Strategy for Restoring Drug Sensitivity to Triple-Negative Breast Cancer

摘要

Doxorubicin (DOXO), cisplatin (CDDP) and paclitaxel (PAC) are most commonly used chemotherapeutic drugs for p53 mutant TNBC; however, the treatments eventually fail due to acquired drug resistance and toxicity. Here we report on the reconstitution of p53 in a p53-independent manner via p73 as an exciting possibility for improving cancer therapy. -TEA, an analog of vitamin E, which exhibits potent anticancer actions in vitro and in vivo, cooperates with DOXO or CDDP to enhance anticancer actions detected by apoptosis in p53 mutant TNBC cell lines. The combination treatments of -TEA with DOXO or CDDP enhanced p73 protein expression, enhanced levels of death receptors-5 (DR5), CD95/APO-1 (Fas), Bax and Noxa proteins, and reduced antiapoptotic Bcl-2 protein levels, all of which are p53 regulated genes. The combination treatments induced enhanced levels of phospho-c-Ab1 and -JNK, as well as induced Yap nuclear translocation, which are upstream events for p73 activation. Data demonstrated that -TEA cooperates with chemotherapeutic drugs (DOXO and CDDP) to induce apoptosis via targeting p53 downstream apoptotic mediators in a p73-dependent manner. Furthermore, in vivo data show that -TEA inhibits DOXO-induced lung metastasis. Taken together, our in vitro and in vivo data suggest that the combination of -TEA plus clinically relevant chemotherapeutic drugs enhances anticancer actions in p53 mutant TNBC cells via activation of p73.