MK-0752

Gamma-secretase inhibitor MK0752 has shown a high therapeutic potential in different solid malignant tumors. Up to now, its antineoplastic effects were not investigated in head and neck squamous cell carcinoma (HNSCC) and particularly in human-papillomavirus (HPV)-positive tumors.

We conducted cytotoxic, migration, and clonogenic assays in two HPV-negative HNSCC cell lines (Cal27 and FaDu) and one HPV-positive cell line (SCC154). Furthermore, in order to assess the pro-apoptotic effects of MK0752, a Caspase 3/7 Glo assay was performed.

Our experiments revealed antineoplastic effects of MK0752 in all three cell lines. Strong cytotoxic and antimigratory potential was shown in all cell lines, with strongest effects observed in the HPV-positive cell line. Meanwhile, anticlonogenic effects were only shown in Cal27 and SCC154. Most importantly, MK0752 induced apoptosis solely in HPV-positive SCC154.

Our novel findings indicate a therapeutic potential of MK0752 in HPV-positive HNSCC. Indeed, further investigation is needed for validation of our results and for the assessment of the mechanistic background.

The aim: This study was set out to assess the potential protective impact of MK0752 (a gamma secretase inhibitor) on sepsis-induced renal injury through modulation of inflammatory and oxidative stress pathways. Materials and methods: Twenty-four Swiss-albino mice aged between eight and twelve week and weighted twenty to thirty-seven grams were randomly allocated into four groups (n=6 in each group). Sham group (laparotomy without cecal ligation and puncture (CLP), sepsis group (laparotomy with CLP), vehicle-treated group (equivalent volume of DMSO before the CLP), MK0752 treated group (5 mg/kg) single daily dose for three days before the CLP. Blood samples were used to assess the serum levels of urea and creatinine. The kidneys were used to assess tissue levels of the TNF-α, IL-10, IL-6, TNFR1, VEGF, notch1, jagged1 and tissue damage by histopathological analysis. Results: The current study shows that pretreatment with MK0752 ameliorates the renal damage by significantly reducing the proinflammatory cytokines and notch1 signaling. Conclusions: Taken together, these results suggest that MK0752 could be protective against the renal injury induced by sepsis through its ameliorative impact on renal architecture and modulating cytokines and Notch1 singling pathway. Further studies regarding the role of Notch signaling pathways would be worthwhile.