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 the chemoresistant cancer stem cells. TRX-E-002-1 is identified as the most potent analog and can induce cell death in all chemoresistant CD44+/MyD88+ ovarian cancer stem cells tested (IC50 ~ 50 nM). 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 i.p. monotherapy at 100 mg/kg significantly decreased i.p. tumor burden compared to vehicle control. When given in combination with Cisplatin, animals receiving the combination of Cisplatin and TRX-E-002-1 showed decreased tumor burden compared to each monotherapy. Finally, TRX-E-002-1 given as maintenance treatment post-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.
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