Fig. 8: UCN-01 has in vivo efficacy for metastatic HCC.
From: Protein kinase C inhibitors override ZEB1-induced chemoresistance in HCC
a To test the toxicity and tolerability of UCN-01, SKHep1 cells were subcutaneous injected to SCID BALB/C mice (105 cells). UCN-01 was administered at a weekly dose of 2 mg/kg for 14 weeks after tumours became palpable. UCN-01 reduced tumour growth and therefore animals survived longer meeting welfare criteria. b SNU387 or SKHep1 cells were injected orthotopically (2.5 × 105 cells, mixed 50/50 with Matrigel, as 60 μl) to the liver parenchyma of SCID BALB/C mice. UCN-01 was administered at weekly intervals after a 10-day healing time. Three weeks after injection, cachexia secondary to weight loss became evident in the control group. The experiment was terminated when weight loss exceeded 20% compared with untreated group. Livers (c) and lungs (d) were analysed for the presence of cancer cells using 800CW-2DG probe. UCN-01 treated animals (T1–T3) showed reduced fluorescence compared with control group (C1–C3). e Histopathological analysis revealed poorly differentiated HCC in livers and lungs as presented in ×40 (low) and ×100 (high) magnifications. The tumour boundaries were marked with dashed lines. In all cases UCN-01 treatment reduced tumour burden significantly (p < 0.05). The arrows are marking the areas of condensed nucleus (Pyknosis) in UCN-01 treated samples marking dead cancer cells. f IHC using phospho-PKC-substrate antibody revealed that normal livers and lungs have marginally low PKC activity (left panels). Primary and secondary HCC cells have significantly higher PKC-substrate phosphorylation (middle panels) and UCN-01 treatment eliminated PKC activity (right panels)
