TRX-E-002-1 Induces c-Jun-Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo

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.