TASIN-1 is a small molecule inhibitor of mutant adenomatous polyposis coli (APC) [1].
Adenomatous polyposis coli (APC) is a multifunctional tumor suppressor gene that is mutated in more than 80% of colon tumors. APC plays an important role in the negative regulation of canonical WNT signaling pathway through proteasomal degradation of b-catenin. APC is involved in cell cycle control, migration, differentiation, and apoptosis [1].
TASIN-1 is a selective inhibitor of mutant APC. In two authentic human CRC cell lines HCT116 (WT APC) and DLD1 (truncated APC1417), TASIN-1 exhibited potent and selective toxicity toward DLD1 cells with IC50 value of 70 nM but not toward HCT116 cells (IC50 >50 μM). TASIN-1 also reduced the endogenous cholesterol biosynthesis rate. TASIN-1 exerted its killing effects primarily by depleting cholesterol through inhibition of emopamil-binding protein (EBP) activity. However, knockdown of truncated APC (>90%) expression desensitized DLD1 cells to TASIN-1, suggesting that APC is required for TASIN-1's cytotoxicity [1].
In nude mice with established DLD1 and HT29 tumors, intraperitoneal injection of TASIN-1 twice daily for 18 days reduced the size of tumor xenografts and tumor growth rates. TASIN-1 resulted in the appearance of apoptotic cells with fragmented nuclei and induced an increase in cleaved caspase 3 and cleaved PARP1. However, TASIN-1 did not inhibit tumor growth in HCT116 (WT APC) xenografts. In a genetically engineered CRC mouse model, TASIN-1 significantly reduced tumor formation in the colons of CPC;Apc mice [1].
Reference:
1.Lu Zhang, Panayotis C. Theodoropoulos, Ugur Eskiocak, et al. Selective targeting of mutant adenomatous polyposis coli (APC) in colorectal cancer. Science Translational Medicine 19 Oct 2016: Vol. 8, Issue 361, pp. 361ra140.