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BMC Cancer

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Open Access 01-12-2021 | Ultrasound | Research

Exposure to low intensity ultrasound removes paclitaxel cytotoxicity in breast and ovarian cancer cells

Authors: Celina Amaya, Shihua Luo, Julio Baigorri, Rogelio Baucells, Elizabeth R. Smith, Xiang-Xi Xu

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

Paclitaxel (Taxol) is a microtubule-stabilizing drug used to treat several solid tumors, including ovarian, breast, non-small cell lung, and pancreatic cancers. The current treatment of ovarian cancer is chemotherapy using paclitaxel in combination with carboplatin as a frontline agent, and paclitaxel is also used in salvage treatment as a second line drug with a dose intensive regimen following recurrence. More recently, a dose dense approach for paclitaxel has been used to treat metastatic breast cancer with success.

Paclitaxel binds to beta tubulin with high affinity and stabilizes microtubule bundles. As a consequence of targeting microtubules, paclitaxel kills cancer cells through inhibition of mitosis, causing mitotic catastrophes, and by additional, not yet well defined non-mitotic mechanism(s).

Results

In exploring methods to modulate activity of paclitaxel in causing cancer cell death, we unexpectedly found that a brief exposure of paclitaxel-treated cells in culture to low intensity ultrasound waves prevented the paclitaxel-induced cytotoxicity and death of the cancer cells. The treatment with ultrasound shock waves was found to transiently disrupt the microtubule cytoskeleton and to eliminate paclitaxel-induced rigid microtubule bundles. When cellular microtubules were labelled with a fluorescent paclitaxel analog, exposure to ultrasound waves led to the disassembly of the labeled microtubules and localization of the signals to perinuclear compartments, which were determined to be lysosomes.

Conclusions

We suggest that ultrasound disrupts the paclitaxel-induced rigid microtubule cytoskeleton, generating paclitaxel bound fragments that undergo degradation. A new microtubule network forms from tubulins that are not bound by paclitaxel. Hence, ultrasound shock waves are able to abolish paclitaxel impact on microtubules.

Thus, our results demonstrate that a brief exposure to low intensity ultrasound can reduce and/or eliminate cytotoxicity associated with paclitaxel treatment of cancer cells in cultures.

Available only for authorised users

Barbuti AM, Chen ZS. Paclitaxel through the ages of anticancer therapy: exploring its role in Chemoresistance and radiation therapy. Cancers (Basel). 2015;7(4):2360–71. https://doi.org/10.3390/cancers7040897.CrossRef

Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4(4):253–65. https://doi.org/10.1038/nrc1317.CrossRefPubMed

Wani MC, Horwitz SB. Nature as a remarkable chemist: a personal story of the discovery and development of Taxol. Anti-Cancer Drugs. 2014;25(5):482–7. https://doi.org/10.1097/CAD.0000000000000063.CrossRefPubMedPubMedCentral

Zhao Y, Mu X, Du G. Microtubule-stabilizing agents: new drug discovery and cancer therapy. Pharmacol Ther. 2016;162:134–43. https://doi.org/10.1016/j.pharmthera.2015.12.006.CrossRefPubMed

Runowicz CD, Wiernik PH, Einzig AI, Goldberg GL, Horwitz SB. Taxol in ovarian cancer. Cancer. 1993;71(4 Suppl):1591–6. https://doi.org/10.1002/cncr.2820710442.CrossRefPubMed

Yang CH, Horwitz SB. Taxol®: the first microtubule stabilizing agent. Int J Mol Sci. 2017;18(8):1733.

Bookman MA. Optimal primary therapy of ovarian cancer. Ann Oncol. 2016;27(Suppl 1):i58–62. https://doi.org/10.1093/annonc/mdw088.CrossRefPubMed

Baird RD, Tan DS, Kaye SB. Weekly paclitaxel in the treatment of recurrent ovarian cancer. Nat Rev Clin Oncol. 2010;7(10):575–82. https://doi.org/10.1038/nrclinonc.2010.120.CrossRefPubMed

Baker VV. Salvage therapy for recurrent epithelial ovarian cancer. Hematol Oncol Clin North Am. 2003;17(4):977–88. https://doi.org/10.1016/S0889-8588(03)00057-1.CrossRefPubMed

10.

Dunder I, Berker B, Atabekoglu C, Bilgin T. Preliminary experience with salvage weekly paclitaxel in women with advanced recurrent ovarian carcinoma. Eur J Gynaecol Oncol. 2005;26(1):79–82.PubMed

11.

Jain A, Dubashi B, Reddy KS, Jain P. Weekly paclitaxel in ovarian cancer-the latest success story. Curr Oncol. 2011;18(1):16–7. https://doi.org/10.3747/co.v18i1.680.CrossRefPubMedPubMedCentral

12.

Canta A, Chiorazzi A, Cavaletti G. Tubulin: a target for antineoplastic drugs into the cancer cells but also in the peripheral nervous system. Curr Med Chem. 2009;16(11):1315–24. https://doi.org/10.2174/092986709787846488.CrossRefPubMed

13.

Kudlowitz D, Muggia F. Clinical features of taxane neuropathy. Anti-Cancer Drugs. 2014;25(5):495–501. https://doi.org/10.1097/CAD.0000000000000051.CrossRefPubMed

14.

Gornstein E, Schwarz TL. The paradox of paclitaxel neurotoxicity: Mechanisms and unanswered questions. Neuropharmacology. 2014;76(Pt A):175–83.CrossRef

15.

Velasco R, Bruna J. Taxane-induced peripheral neurotoxicity. Toxics. 2015;3(2):152–69. https://doi.org/10.3390/toxics3020152.CrossRefPubMedPubMedCentral

16.

Griffiths C, Kwon N, Beaumont JL, Paice JA. Cold therapy to prevent paclitaxel-induced peripheral neuropathy. Support Care Cancer. 2018;26(10):3461–9. https://doi.org/10.1007/s00520-018-4199-9.CrossRefPubMed

17.

Hanai A, Ishiguro H, Sozu T, Tsuda M, Yano I, Nakagawa T, et al. Effects of cryotherapy on objective and subjective symptoms of paclitaxel-induced neuropathy: prospective self-controlled trial. J Natl Cancer Inst. 2018;110(2):141–8. https://doi.org/10.1093/jnci/djx178.CrossRefPubMed

18.

Mielke S, Sparreboom A, Mross K. Peripheral neuropathy: a persisting challenge in paclitaxel-based regimes. Eur J Cancer. 2006;42(1):24–30. https://doi.org/10.1016/j.ejca.2005.06.030.CrossRefPubMed

19.

Staff NP, Fehrenbacher JC, Caillaud M, Damaj MI, Segal RA, Rieger S. Pathogenesis of paclitaxel-induced peripheral neuropathy: a current review of in vitro and in vivo findings using rodent and human model systems. Exp Neurol. 2020;324:113121. https://doi.org/10.1016/j.expneurol.2019.113121.CrossRefPubMed

20.

Freites-Martinez A, Chan D, Sibaud V, Shapiro J, Fabbrocini G, Tosti A, et al. Assessment of quality of life and treatment outcomes of patients with persistent Postchemotherapy alopecia. JAMA Dermatol. 2019;155(6):724–8. https://doi.org/10.1001/jamadermatol.2018.5071.CrossRefPubMedPubMedCentral

21.

Prevezas C, Matard B, Pinquier L, Reygagne P. Irreversible and severe alopecia following docetaxel or paclitaxel cytotoxic therapy for breast cancer. Br J Dermatol. 2009;160(4):883–5. https://doi.org/10.1111/j.1365-2133.2009.09043.x.CrossRefPubMed

22.

Rossi A, Fortuna MC, Caro G, Pranteda G, Garelli V, Pompili U, et al. Chemotherapy-induced alopecia management: clinical experience and practical advice. J Cosmet Dermatol. 2017;16(4):537–41. https://doi.org/10.1111/jocd.12308.CrossRefPubMedPubMedCentral

23.

Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979;277(5698):665–7. https://doi.org/10.1038/277665a0.CrossRefPubMed

24.

Schiff PB, Horwitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci U S A. 1980;77(3):1561–5. https://doi.org/10.1073/pnas.77.3.1561.CrossRefPubMedPubMedCentral

25.

Bhalla KN. Microtubule-targeted anticancer agents and apoptosis. Oncogene. 2003;22(56):9075–86. https://doi.org/10.1038/sj.onc.1207233.CrossRefPubMed

26.

Blagosklonny MV, Fojo T. Molecular effects of paclitaxel: myths and reality (a critical review). Int J Cancer. 1999;83(2):151–6. https://doi.org/10.1002/(SICI)1097-0215(19991008)83:2<151::AID-IJC1>3.0.CO;2-5.

27.

Morse DL, Gray H, Payne CM, Gillies RJ. Docetaxel induces cell death through mitotic catastrophe in human breast cancer cells. Mol Cancer Ther. 2005;4(10):1495–504. https://doi.org/10.1158/1535-7163.MCT-05-0130.CrossRefPubMed

28.

Weaver BA. How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;25(18):2677–81. https://doi.org/10.1091/mbc.e14-04-0916.CrossRefPubMedPubMedCentral

29.

Horwitz SB. Taxol (paclitaxel): mechanisms of action. Ann Oncol. 1994;5(Suppl 6):S3–6.PubMed

30.

Field JJ, Kanakkanthara A, Miller JH. Microtubule-targeting agents are clinically successful due to both mitotic and interphase impairment of microtubule function. Bioorg Med Chem. 2014;22(18):5050–9. https://doi.org/10.1016/j.bmc.2014.02.035.CrossRefPubMed

31.

Komlodi-Pasztor E, Sackett D, Wilkerson J, Fojo T. Mitosis is not a key target of microtubule agents in patient tumors. Nat Rev Clin Oncol. 2011;8(4):244–50. https://doi.org/10.1038/nrclinonc.2010.228.CrossRefPubMed

32.

Komlodi-Pasztor E, Sackett DL, Fojo AT. Inhibitors targeting mitosis: tales of how great drugs against a promising target were brought down by a flawed rationale. Clin Cancer Res. 2012;18(1):51–63. https://doi.org/10.1158/1078-0432.CCR-11-0999.CrossRefPubMed

33.

Mitchison TJ, Pineda J, Shi J, Florian S. Is inflammatory micronucleation the key to a successful anti-mitotic cancer drug? Open Biol. 2017;7(11):170182. https://doi.org/10.1098/rsob.170182.CrossRefPubMedPubMedCentral

34.

Xie SB, Ogden A, Aneja R, Zhou J. Microtubule-binding proteins as promising biomarkers of paclitaxel sensitivity in Cancer chemotherapy. Med Res Rev. 2016;36(2):300–12. https://doi.org/10.1002/med.21378.CrossRefPubMed

35.

Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB. Mechanisms of Taxol resistance related to microtubules. Oncogene. 2003;22(47):7280–95. https://doi.org/10.1038/sj.onc.1206934.CrossRefPubMedPubMedCentral

36.

Miller DL, Smith NB, Bailey MR, Czarnota GJ, Hynynen K, Makin IR, et al. Overview of therapeutic ultrasound applications and safety considerations. J Ultrasound Med. 2012;31(4):623–34. https://doi.org/10.7863/jum.2012.31.4.623.CrossRefPubMedPubMedCentral

37.

Robertson VJ, Baker KG. A review of therapeutic ultrasound: effectiveness studies. Phys Ther. 2001;81(7):1339–50 Centre for Reviews and Dissemination (UK).CrossRef

38.

ter Haar G. Therapeutic applications of ultrasound. Prog Biophys Mol Biol. 2007;93(1–3):111–29. https://doi.org/10.1016/j.pbiomolbio.2006.07.005.CrossRefPubMed

39.

Ahmadi F, McLoughlin IV, Chauhan S, ter-Haar G. Bio-effects and safety of low-intensity, low-frequency ultrasonic exposure. Prog Biophys Mol Biol. 2012;108(3):119–38. https://doi.org/10.1016/j.pbiomolbio.2012.01.004.CrossRefPubMed

40.

Dalecki D. Mechanical bioeffects of ultrasound. Annu Rev Biomed Eng. 2004;6(1):229–48. https://doi.org/10.1146/annurev.bioeng.6.040803.140126.CrossRefPubMed

41.

Robertson VJ, Ward AR. Subaqueous ultrasound: 45kHz and 1MHz machines compared. Arch Phys Med Rehabil. 1995;76(6):569–75. https://doi.org/10.1016/S0003-9993(95)80513-3.CrossRefPubMed

42.

Reher P, Doan N, Bradnock B, Meghji S, Harris M. Therapeutic ultrasound for osteoradionecrosis: an in vitro comparison between 1 MHz and 45 kHz machines. Eur J Cancer. 1998;34(12):1962–8. https://doi.org/10.1016/S0959-8049(98)00238-X.CrossRefPubMed

43.

Doan N, Reher P, Meghji S, Harris M. In vitro effects of therapeutic ultrasound on cell proliferation, protein synthesis, and cytokine production by human fibroblasts, osteoblasts, and monocytes. J Oral Maxillofac Surg. 1999;57(4):409–19; discussion 420. https://doi.org/10.1016/S0278-2391(99)90281-1.CrossRefPubMed

44.

Reher P, Doan N, Bradnock B, Meghji S, Harris M. Effect of ultrasound on the production of IL-8, basic FGF and VEGF. Cytokine. 1999;11(6):416–23. https://doi.org/10.1006/cyto.1998.0444.CrossRefPubMed

45.

Barnett SB. Thresholds for nonthermal bioeffects: theoretical and experimental basis for a threshold index. Ultrasound Med Biol. 1998;24:S41–9.CrossRef

46.

Fischell TA, Abbas MA, Grant GW, Siegel RJ. Ultrasonic energy. Effects on vascular function and integrity. Circulation. 1991;84(4):1783–95. https://doi.org/10.1161/01.CIR.84.4.1783.CrossRefPubMed

47.

Scarponi C, Nasorri F, Pavani F, Madonna S, Sestito R, Simonacci M, et al. Low-frequency low-intensity ultrasounds do not influence the survival and immune functions of cultured keratinocytes and dendritic cells. J Biomed Biotechnol. 2009;2009:193260.CrossRef

48.

Sunny Y, Bawiec CR, Nguyen AT, Samuels JA, Weingarten MS, Zubkov LA, et al. Optimization of un-tethered, low voltage, 20-100kHz flexural transducers for biomedical ultrasonics applications. Ultrasonics. 2012;52(7):943–8. https://doi.org/10.1016/j.ultras.2012.03.004.CrossRefPubMedPubMedCentral

49.

Abramavičius S, Volkevičiūtė A, Tunaitytė A, Venslauskas M, Bubulis A, Bajoriūnas V, et al. Low-frequency (20 kHz) ultrasonic modulation of drug action. Ultrasound Med Biol. 2020;46(11):3017–31. https://doi.org/10.1016/j.ultrasmedbio.2020.07.002.CrossRefPubMed

50.

Iida K, Luo H, Hagisawa K, Akima T, Shah PK, Naqvi TZ, et al. Noninvasive low-frequency ultrasound energy causes vasodilation in humans. J Am Coll Cardiol. 2006;48(3):532–7. https://doi.org/10.1016/j.jacc.2006.03.046.CrossRefPubMed

51.

Samuels JA, Weingarten MS, Margolis DJ, Zubkov L, Sunny Y, Bawiec CR, et al. Low-frequency (<100 kHz), low-intensity (<100 mW/cm (2)) ultrasound to treat venous ulcers: a human study and in vitro experiments. J Acoust Soc Am. 2013;134(2):1541–7. https://doi.org/10.1121/1.4812875.CrossRefPubMedPubMedCentral

52.

Hrazdira I, Skorpıkova J, Dolnıkova M. Ultrasonically induced alterations of cultured tumour cells. Eur J Ultrasound. 1998;8(1):43–9. https://doi.org/10.1016/S0929-8266(98)00049-4.CrossRefPubMed

53.

Adler J, Necas O, Hrazdira I. Dissassembly of microtubules due to low intensity ultrasound. Folia Biol (Praha). 1993;39(1):55–7.

54.

Samandari M, Abrinia K, Mokhtari-Dizaji M, Tamayol A. Ultrasound induced strain cytoskeleton rearrangement: an experimental and simulation study. J Biomech. 2017;60:39–47. https://doi.org/10.1016/j.jbiomech.2017.06.003.CrossRefPubMed

55.

Skorpıkova J, Dolnıkova M, Hrazdira I, Janisch R. Changes in microtubules and microfilaments due to a combined effect of ultrasound and cytostatics in HeLa cells. Folia Biol (Praha). 2001;47(4):143–7.

56.

Cachon J, Cachon M, Bruneton J-N. An ultrastructural study of the effects of very high frequency ultrasound on a microtubular system (Axopods of a heliozoan). Biol Cell. 1981;40:69–72.

57.

Udroiu I, Marinaccio J, Bedini A, Giliberti C, Palomba R, Sgura A. Genomic damage induced by 1-MHz ultrasound in vitro. Environ Mol Mutagen. 2018;59(1):60–8. https://doi.org/10.1002/em.22124.CrossRefPubMed

58.

Emoto M. Development of a Cancer treatment with the concomitant use of low-intensity ultrasound: entering the age of simultaneous diagnosis and treatment. Diagnostics (Basel). 2014;4(2):47–56. https://doi.org/10.3390/diagnostics4020047.CrossRef

59.

Capo-chichi CD, Roland IH, Vanderveer L, Bao R, Yamagata T, Hirai H, et al. Anomalous expression of epithelial differentiation-determining GATA factors in ovarian tumorigenesis. Cancer Res. 2003;63(16):4967–77.PubMed

60.

Hamilton TC, Young RC, Louie KG, Behrens BC, McKoy WM, Grotzinger KR, et al. Characterization of a xenograft model of human ovarian carcinoma which produces ascites and intraabdominal carcinomatosis in mice. Cancer Res. 1984;44(11):5286–90.PubMed

61.

Capo-chichi CD, Cai KQ, Simpkins F, Ganjei-Azar P, Godwin AK, Xu XX. Nuclear envelope structural defects cause chromosomal numerical instability and aneuploidy in ovarian cancer. BMC Med. 2011;9(1):28. https://doi.org/10.1186/1741-7015-9-28.CrossRefPubMedPubMedCentral

62.

Capo-Chichi CD, Yeasky TM, Smith ER, Xu XX. Nuclear envelope structural defect underlies the main cause of aneuploidy in ovarian carcinogenesis. BMC Cell Biol. 2016;17(1):37. https://doi.org/10.1186/s12860-016-0114-8.CrossRefPubMedPubMedCentral

63.

Smith ER, Meng Y, Moore R, Tse JD, Xu AG, Xu XX. Nuclear envelope structural proteins facilitate nuclear shape changes accompanying embryonic differentiation and fidelity of gene expression. BMC Cell Biol. 2017;18(1):8. https://doi.org/10.1186/s12860-017-0125-0.CrossRefPubMedPubMedCentral

64.

Smith ER, Leal J, Amaya C, Li B, Xu XX. Nuclear Lamin A/C Expression Is a Key Determinant of Paclitaxel Sensitivity. Mol Cell Biol. 2021:00648–20. https://doi.org/10.1128/MCB.00648-20 Online ahead of print.

65.

Michalakis J, Georgatos SD, de Bree E, Polioudaki H, Romanos J, Georgoulias V, et al. Short-term exposure of cancer cells to micromolar doses of paclitaxel, with or without hyperthermia, induces long-term inhibition of cell proliferation and cell death in vitro. Ann Surg Oncol. 2007;14(3):1220–8. https://doi.org/10.1245/s10434-006-9305-4.CrossRefPubMed

66.

Gao Q, Walmsley AD, Cooper PR, Scheven BA. Ultrasound stimulation of different dental stem cell populations: role of mitogen-activated protein kinase signaling. J Endod. 2016;42(3):425–31. https://doi.org/10.1016/j.joen.2015.12.019.CrossRefPubMed

67.

Zhai Y, Borisy GG. Quantitative determination of the proportion of microtubule polymer present during the mitosis-interphase transition. J Cell Sci. 1994;107(Pt 4):881–90. https://doi.org/10.1242/jcs.107.4.881.CrossRefPubMed

68.

Ben-Ze'ev A, Farmer SR, Penman S. Mechanisms of regulating tubulin synthesis in cultured mammalian cells. Cell. 1979;17(2):319–25. https://doi.org/10.1016/0092-8674(79)90157-0.CrossRefPubMed

69.

Gonzalez-Garay ML, Cabral F. Overexpression of an epitope-tagged beta-tubulin in Chinese hamster ovary cells causes an increase in endogenous alpha-tubulin synthesis. Cell Motil Cytoskeleton. 1995;31(4):259–72. https://doi.org/10.1002/cm.970310403.CrossRefPubMed

70.

Huff LM, Sackett DL, Poruchynsky MS, Fojo T. Microtubule-disrupting chemotherapeutics result in enhanced proteasome-mediated degradation and disappearance of tubulin in neural cells. Cancer Res. 2010;70(14):5870–9. https://doi.org/10.1158/0008-5472.CAN-09-4281.CrossRefPubMedPubMedCentral

71.

Johnson GV, Litersky JM, Whitaker JN. Proteolysis of microtubule-associated protein 2 and tubulin by cathepsin D. J Neurochem. 1991;57(5):1577–83. https://doi.org/10.1111/j.1471-4159.1991.tb06354.x.CrossRefPubMed

72.

Caron JM, Jones AL, Rall LB, Kirschner MW. Autoregulation of tubulin synthesis in enucleated cells. Nature. 1985;317(6038):648–51.CrossRef

73.

Lin Z, Gasic I, Chandrasekaran V, Peters N, Shao S, Mitchison TJ, et al. TTC5 mediates autoregulation of tubulin via mRNA degradation. Science. 2020;367(6473):100–4. https://doi.org/10.1126/science.aaz4352.CrossRefPubMed

Title: Exposure to low intensity ultrasound removes paclitaxel cytotoxicity in breast and ovarian cancer cells
Authors: Celina Amaya
Shihua Luo
Julio Baigorri
Rogelio Baucells
Elizabeth R. Smith
Xiang-Xi Xu
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Ultrasound
Breast Cancer
Ovarian Cancer
Ovarian Cancer
Breast Cancer
Ultrasound
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08722-7

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