TRX-E-002-1 decreases tumor burden and activates c-jun in vivo. Mice were treated i.p. daily with 50 mg/kg or 100 mg/kg TRX-E-002-1 . (A) quantification of total i.p. tumor burden at end of study; (B) western blot analysis for p-c-Jun and total c-Jun in residual tumors from C, control mice or T, mice treated with TRX-E-002-1 100 mg/kg. Representative western blot from two controls and two TRX-E-002-1- treated mice; (C) quantification total i.p. tumor burden at end of maintenance treatment
ARTICLE ABSTRACT
Chemoresistance is a major hurdle in the management of patients with epithelial ovarian cancer and is responsible for its high mortality. Studies have shown that chemoresistance is due to the presence of a subgroup of cancer cells with stemness properties and a high capacity for tumor repair. We have developed a library of super-benzopyran analogues to generate potent compounds that can induce cell death in chemoresistant cancer stem cells. TRX-E-002-1 is identified as the most potent analogue and can induce cell death in all chemoresistant CD44+/MyD88+ ovarian cancer stem cells tested (IC50 = 50 nmol/L). TRX-E-002-1 is also potent against spheroid cultures formed from cancer stem cells, chemosensitive CD44−/MyD88− ovarian cancer cells, and heterogeneous cultures of ovarian cancer cells. Cell death was associated with the phosphorylation and increased levels of c-Jun and induction of caspases. In vivo, TRX-E-002-1 given as daily intraperitoneal monotherapy at 100 mg/kg significantly decreased intraperitoneal tumor burden compared with vehicle control. When given in combination with cisplatin, animals receiving the combination of cisplatin and TRX-E-002-1 showed decreased tumor burden compared with each monotherapy. Finally, TRX-E-002-1 given as maintenance treatment after paclitaxel significantly delayed disease recurrence. Our results suggest that TRX-E-002-1 may fill the current need for better therapeutic options in the control and management of recurrent ovarian cancer and may help improve patient survival. Mol Cancer Ther; 15(6); 1279–90. ©2016 AACR.
