:1873–1878

    PubMed  Google Scholar 

  38. Liu F, Zhang L, Hoffman RM et al (2010) Vessel destruction by tumor-targeting Salmonella typhimurium A1-R is enhanced by high tumor vascularity. Cell Cycle 9:4518–4524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Murakami T, Hiroshima Y, Zhang Y et al (2018) Tumor-targeting Salmonella typhimurium A1-R promotes tumoricidal CD8(+) T cell tumor infiltration and arrests growth and metastasis in a syngeneic pancreatic-cancer orthotopic mouse model. J Cell Biochem 119:634–639

    Article  CAS  PubMed  Google Scholar 

  40. Yano S, Zhang Y, Zhao M et al (2014) Tumor-targeting Salmonella typhimurium A1-R decoys quiescent cancer cells to cycle as visualized by FUCCI imaging and become sensitive to chemotherapy. Cell Cycle 13:3958–3963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yano S, Takehara K, Zhao M et al (2015) Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging. Cell Cycle 15:1715–1723

    Article  CAS  Google Scholar 

  42. Kim JE, Phan TX, Nguyen VH, Dinh-Vu HV (2015) Salmonella typhimurium suppresses tumor growth via the pro-inflammatory cytokine interleukin-1β. Theranostics 5:1328–1342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. al-Ramadi BK, Fernandez-Cabezudo MJ, El-Hasasna H, Al-Salam S, Bashir G, Chouaib S (2009) Potent anti-tumor activity of systemically-administered IL2-expressing Salmonella correlates with decreased angiogenesis and enhanced tumor apoptosis. Clin Immunol 130:89–97

    Article  CAS  PubMed  Google Scholar 

  44. Kawaguchi K, Miyake K, Zhao M, Kiyuna T, Igarashi K, Miyake M, Higuchi T, Oshiro H, Bouvet M, Unno M, Hoffman RM (2018) Tumor targeting Salmonella typhimurium A1-R in combination with gemcitabine (GEM) regresses partially GEM-resistant pancreatic cancer patient-derived orthotopic xenograft (PDOX) nude mouse models. Cell Cycle 17(16):2019–2026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Vola M, Monaco A, Bascuas T, Rimsky G, Agorio CI, Chabalgoity JA et al (2018) TLR7 agonist in combination with Salmonella as an effective antimelanoma immunotherapy. Immunotherapy 10:665–679

    Article  CAS  PubMed  Google Scholar 

  46. Wen M, Zheng JH, Choi JM, Pei J, Li CH, Li SY, Kim IY, Lim SH, Jung TY, Moon KS, Min JJ, Jung S (2018) Genetically-engineered Salmonella typhimurium expressing TIMP-2 as a therapeutic intervention in an orthotopic glioma mouse model. Cancer Lett 433:140–146

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This paper is dedicated to the memory of A. R. Moossa, M.D., Sun Lee, M.D and Professor Li Jiaxi.

Author information

Authors and Affiliations

  1. AntiCancer Inc., San Diego, CA, USA

    Kentaro Miyake, Ming Zhao, Tasuku Kiyuna, Kei Kawaguchi, Kentaro Igarashi, Masuyo Miyake & Robert M. Hoffman

  2. Department of Surgery, University of California, San Diego, CA, USA

    Kentaro Miyake, Tasuku Kiyuna, Kei Kawaguchi, Kentaro Igarashi, Masuyo Miyake, Thinzar M. Lwin, Michael Bouvet & Robert M. Hoffman

  3. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Kentaro Miyake, Takashi Murakami, Masuyo Miyake & Itaru Endo

  4. Department of Obstetrics and Gynecology, Kawasaki Medical School, Okayama, Japan

    Takuya Murata & Koichiro Shimoya

  5. AntiCancer Japan Inc., Narita, Japan

    Chihiro Hozumi, Shin Komatsu & Takashi Kikuchi

  6. Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA

    Shree Ram Singh

Authors
  1. Kentaro Miyake
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takuya Murata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ming Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tasuku Kiyuna
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kei Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kentaro Igarashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masuyo Miyake
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thinzar M. Lwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chihiro Hozumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shin Komatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Takashi Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michael Bouvet
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Koichiro Shimoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Shree Ram Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Itaru Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Robert M. Hoffman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KM: Project development, data collection, data analysis, manuscript writing; TM, TM, MZ, TK, KK, KI, MM, TML, CH, SK, TK: data collection, data analysis; MB, KS, SRS, IE: data analysis; SRS : data analysis, manuscript writing and revision; RMH project development, data collection, data analysis, manuscript writing.

Corresponding authors

Correspondence to Takuya Murata, Michael Bouvet, Shree Ram Singh, Itaru Endo or Robert M. Hoffman.

Ethics declarations

Conflict of interest

KM, TK, KK, KI, MM and RMH are or were unsalaried associates of AntiCancer, Inc. MZ is an employee of AntiCancer Inc.. CH, SK and TK are unsalaried associates of AntiCancer Japan. AntiCancer Inc. and AntiCancer Japan use PDOX models for contract reserach. There are no other competing commercial interests.

Ethical approval

All animal studies were conducted in accordance with the principles and procedures outlined in the National Institutes of Health Guide for the Care and Use of Animals under Assurance Number A3873-1. For patient studies, an informed consent was obtained, and PDOX studies were approved by the Institutional Ethics Committee of Kawasaki Medical School.

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

Miyake, K., Murata, T., Murakami, T. et al. Tumor-targeting Salmonella typhimurium A1-R overcomes nab-paclitaxel resistance in a cervical cancer PDOX mouse model. Arch Gynecol Obstet 299, 1683–1690 (2019). https://doi.org/10.1007/s00404-019-05147-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-019-05147-3

Keywords

Search

Navigation