Sulfasalazine unveils a contact-independent HSV-TK/ganciclovir gene therapy bystander effect in malignant gliomas.
The efficacy of HSV-TK/ganciclovir-based gene therapy on malignant gliomas largely relies on the amplitude of the bystander effect. In these experiments, the anti-inflammatory drug Sulfasalazine increased the HSV-TK/ganciclovir bystander effect in C6, 9L and LN18 cells but not in U87 glioma cells. Using bi-compartmental culture devices and conditioned medium transfer experiments, we showed that in C6, 9L and LN18 cells but not in U87 cells, Sulfasalazine also unveiled a new, contact-independent mechanism of HSV-TK/ganciclovir bystander effect. Upon treatment with ganciclovir, human LN18-TK but not U87-TK cells synthetized and released TNF-alpha in the culture medium. Sulfasalazine sensitized glioma cells to the toxic effect of TNF-alpha and enhanced its secretion in LN18-TK cells in response to GCV treatment. The caspase-8 inhibitor Z-IETD-FMK and a blocking antibody to TNF-alpha both inhibited the contact-independent bystander effect in LN18 cells. Taken together, these results suggest that TNF-alpha mediates the contact-independent bystander effect in LN18 cells. The treatment with GCV and/or Sulfasalazine of tumor xenografts consisting of a mix of 98% C6 and 2% C6-TK cells shows that Sulfasalazine is also a potent adjunct to the in vivo treatment of gliomas.
Robe
Pierre A
PA
Center for Biomedical Integrated Genoproteomics (CBIG) and Center for Cellular and Molecular Neurobiology (CNCM), University of Liège, Belgium. pierre.robe@ulg.ac.be
Nguyen-Khac
Minh-Tuan
MT
Lambert
Frederic
F
Lechanteur
Chantal
C
Jolois
Olivier
O
Ernst-Gengoux
Patricia
P
Rogister
Bernard
B
Bours
Vincent
V
D024201:Bystander Effect / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy; D005910:Glioma / Q000188:drug therapy / Q000628:therapy*; D006801:Humans; D018139:Simplexvirus / Q000235:genetics*; D012460:Sulfasalazine / Q000627:therapeutic use*; D013937:Thymidine Kinase / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D012460:Sulfasalazine; D013937:Thymidine Kinase; D015774:Ganciclovir