Side populations of glioblastoma cells are less sensitive to HSV-TK/GCV suicide gene therapy system than the non-side population

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.

[1]  E. De Clercq,et al.  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. , 1993, The Journal of biological chemistry.

[2]  R. Snyder,et al.  ABCG2‐associated resistance to Hoechst 33342 and topotecan in a murine cell model with constitutive expression of side population characteristics , 2009, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[3]  Z. Ram,et al.  In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. , 1992, Science.

[4]  E. Holland,et al.  Cancer stem cells and survival pathways , 2008, Cell cycle.

[5]  D. Louis.  WHO classification of tumours of the central nervous system , 2007 .

[6]  F. Moolten.  Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. , 1986, Cancer research.

[7]  Brett L Carlson,et al.  Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts. , 2009, Neuro-oncology.

[8]  V. Heidecke,et al.  Immune response induced by retrovirus-mediated HSV-tk/GCV pharmacogene therapy in patients with glioblastoma multiforme , 2000, Gene Therapy.

[9]  L. Doyle,et al.  Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. , 2000, Cancer research.

[10]  C. Kao,et al.  Enhanced combined tumor-specific oncolysis and suicide gene therapy for prostate cancer using M6 promoter , 2009, Cancer Gene Therapy.

[11]  H. Nakauchi,et al.  The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype , 2001, Nature Medicine.

[12]  M. Israel,et al.  The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[13]  P. Forsyth,et al.  Long-term Glioblastoma Multiforme Survivors: a Population-based Study , 1998, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[14]  B. Scheithauer,et al.  The 2007 WHO classification of tumours of the central nervous system , 2007, Acta Neuropathologica.

[15]  Tatsuya Ozawa,et al.  PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. , 2009, Cell stem cell.

[16]  H. Yamasaki,et al.  Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication. , 2000, Cancer research.

[17]  D. Ilsley,et al.  Acyclic guanosine analogs inhibit DNA polymerases alpha, delta, and epsilon with very different potencies and have unique mechanisms of action. , 1995, Biochemistry.

[18]  J. Rosen,et al.  Stem cells in the etiology and treatment of cancer. , 2006, Current opinion in genetics & development.

[19]  S. Kohno,et al.  Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. , 2005, Cancer research.

[20]  Christof M. Kramm,et al.  Temozolomide enhances herpes simplex virus thymidine kinase/ganciclovir therapy of malignant glioma , 2001, Cancer Gene Therapy.

[21]  P. Dirks,et al.  Cancer stem cells in nervous system tumors , 2004, Oncogene.