Figure 2. Pictilisib exhibited anti-tumor activity and synergized with cisplatin in vitro and in vivo.

A, Tumor growth curve of PDX BL0269 (JAX#TM00015). Tumors grew more slowly in all treatment groups than the control group (CTRL). The median time of the tumor growth to 10 times the baseline was 15.5, 27, 28, 41.5 and 42 days for control (CTRL), pictilisib (PIC), cisplatin (CIS), concurrent combination (COM) and sequential (SEQ) treatment groups, respectively. B, Median survival of treatment groups and control. Median survival of CTRL, PIC, CIS, COM and SEQ groups were 18.5, 33.5, 30, 42 and 47 days, respectively. All treatment groups had longer lifespan than the control group (p<0.01). No significant difference was found between CIS and PIC (p=0.1864), or between COM and SEQ groups (p=0.1562). There was longer survival in the COM and SEQ groups than in the PIC and CIS groups (p<0.01). C and D, Western blot analysis of tumor samples obtained 3 days after treatment. The expression of p-AKT and p-ERK were suppressed among all treatment groups (C). In contrast, the expression of p-AKT and p-ERK rebounded when tumor became resistant (D). E, Dose response curve of TCCSUP bladder cancer cells treated with different concentrations of pictilisib and cisplatin as determined in a 72-hour cell viability assay. Compared to treatment with cisplatin alone, pictilisib enhanced the cytotoxicity of cisplatin, especially at a lower dose of cisplatin (<1μM). F, Quantitative analysis of western blot of p-AKT and p-S6 in TCCSUP cells after treatment with cisplatin (2 μM) or gemcitabine (0.5 μM) for 24 hours, or in combination with pictilisib (1 μM) for 1 hour. Pictilisib reduced the up-regulation of p-AKT induced by cisplatin treatment at 24 hours and decreased the expression of the downstream effector p-S6 in TCCSUP cells. ns=non-significant, * p<0.05; ** p<0.01.