Details

Autor(en) / Beteiligte

• Voissiere, Aurélien
• Weber, Valérie
• Gerard, Yvain
• Rédini, Françoise
• Raes, Florian
• Chezal, Jean-Michel
• Degoul, Françoise
• Peyrode, Caroline
• Miot-Noirault, Elisabeth

Titel

Proteoglycan-targeting applied to hypoxia-activated prodrug therapy in chondrosarcoma: first proof-of-concept

Ist Teil von

• Oncotarget, 2017-11, Vol.8 (56), p.95824-95840

Ort / Verlag

United States: Impact journals

Erscheinungsjahr

2017

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Due to its abundant chondrogenic matrix and hypoxic tissue, chondrosarcoma is chemo- and radio-resistant. Our group has developed a proteoglycan targeting strategy by using a quaternary ammonium (QA) function as a carrier of DNA alkylating agents to chondrosarcoma environment. Here, we assessed the relevance of this strategy applied to hypoxia-activated prodrugs, by conjugating a QA to 2-nitroimidazole phosphoramidate. This derivative, named as , was evaluated respectively to its non-QA equivalent and to a QA-conjugated but non-hypoxia activated. Firstly binding to aggrecan was confirmed from dissociation constant determined by Surface Plasmon Resonance. , in HEMC-SS chondrosarcoma cells cultured in monolayer and in spheroids, showed higher cytotoxic activity in hypoxia versus normoxia, and led to a strong accumulation of cells in S phase and apoptosis. , a HEMC-SS xenograft model was implanted on SCID mice and characterized for hypoxia by photoacoustic imaging as well as proteoglycan content. When HEMC-SS bearing mice were given at 47 μmol/kg according to a q4d x 6 schedule, a significant 62.1% inhibition of tumor growth was observed, without associated hematological side effects. Mechanistic studies of treated tumors highlighted decrease in mitotic index associated to increase in both p21 and p53S15 markers. Interestingly, treatment induced an increase of DNA damages as measured by γH2AX predominantly found in pimonidazole-positive hypoxic areas. These preclinical results are the first to demonstrate the interest of addressing hypoxia-activated prodrugs selectively to proteoglycan of chondrogenic tumor tissue, as a promising therapeutic strategy.