Preclinical model in HCC: the SGK1 kinase inhibitor SI113 blocks tumor progressionin vitroandin vivoand synergizes with radiotherapy

Abstract

The SGK1 kinase is pivotal in signal transduction pathways operating in cell transformation and tumor progression. Here, we characterize in depth a novel potent and selective pyrazolo[3,4-d]pyrimidine-based SGK1 inhibitor. This compound, named SI113, active in vitro in the sub-micromolar range, inhibits SGK1-dependent signaling in cell lines in a dose- and time-dependent manner. We recently showed that SI113 slows down tumor growth and induces cell death in colon carcinoma cells, when used in monotherapy or in combination with paclitaxel. We now demonstrate for the first time that SI113 inhibits tumour growth in hepatocarcinoma models in vitro and in vivo. SI113-dependent tumor inhibition is dose- and time-dependent. In vitro and in vivo SI113-dependent SGK1 inhibition determined a dramatic increase in apotosis/necrosis, inhibited cell proliferation and altered the cell cycle profile of treated cells. Proteome-wide biochemical studies confirmed that SI113 down-regulates the abundance of proteins downstream of SGK1 with established roles in neoplastic transformation, e.g. MDM2, NDRG1 and RAN network members. Consistent with knock-down and over-expressing cellular models for SGK1, SI113 potentiated and synergized with radiotherapy in tumor killing. No short-term toxicity was observed in treated animals during in vivo SI113 administration. These data show that direct SGK1 inhibition can be effective in hepatic cancer therapy, either alone or in combination with radiotherapy.

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

“…4, panels A and B). In the SI113 treated samples, expression of BCL2, as well as the phosphorylation of p-MDM2 (serine 166) were reduced, consistently with previously published observations [31,35,44], whereas the expression of p53, BECN1 and LC3BI/II was increased, as expected [31,40]. In the 64 CuCl 2 treated cells we only recorded modifications affecting p53, BCL2 and TCR1.…”

“…We therefore decided to use the maximum dose of 40 MBq in all the other cells. In a time-course experimental set, we determined that the maximum effect of response occurred at 72 h. Interestingly this timing paralleled the observed response to SI113 in previous experiments [35,36]. In order to test the possible co-operation between the SI113-dependent SGK1 inhibition and copper-64 administration, we carried out a co-treatment test, confirming that the combination of SI113-dependent SGK1 inhibition and copper-64 administration was more effective in inducing cell death than either agent alone.…”

“…We therefore explored the possibility that SI113-dependent [36,37]. We evaluated the effect of SI113 on 64 CuCl 2 radiosensitivity of LI, ADF and T98G cells 24h after plating.…”

“…Among these molecules, SI113 has been demonstrated to inhibit SGK1 activity, while being much less effective on AKT1, ABL and SRC [35]. SI113 induces cell death, alters the growth rate, promotes autophagy and synergizes with taxanes and radiotherapy in hepatocarcinoma and glioblastoma cells in vitro as well as in vivo, also by favoring a cellular sensibilization to these treatments [35][36][37][38]. Based on the apparent lack of toxicity and the consistent ability of SI113 to negatively modulate the chemo-radio resistance [36], in the present work we investigated the potential combined use of 64 CuCl 2 and SI113 in GBMs cellular models.…”

“…Recently the SGK1 inhibitor, SI113, has shown a potential role in the treatment of several cancers, showing an absence of short-term toxicity. Interestingly, SI113 has demonstrated ability to synergize with radiotherapy in hepatic tumor models and glioblastoma, acting presumably as a cell sensitizer toward β-particles [36,39,40].…”