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Strahlentherapie und Onkologie
Published in: Strahlentherapie und Onkologie 4/2016

01-04-2016 | Original Article

Radiosensitization in esophageal squamous cell carcinoma

Effect of polo-like kinase 1 inhibition

Authors: Jenny Ling-Yu Chen, M.D., Jo-Pai Chen, M.D., Yu-Sen Huang, M.D., Yuan-Chun Tsai, B.S., Ming-Hsien Tsai, M.S., Fu-Shan Jaw, Ph.D., Jason Chia-Hsien Cheng, M.D., Ph.D., Sung-Hsin Kuo, M.D., Ph.D., Ming-Jium Shieh, M.D., Ph.D.

Published in: Strahlentherapie und Onkologie | Issue 4/2016

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Abstract

Purpose

This study examined the efficacy of polo-like kinase 1 (PLK1) inhibition on radiosensitivity in vitro and in vivo by a pharmacologic approach using the highly potent PLK1 inhibitor volasertib.

Methods and materials

Human esophageal squamous cell carcinoma (ESCC) cell lines KYSE 70 and KYSE 150 were used to evaluate the synergistic effect of volasertib and irradiation in vitro using cell viability assay, colony formation assay, cell cycle phase analysis, and western blot, and in vivo using ectopic tumor models.

Results

Volasertib decreased ESCC cell proliferation in a dose- and time-dependent manner. Combination of volasertib and radiation caused G2/M cell cycle arrest, increased cyclin B levels, and induced apoptosis. Volasertib significantly enhanced radiation-induced death in ESCC cells by a mechanism involving the enhancement of histone H3 phosphorylation and significant cell cycle interruption. The combination of volasertib plus irradiation delayed the growth of ESCC tumor xenografts markedly compared with either treatment modality alone.

Conclusions

The in vitro results suggested that targeting PLK1 might be a viable approach to improve the effects of radiation in ESCC. In vivo studies showed that PLK1 inhibition with volasertib during irradiation significantly improved local tumor control when compared to irradiation or drug treatment alone.
Appendix
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Literature
1.
Llamazares S, Moreira A, Tavares A, Girdham C, Spruce BA et al (1991) Polo encodes a protein kinase homolog required for mitosis in Drosophila. Genes Dev 5:2153–2165CrossRefPubMed
2.
Golsteyn RM, Mundt KE, Fry AM, Nigg EA (1995) Cell cycle regulation of the activity and subcellular localization of Plk1, a human protein kinase implicated in mitotic spindle function. J Cell Biol 129:1617–1628CrossRefPubMed
3.
van Vugt MA, Bras A, Medema RH (2004) Polo-like kinase-1 controls recovery from a G2 DNA damage-induced arrest in mammalian cells. Mol Cell 15:799–811CrossRefPubMed
4.
5.
Gilmartin AG, Bleam MR, Richter MC, Erskine SG, Kruger RG et al (2009) Distinct concentration-dependent effects of the polo-like kinase 1-specific inhibitor GSK461364A, including differential effect on apoptosis. Cancer Res 69:6969–6977CrossRefPubMed
6.
Schmit TL, Zhong W, Setaluri V, Spiegelman VS, Ahmad N (2009) Targeted depletion of Polo-like kinase (Plk) 1 through lentiviral shRNA or a small-molecule inhibitor causes mitotic catastrophe and induction of apoptosis in human melanoma cells. J Invest Dermatol 129:2843–2853CrossRefPubMedPubMedCentral
7.
Degenhardt Y, Lampkin T (2010) Targeting Polo-like kinase in cancer therapy. Clin Cancer Res 16:384–389CrossRefPubMed
8.
Yim H (2013) Current clinical trials with polo-like kinase 1 inhibitors in solid tumors. Anticancer Drugs 24:999–1006CrossRefPubMed
9.
Schoffski P, Awada A, Dumez H, Gil T, Bartholomeus S et al (2012) A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours. Eur J Cancer 48:179–186CrossRefPubMed
10.
Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A et al (2009) BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res 15:3094–3102CrossRefPubMed
11.
Gerster K, Shi W, Ng B, Yue S, Ito E et al (2010) Targeting polo-like kinase 1 enhances radiation efficacy for head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 77:253–260CrossRefPubMed
12.
Harris PS, Venkataraman S, Alimova I, Birks DK, Donson AM et al (2012) Polo-like kinase 1 (PLK1) inhibition suppresses cell growth and enhances radiation sensitivity in medulloblastoma cells. BMC Cancer 12:80CrossRefPubMedPubMedCentral
13.
Krause M, Kummer B, Deparade A, Eicheler W, Pfitzmann D et al (2013) Simultaneous PLK1 inhibition improves local tumour control after fractionated irradiation. Radiother Oncol 108:422–428CrossRefPubMed
14.
Tandle AT, Kramp T, Kil WJ, Halthore A, Gehlhaus K et al (2013) Inhibition of polo-like kinase 1 in glioblastoma multiforme induces mitotic catastrophe and enhances radiosensitisation. Eur J Cancer 49:3020–3028CrossRefPubMedPubMedCentral
15.
Bogado RF, Pezuk JA, de Oliveira HF, Tone LG, Brassesco MS (2015) BI 6727 and GSK461364 suppress growth and radiosensitize osteosarcoma cells, but show limited cytotoxic effects when combined with conventional treatments. Anticancer Drugs 26:56–63CrossRefPubMed
16.
Lund-Andersen C, Patzke S, Nahse-Kumpf V, Syljuasen RG (2014) PLK1-inhibition can cause radiosensitization or radioresistance dependent on the treatment schedule. Radiother Oncol 110:355–361CrossRefPubMed
17.
Guan R, Tapang P, Leverson JD, Albert D, Giranda VL et al (2005) Small interfering RNA-mediated Polo-like kinase 1 depletion preferentially reduces the survival of p53-defective, oncogenic transformed cells and inhibits tumor growth in animals. Cancer Res 65:2698–2704CrossRefPubMed
18.
Ando K, Ozaki T, Yamamoto H, Furuya K, Hosoda M et al (2004) Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation. J Biol Chem 279:25549–25561CrossRefPubMed
19.
Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr et al (1999) Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85 – 01). Radiation Therapy Oncology Group. JAMA 281:1623–1627CrossRefPubMed
20.
Feng YB, Lin DC, Shi ZZ, Wang XC, Shen XM et al (2009) Overexpression of PLK1 is associated with poor survival by inhibiting apoptosis via enhancement of survivin level in esophageal squamous cell carcinoma. Int J Cancer 124:578–588CrossRefPubMed
21.
Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27-55
22.
Lens SM, Voest EE, Medema RH (2010) Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer 10:825–841CrossRefPubMed
23.
24.
Yom SS (2015) Accelerated repopulation as a cause of radiation treatment failure in non-small cell lung cancer: review of current data and future clinical strategies. Semin Radiat Oncol 25:93–99CrossRefPubMed
25.
Marks LB, Dewhirst M (1991) Accelerated repopulation: friend or foe? Exploiting changes in tumor growth characteristics to improve the “efficiency” of radiotherapy. Int J Radiat Oncol Biol Phys 21:1377–1383CrossRefPubMed
26.
Ji J, Wu K, Wu M, Zhan Q (2010) p53 functional activation is independent of its genotype in five esophageal squamous cell carcinoma cell lines. Front Med China 4:412–418CrossRefPubMed
27.
Liebmann J, Cook JA, Fisher J, Teague D, Mitchell JB (1994) In vitro studies of Taxol as a radiation sensitizer in human tumor cells. J Natl Cancer Inst 86:441–446CrossRefPubMed
28.
Guastalla JP 3rd, Dieras V (2003) The taxanes: toxicity and quality of life considerations in advanced ovarian cancer. Br J Cancer 89:S16–S22CrossRefPubMed
29.
Gligorov J, Lotz JP (2004) Preclinical pharmacology of the taxanes: implications of the differences. Oncologist 9:3–8CrossRefPubMed
30.
Soni DV, Sramkoski RM, Lam M, Stefan T, Jacobberger JW (2008) Cyclin B1 is rate limiting but not essential for mitotic entry and progression in mammalian somatic cells. Cell Cycle 7:1285–1300CrossRefPubMed
31.
Liu X, Erikson RL (2002) Activation of Cdc2/cyclin B and inhibition of centrosome amplification in cells depleted of Plk1 by siRNA. Proc Natl Acad Sci U S A 99:8672–8676CrossRefPubMedPubMedCentral
Metadata
Title
Radiosensitization in esophageal squamous cell carcinoma
Effect of polo-like kinase 1 inhibition
Authors
Jenny Ling-Yu Chen, M.D.
Jo-Pai Chen, M.D.
Yu-Sen Huang, M.D.
Yuan-Chun Tsai, B.S.
Ming-Hsien Tsai, M.S.
Fu-Shan Jaw, Ph.D.
Jason Chia-Hsien Cheng, M.D., Ph.D.
Sung-Hsin Kuo, M.D., Ph.D.
Ming-Jium Shieh, M.D., Ph.D.
Publication date
01-04-2016
Publisher
Springer Berlin Heidelberg
Published in
Strahlentherapie und Onkologie / Issue 4/2016
Print ISSN: 0179-7158
Electronic ISSN: 1439-099X
DOI
https://doi.org/10.1007/s00066-016-0951-6

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