The PYK2 inhibitor PF-562271 enhances the effect of temozolomide on tumor growth in a C57Bl/6-Gl261 mouse glioma model
Background: The introduction of potential to deal with temozolomide (TMZ), a typical chemotherapeutic, limits the effective management of glioblastoma (GBM). Focal adhesion kinase (FAK) and proline wealthy tyrosine kinase 2 (Pyk2) regulate proliferation and invasion of GBM cells. We discovered that TMZ activates FAK and Pyk2 signaling in GBM. We hypothesized that medicinal inhibitors of Pyk2/FAK along with TMZ can boost the inhibitory aftereffect of TMZ on tumor growth and dispersal and enhance the treatment outcome.
Methods: Primary human GBM cell cultures along with a C57Bl/6-GL261 mouse glioma implantation model were utilised. Pyk2 (Tyr579/580) and FAK (Tyr925) phosphorylation was examined by western blotting. Viability, cell cycle, migration, invasion and invadopodia formation were investigated in vitro. Animal survival, tumor size and invasion, TUNEL apoptotic cell dying and also the Ki67 proliferation index were evaluated in vivo upon treatment with TMZ (50 mg/kg, once/day, orally) and also the Pyk2/FAK inhibitor PF-562271 (once/daily, 50 mg/kg, orally) versus. TMZ monotherapy.
Results: In vitro studies revealed considerably reduced viability, cell cycle progression, invasion and invadopodia with TMZ (100 µM) PF-562271 (16 nM) in contrast to TMZ alone. In vivo studies shown that combinatorial treatment brought to prominent reductions in tumor size and invasive margins, extensive indications of apoptosis along with a reduced proliferation index, plus a 15% rise in the rate of survival in creatures, in contrast to TMZ monotherapy.
Conclusion: TMZ PF-562271 eliminates TMZ-related Pyk2/FAK activation in GBM and increases the treatment effectiveness.