Preferential radiosensitization to glioblastoma cancer stem cell‑like cells by a Hsp90 inhibitor, N‑vinylpyrrolidone‑AUY922

Tani,Toshiaki; Tojo,Naomi; Ohnishi,Ken

doi:10.3892/ol.2022.13222

Preferential radiosensitization to glioblastoma cancer stem cell‑like cells by a Hsp90 inhibitor, N‑vinylpyrrolidone‑AUY922

Authors:
- Toshiaki Tani
- Naomi Tojo
- Ken Ohnishi
View Affiliations

Affiliations: Radiological Technology Section, QST Hospital, National Institutes for Quantum and Radiological Science and Technology, Chiba 263‑8555, Japan, Department of Biology, Ibaraki Prefectural University of Health Sciences, Inashiki, Ibaraki 300‑0394, Japan
Published online on: January 31, 2022 https://doi.org/10.3892/ol.2022.13222
Article Number: 102
Copyright: © Tani et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study examined the radiosensitization induced by a heat shock protein 90 inhibitor, N‑vinylpyrrolidone (NVP)‑AUY922, in CD133‑positive cells in a hypoxic area of T98G spheroids. CD133‑positive cells that are induced in the hypoxic microenvironment of spheroids have previously been reported to exhibit cancer stem cell‑like properties. The present study used CD133‑positive cells from a glioblastoma cell line (T98G) as cancer stem cell‑like cells. CD133‑positive and negative cells were sorted from T98G spheroids using fluorescence‑activated cell sorting and used for colony formation assay. Colony formation assay results indicated that NVP‑AUY922 enhanced radiosensitivity more strongly in CD133‑positive cells compared with CD133‑negative cells. This result showed that NVP‑AUY922 was a preferential radiosensitization candidate targeting glioblastoma cancer stem cells. The mechanisms underlying radiosensitization by NVP‑AUY922 are discussed in relation to the properties of cancer stem cells. Overall, HIF‑1α inhibition by NVP‑AUY922 may induce higher sensitization of cancer stem cells to radiation.

View Figures

View References

1	Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, et al: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10:459–466. 2009. View Article : Google Scholar : PubMed/NCBI
2	Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI
3	Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Binger DD and Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI
4	Beier D, Schulz JB and Beier CP: Chemoresistance of glioblastoma cancer stem cells-much more complex than expected. Mol Cancer. 10:1282011. View Article : Google Scholar : PubMed/NCBI
5	Mannino M and Chalmers AJ: Radioresistance of glioma stem cells: Intrinsic characteristic or property of the ‘microenvironment-stem cell unit’? Mol Oncol. 5:374–386. 2011. View Article : Google Scholar : PubMed/NCBI
6	Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL and Rich JN: Cancer stem cells in glioblastoma. Genes Dev. 29:1203–1217. 2015. View Article : Google Scholar : PubMed/NCBI
7	Ohnishi K, Tani T, Bando S, Kubota N, Fujii Y, Hatano O and Harada H: Plastic induction of CD133AC133-positive cells in the microenvironment of glioblastoma spheroid. Int J Oncol. 45:581–586. 2014. View Article : Google Scholar : PubMed/NCBI
8	Sutherland RM: Cell and environment interactions in tumor microregions: The multicell spheroid model. Science. 240:177–184. 1988. View Article : Google Scholar : PubMed/NCBI
9	Ohnishi K, Tani T, Tojo N and Sagara JI: Glioblastoma cell line shows phenotypes of cancer stem cells in hypoxic microenvironment of spheroids. Biochem Biophys Res Commun. 546:150–154. 2021. View Article : Google Scholar : PubMed/NCBI
10	Trepel J, Mollapour M, Giaccone G and Neckers L: Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer. 10:537–549. 2010. View Article : Google Scholar : PubMed/NCBI
11	Yuno A, Lee MJ, Lee S, Tomita Y, Rekhtman D, Moore B and Trepel JB: Clinical evaluation and biomarker profiling of Hsp90 inhibitors. Methods Mol Biol. 1709:423–441. 2018. View Article : Google Scholar : PubMed/NCBI
12	Dote H, Burgan WE, Camphausen K and Tofilon PJ: Inhibition of hsp90 compromises the DNA damage response to radiation. Cancer Res. 66:9211–9220. 2006. View Article : Google Scholar : PubMed/NCBI
13	Camphausen K and Tofilon PJ: Inhibition of Hsp90: A multitarget approach to radiosensitization. Clin Cancer Res. 13:4326–4330. 2007. View Article : Google Scholar : PubMed/NCBI
14	Jhaveri K, Taldone T, Modi S and Chiosis G: Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta. 1823:742–755. 2012. View Article : Google Scholar : PubMed/NCBI
15	Gaspar N, Sharp SY, Pacey S, Jones C, Walton M, Vassal G, Eccles S, Pearson A and Workman P: Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells. Cancer Res. 69:1966–1975. 2009. View Article : Google Scholar : PubMed/NCBI
16	Piper PW and Millson SH: Mechanisms of resistance to Hsp90 inhibitor drugs: A complex mosaic emerges. Pharmaceuticals (Basel). 4:1400–1422. 2011. View Article : Google Scholar : PubMed/NCBI
17	Jarosz D: HSP90: A global regulator of the genotype-to-phenotype map in cancers. Adv Cancer Res. 129:225–247. 2016. View Article : Google Scholar : PubMed/NCBI
18	Lee KH, Lee JH, Han SW, Im SA, Kim TY, Oh DY and Bang YJ: Antitumor activity of NVP-AUY922, a novel heat shock protein 90 inhibitor, in human gastric cancer cells is mediated through proteasomal degradation of client proteins. Cancer Sci. 102:1388–1395. 2011. View Article : Google Scholar : PubMed/NCBI
19	Gaspar N, Sharp SY, Eccles SA, Gowan S, Popov S, Jones C, Pearson A, Vassal G and Workman P: Mechanistic evalution of the novel HSP90 inhibitor NVP-AUY92 in adult and pediatric glioblastoma. Mol Cancer Ther. 9:1219–1233. 2010. View Article : Google Scholar : PubMed/NCBI
20	Zaidi S, McLaughlin M, Bhide SA, Eccles SA, Workman P, Nutting CM, Huddart RA and Harrington KJ: The HSP90 inhibitor NVP-AUY922 radiosensitizes by abrogation of homologous recombination resulting in mitotic entry with unresolved DNA damage. PLoS One. 7:e354362012. View Article : Google Scholar : PubMed/NCBI
21	Gandhi N, Wild AT, Chettiar ST, Aziz K, Kato Y, Gajula RP, Williams RD, Cades JA, Annadanam A, Song D, et al: Novel Hsp90 inhibitor NVP-AUY922 radiosensitizes prostate cancer cells. Cancer Biol Ther. 14:347–356. 2013. View Article : Google Scholar : PubMed/NCBI
22	Hashida S, Yamamoto H, Shien K, Ohtsuka T, Suzawa K, Maki Y, Furukawa M, Soh J, Asano H, Tsukuda K, et al: Hsp90 inhibitor NVP-AUY922 enhances the radiation sensitivity of lung cancer cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors. Oncol Rep. 33:1499–1504. 2015. View Article : Google Scholar : PubMed/NCBI
23	Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, et al: Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 458:780–783. 2009. View Article : Google Scholar : PubMed/NCBI
24	Man J, Shoemake JD, Ma T, Rizzo AE, Godley AR, Wu Q, Mohammadi AM, Bao S, Rich JN and Yu JS: Hyperthermia sensitizes glioma stem-like cells to radiation by inhibiting AKT signaling. Cancer Res. 75:1760–1769. 2015. View Article : Google Scholar : PubMed/NCBI
25	Heddleston JM, Li Z, McLendon RE, Hjelmeland AB and Rich JN: The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 8:3274–3284. 2009. View Article : Google Scholar : PubMed/NCBI
26	Mao XG, Yan M, Xue XY, Zhang X, Ren HG, Guo G, Wang P, Zhang W and Huo JL: Overexpression of ZNF217 in glioblastoma contributes to the maintenance of glioma stem cells regulated by hypoxia-inducible factors. Lab Invest. 91:1068–1078. 2011. View Article : Google Scholar : PubMed/NCBI
27	Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, Engh J, Iwama T, Kunisada T, Kassam AB, et al: Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene. 28:3949–3959. 2009. View Article : Google Scholar : PubMed/NCBI
28	Bar EE, Lin A, Mahairaki V, Matsui W and Eberhart CG: Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am J Pathol. 177:1491–1502. 2010. View Article : Google Scholar : PubMed/NCBI
29	Iida H, Suzuki M, Goitsuka R and Ueno H: Hypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX2. Int J Oncol. 40:71–79. 2012.PubMed/NCBI
30	Kolenda J, Jensen SS, Aaberg-Jessen C, Christensen K, Andersen C, Brünner N and Kristensen BW: Effects of hypoxia on expression of a panel of stem cell and chemoresistance markers in glioblastoma-derived spheroids. J Neurooncol. 103:43–58. 2011. View Article : Google Scholar : PubMed/NCBI