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Synergistic anti-tumor effect of paclitaxel and miR-34a combined with ultrasound microbubbles on cervical cancer in vivo and in vitro

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Abstract

Purpose

Improved therapeutic options for cervical cancer are needed. The purpose of this study was to evaluate the synergetic, inhibitory effects of ultrasound-mediated paclitaxel (PTX)- and miR-34a-loaded microbubbles (MBs) on cervical cancer.

Methods

U14 cervical cancer cells and xenograft mouse tumors were treated with PTX-miR-34a-MBs.

Results

Levels of miR-34a increased in vitro and vivo after treatment with ultrasound-mediated PTX-miR-34a-MBs. Furthermore, this treatment decreased the proliferation of cervical cancer cells, microvessel density, and the expression of Bcl-2 and CDK6, both in vitro and in vivo. Furthermore, Bax expression was increased in the in vivo model. And, tumor volume and weight were significantly reduced by 78.57% and 87.97%, respectively (P < 0.01).

Conclusions

These results indicate that ultrasound-mediated PTX-miR-34a-MBs synergistically inhibit the growth of cervical cancer via the upregulation of miR-34a and downregulation of Bcl-2 and CDK6. Thus, PTX-miR-34a-MBs in combination with ultrasound microbubbles are a promising anticancer delivery strategy for treating cervical cancer.

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References

  1. Koh WJ, Greer BE, Abu-Rustum NR, Apte SM, Campos SM, Cho KR, Chu C, Cohn D, Crispens MA, Dorigo O, Eifel PJ. Cervical Cancer, Version 2.2015. J Natl Compr Cancer Netw. 2015;13:395–404.

    Article  CAS  Google Scholar 

  2. Filipi K, Xhani A. Assessment of cervical cytological data in Albanian females. Asian Pac J Cancer Prev. 2014;15:2129–32.

    Article  Google Scholar 

  3. Tungsrithong N, Kasinpila C, Maneenin C, Namujju PB, Lehtinen M, Anttila A, Promthet S. Lack of significant effects of Chlamydia trachomatis infection on cervical cancer risk in a nested case-control study in North-East Thailand. Asian Pac J Cancer Prev. 2014;15:1497–500.

    Article  Google Scholar 

  4. Zhou X, Gu Y, Zhang SL. Association between p53 codon 72 polymorphism and cervical cancer risk among Asians: a HuGE review and meta-analysis. Asian Pac J Cancer Prev. 2012;13:4909–14.

    Article  Google Scholar 

  5. Green JA, Kirwan JJ, Tierney J, Vale CL, Symonds PR, Fresco LL, Williams C, Collingwood M. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev. 2005;3:2476–9.

    Google Scholar 

  6. Takai N, Kira N, Ishii T, Nishida M, Nasu K, Narahara H. Novel chemotherapy using histone deacetylase inhibitors in cervical cancer. Asian Pac J Cancer Prev. 2011;12:575–80.

    PubMed  Google Scholar 

  7. Lu QL, Liang HD, Partridge T, Blomley MJ. Microbubble ultrasound improves the efficiency of gene transduction in skeletal muscle in vivo with reduced tissue damage. Gene Ther. 2003;10:396–405.

    Article  CAS  Google Scholar 

  8. Bekeredjian R, Kuecherer HF, Kroll RD, Katus HA, Hardt SE. Ultrasound-targeted microbubble destruction augments protein delivery into testes. Urology. 2007;69:386–9.

    Article  Google Scholar 

  9. Bolhassani A, Safaiyan S, Rafati S. Improvement of different vaccine delivery systems for cancer therapy. Mol Cancer. 2011;10:3.

    Article  CAS  Google Scholar 

  10. Geis NA, Mayer CR, Kroll RD, Hardt SE, Katus HA, Bekeredjian R. Spatial distribution of ultrasound targeted microbubble destruction increases cardiac transgene expression but not capillary permeability. Ultrasound Med Biol. 2009;35:1119–26.

    Article  Google Scholar 

  11. Wang TY, Choe JW, Pu K, Devulapally R, Bachawal S, Machtaler S, Chowdhury SM, Luong R, Tian L, Khuri-Yakub B, Rao J. Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer. J Control Release. 2015;203:99–108.

    Article  CAS  Google Scholar 

  12. Hou Z, Li L, Zhan C, Zhu P, Chang D, Jiang Q, Ye S, Yang X, Li Y, Xie L, Zhang Q. Preparation and in vitro evaluation of an ultrasound-triggered drug delivery system: 10-Hydroxycamptothecin loaded PLA microbubbles. Ultrasonics. 2012;52:836–41.

    Article  CAS  Google Scholar 

  13. Liu L, Chang S, Sun J, Zhu S, Yin M, Zhu Y, Wang Z, Xu RX. Ultrasound-mediated destruction of paclitaxel and oxygen loaded lipid microbubbles for combination therapy in ovarian cancer xenografts. Cancer Lett. 2015;361:147–54.

    Article  CAS  Google Scholar 

  14. Couto M, Cates C. Laboratory guidelines for animal care. Methods Mol Biol. 2019;1920:407–30.

    Article  CAS  Google Scholar 

  15. Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst. 1992;84:1875–87.

    Article  CAS  Google Scholar 

  16. Jin H, Pan Y, He L, Zhai H, Li X, Zhao L, Sun L, Liu J, Hong L, Song J, Xie H. p75 neurotrophin receptor inhibits invasion and metastasis of gastric cancer. Mol Cancer Res. 2007;5:423–33.

    Article  CAS  Google Scholar 

  17. Iwanaga K, Tominaga K, Yamamoto K, Habu M, Maeda H, Akifusa S, Tsujisawa T, Okinaga T, Fukuda J, Nishihara T. Local delivery system of cytotoxic agents to tumors by focused sonoporation. Cancer Gene Ther. 2007;14:354–63.

    Article  CAS  Google Scholar 

  18. Chen Z, Xie M, Wang X, Lv Q, Ding S. Efficient gene delivery to myocardium with ultrasound targeted microbubble destruction and polyethylenimine. J Huazhong Univ Sci Technol Med Sci. 2008;28:613–7.

    Article  CAS  Google Scholar 

  19. Yang D, Gao YH, Tan KB, Zuo ZX, Yang WX, Hua X, Li PJ, Zhang Y, Wang G. Inhibition of hepatic fibrosis with artificial microRNA using ultrasound and cationic liposome-bearing microbubbles. Gene Ther. 2013;20:1140–8.

    Article  CAS  Google Scholar 

  20. Wang P, Yin T, Li J, Zheng B, Wang X, Wang Y, Zheng J, Zheng R, Shuai X. Ultrasound-responsive microbubbles for sonography-guided siRNA delivery. Nanomedicine. 2016;12:1139–49.

    Article  CAS  Google Scholar 

  21. Hwang SJ, Shroyer KR. Biomarkers of cervical dysplasia and carcinoma. J Oncol. 2012;2012:507286.

    Article  Google Scholar 

  22. Kong YW, Ferland-McCollough D, Jackson TJ, Bushell M. microRNAs in cancer management. Lancet Oncol. 2012;13:249–58.

    Article  Google Scholar 

  23. Malumbres M. miRNAs versus oncogenes: the power of social networking. Mol Syst Biol. 2012;8:569.

    Article  Google Scholar 

  24. He L, He X, Lim LP, De Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson AL. A microRNA component of the p53 tumour suppressor network. Nature. 2007;447:1130–4.

    Article  CAS  Google Scholar 

  25. Pereira PM, Marques JP, Soares AR, Carreto L, Santos MAS. MicroRNA expression variability in human cervical tissues. PLoS One. 2010;5:e11780.

    Article  Google Scholar 

  26. zur Hausen H. The search for infectious causes of human cancers: where and why (Nobel Lecture). Angew Chem Int Ed. 2009;48:5798–808.

    Article  CAS  Google Scholar 

  27. Martinez I, Gardiner AS, Board KF, Monzon FA, Edwards RP, Khan SA. Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells. Oncogene. 2008;27:2575–82.

    Article  CAS  Google Scholar 

  28. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3:1101–8.

    Article  CAS  Google Scholar 

  29. Sun F, Fu H, Liu Q, Tie Y, Zhu J, Xing R, Sun Z, Zheng X. Downregulation of CCND1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Lett. 2008;582:1564–8.

    Article  CAS  Google Scholar 

  30. Zhao Y, Tu MJ, Wang WP, Qiu JX, Yu AX, Yu AM. Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest. Sci Rep. 2016;6:26611.

    Article  CAS  Google Scholar 

  31. Petrioli R, Paolelli L, Francini E, Manganelli A, Salvestrini F, Francini G. Weekly docetaxel and epirubicin in treatment of advanced hormone-refractory prostate cancer. Urology. 2007;69:142–6.

    Article  Google Scholar 

  32. Wu J, Nyborg WL. Ultrasound, cavitation bubbles and their interaction with cells. Adv Drug Deliv Rev. 2008;60:1103–16.

    Article  CAS  Google Scholar 

  33. Sorace AG, Warram JM, Umphrey H, Hoyt K. microbubble-mediated ultrasonic techniques for improved chemotherapeutic delivery in cancer. J Drug Target. 2012;20:43–54.

    Article  Google Scholar 

  34. Zhang L, Yang X, Lv Y, Xin X, Qin C, Han X, Yang L, He W, Yin L. Cytosolic co-delivery of miRNA-34a and docetaxel with core-shell nanocarriers via caveolae-mediated pathway for the treatment of metastatic breast cancer. Sci Rep. 2017;7:46186.

    Article  CAS  Google Scholar 

  35. Zhao Y, Tu MJ, Yu YF, Wang WP, Chen QX, Qiu JX, Yu AX, Yu AM. Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth. Biochem Pharmacol. 2015;98:602–13.

    Article  CAS  Google Scholar 

  36. Li L, Wu C, Yue Z. miRNA-34a enhances the sensitivity of gastric cancer cells to treatment with paclitaxel by targeting E2F5. Oncol Lett. 2017;13:4837–42.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Medical College of Three Gorges University, Hubei Key Laboratory of the Tumor Microenvironment and Immunotherapy Foundation of China [Grant numbers 2016KZL09, 2015KZL05, and 2016PY052].

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Authors and Affiliations

  1. Medical College of China, Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Three Gorges University, Yichang, 443002, Hubei Province, China

    J. Yu, Y. Zhao, C. Liu, M. Zhao, Y. Ma & J. Jiang

  2. Department of Ultrasonography, Hubei Cancer Hospital, Wuhan, 430079, Hubei Province, China

    J. Yu

  3. Department of Ultrasonography, The Second Clinical Medical College of China, Three Gorges University, Yichang, 443002, Hubei Province, China

    B. Hu

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  1. J. Yu
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Correspondence to Y. Zhao.

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Yu, J., Zhao, Y., Liu, C. et al. Synergistic anti-tumor effect of paclitaxel and miR-34a combined with ultrasound microbubbles on cervical cancer in vivo and in vitro. Clin Transl Oncol 22, 60–69 (2020). https://doi.org/10.1007/s12094-019-02131-w

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  • DOI: https://doi.org/10.1007/s12094-019-02131-w

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