Ethyl-2-amino-pyrrole-3-carboxylates are active against imatinib-resistant gastrointestinal stromal tumors in vitro and in vivo

We showed recently that ethyl-2-amino-pyrrole-3-carboxylates (EAPCs) exhibit potent antiproliferative activities against a broad spectrum of soft tissue sarcoma and gastrointestinal stromal tumor (GIST) cell lines in vitro. The molecular mechanism of action was owing to inhibition of tubulin polymerization and induction of a robust G2/M cell-cycle arrest, leading to the accumulation of tumor cells in the M-phase and induction of apoptosis. Given that more than 50% of the patients with GISTs develop resistance to imatinib (IM) over the 2 years of IM-based therapy, we examined whether EAPCs exhibit activity against IM-resistant GISTs in vitro and in vivo. A real-time antiproliferation assay illustrated the potent antiproliferative activities of EAPCs against IM-sensitive and IM-resistant GISTs. This was in agreement with the colony formation assay, which revealed potent antiproliferative activities of EAPCs against IM-resistant GISTs, being much stronger when compared with IM and doxorubicin, a topoisomerase II inhibitor. Next, we tested the efficacy of EAPCs in the xenograft model of GISTs, exhibiting secondary IM resistance owing to RTK switch (loss of c-KIT/gain of FGFR2α). A total of 30 5- to 8-week-old female nu/nu mice were subcutaneously inoculated into the flank areas with IM-resistant GIST-T1-R cells (100 μl of 1×107 GIST T-1R cells/ml suspension, in Dulbecco’s PBS). Mice were randomized as control (untreated), IM (50 mg/kg), EAPC-20 (10 mg/kg) or EAPC-24 (1...
Source: Anti-Cancer Drugs - Category: Cancer & Oncology Tags: PRECLINICAL REPORTS Source Type: research