Figure 4.

SC-43 shows more effective tumor inhibition than regorafenib in a CRC subcutaneous tumor model. (A) Tumor sizes were measured at the times indicated after mice received regorafenib (10 mg/kg per day), SC-43 (10 mg/kg per day), or vehicle. Points, mean (n = 7); bars, SEM. *P < .05, **P < .01. (B) Tumor weight was measured on day 25 after tumor excision. Columns, mean; bars, SD. *P < .05, **P < .01. (C, upper panels) The Levels of p-STAT3^Tyr705 and STAT3 were measured by Western blotting on day 25 after excision of vehicle-, regorafenib-, and SC-43–treated tumors. β-Actin was used as a loading control. (Lower panels) SHP-1 activity was measured in vehicle-, regorafenib-, and sc-43–treated tumors on day 25 after tumor excision. Columns, mean; bars, SD. *P < .05, **P < .01. (D) SC-43 induced potent apoptosis in CRC which was mediated through SC-43–enhanced SHP-1 activity. SC-43 had the potential to dock to the inhibitory N-SH2 domain and the catalytic PTP domain of SHP-1, resulting in the direct relief of autoinhibition of SHP-1. The activity Of SHP-1 tyrosine phosphatase specifically increased the susceptibility to p-STAT3^Tyr705, which was the major trigger of apoptosis.