Abstract
Side populations of glioblastoma cells are resistant to chemotherapy basically due to ABCG2-mediated efflux of small-molecule drugs. The herpes simplex virus thymidine kinase/ganciclovir suicide gene therapy system is one of the best-characterized strategies for malignant tumors including glioblastoma. Since this system involves a small-molecule drug ganciclovir, we wonder if glioblastoma side population cells are able to “pump out” ganciclovir and thus resistant to this suicide gene therapy. By 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, we found that side populations are more resistant to this system than non-side populations. By flow cytometry and competition assay, we found that ganciclovir is a substrate for ABCG2.
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Ahn M.; Lee S. J.; Li X.; Jiménez J. A.; Zhang Y. P.; Bae K. H.; Mohammadi Y.; Kao C.; Gardner T. A. Enhanced combined tumor-specific oncolysis and suicide gene therapy for prostate cancer using M6 promoter. Cancer Gene Ther 16: 73–82; 2009.
Balzarini J.; Bohman C.; De Clercq E. Differential mechanism of cytostatic effect of (E)-5-(2-bromovinyl)-2′-deoxyuridine, 9-(1,3-dihydroxy-2-propoxymethyl)guanine, and other antiherpetic drugs on tumor cells transfected by the thymidine kinase gene of herpes simplex virus type 1 or type 2. J Biol Chem 268: 6332–6337; 1993.
Bleau A. M.; Hambardzumyan D.; Ozawa T.; Fomchenko E. I.; Huse J. T.; Brennan C. W.; Holland E. C. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4: 226–235; 2009.
Culver K. W.; Ram Z.; Wallbridge S.; Ishii H.; Oldfield E. H.; Blaese R. M. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 256: 1550–1552; 1992.
Fick J.; Barker 2nd F. G.; Dazin P.; Westphale E. M.; Beyer E. C.; Israel M. A. The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro. Proc Natl Acad Sci USA 92: 11071–11075; 1995.
Hambardzumyan D.; Becher O. J.; Holland E. C. Cancer stem cells and survival pathways. Cell Cycle 7: 1371–1378; 2008.
Ilsley D. D.; Lee S. H.; Miller W. H.; Kuchta R. D. Acyclic guanosine analogs inhibit DNA polymerases alpha, delta, and epsilon with very different potencies and have unique mechanisms of action. Biochemistry 34: 2504–2510; 1995.
Kitange G. J.; Carlson B. L.; Schroeder M. A.; Grogan P. T.; Lamont J. D.; Decker P. A.; Wu W.; James C. D.; Sarkaria J. N. Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts. Neuro Oncol 11: 281–291; 2009.
Louis D. N.; Ohgaki H.; Wiestler O. D.; Cavenee W. K.; Burger P. C.; Jouvet A.; Scheithauer B. W.; Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114: 97–109; 2007.
Mesnil M.; Yamasaki H. Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication. Cancer Res 60: 3989–3999; 2000.
Moolten F. L. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res 46: 5276–5281; 1986.
Moriuchi S.; Glorioso J. C.; Maruno M.; Izumoto S.; Wolfe D.; Huang S.; Cohen J. B.; Yoshimine T. Combination gene therapy for glioblastoma involving herpes simplex virus vector-mediated codelivery of mutant IkappaBalpha and HSV thymidine kinase. Cancer Gene Ther 12: 487–496; 2005.
Nakamura Y.; Oka M.; Soda H.; Shiozawa K.; Yoshikawa M.; Itoh A.; Ikegami Y.; Tsurutani J.; Nakatomi K.; Kitazaki T.; Doi S.; Yoshida H.; Kohno S. Gefitinib (“Iressa”, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. Cancer Res 65: 1541–1546; 2005.
Rabindran S. K.; Ross D. D.; Doyle L. A.; Yang W.; Greenberger L. M. Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. Cancer Res 60: 47–50; 2000.
Rainov N. G.; Fels C.; Droege J. W.; Schäfer C.; Kramm C. M.; Chou T. C. Temozolomide enhances herpes simplex virus thymidine kinase/ganciclovir therapy of malignant glioma. Cancer Gene Ther 8: 662–668; 2001.
Rainov N. G.; Kramm C. M.; Banning U.; Riemann D.; Holzhausen H. J.; Heidecke V.; Burger K. J.; Burkert W.; Korholz D. Immune response induced by retrovirus-mediated HSV-tk/GCV pharmacogene therapy in patients with glioblastoma multiforme. Gene Ther 7: 1853–1858; 2000.
Scott J. N.; Rewcastle N. B.; Brasher P. M.; Fulton D.; Hagen N. A.; MacKinnon J. A.; Sutherland G.; Cairncross J. G.; Forsyth P. Long-term glioblastoma multiforme survivors: a population-based study. Can J Neurol Sci 25: 197–201; 1998.
Singh S. K.; Clarke I. D.; Hide T.; Dirks P. B. Cancer stem cells in nervous system tumors. Oncogene 23: 7267–7273; 2004.
Smith P. J.; Furon E.; Wiltshire M.; Campbell L.; Feeney G. P.; Snyder R. D.; Errington R. J. ABCG2-associated resistance to Hoechst 33342 and topotecan in a murine cell model with constitutive expression of side population characteristics. Cytometry A 75: 924–933; 2009.
Zhang M.; Rosen J. M. Stem cells in the etiology and treatment of cancer. Curr Opin Genet Dev 16: 60–64; 2006.
Zhou S.; Schuetz J. D.; Bunting K. D.; Colapietro A. M.; Sampath J.; Morris J. J.; Lagutina I.; Grosveld G. C.; Osawa M.; Nakauchi H.; Sorrentino B. P. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7: 1028–1034; 2001.
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Editor: J. Denry Sato
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Hu, W., Liu, W. Side populations of glioblastoma cells are less sensitive to HSV-TK/GCV suicide gene therapy system than the non-side population. In Vitro Cell.Dev.Biol.-Animal 46, 497–501 (2010). https://doi.org/10.1007/s11626-010-9274-6
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DOI: https://doi.org/10.1007/s11626-010-9274-6