RESUMO
Cancer cells can acquire resistance to targeted therapeutic agents when the designated targets or their downstream signaling molecules develop protein conformational or activity changes. There is an increasing interest in developing polypharmacologic anticancer agents to target multiple oncoproteins or signaling pathways in cancer cells. The microRNA 125a5p (miR125a5p) is a tumor suppressor, and its expression has frequently been downregulated in tumors. By contrast, the antiapoptotic molecule BIRC5/SURVIVIN is highly expressed in tumors but not in the differentiated normal tissues. In the present study, the development of a BIRC5 gene promoterdriven, miR125a5p expressing, polyLlysineconjugated magnetite iron polypharmacologic nanodrug (pLMNPpSur125a) was reported. The cancer cells selfactivating property and the anticancer effects of this nanodrug were examined in both the multidrug efflux protein ABCB1/MDR1expressing/nonexpressing cancer cells in vitro and in vivo. It was demonstrated that pLMNPpSur125a decreased the expression of ERBB2/HER2, HDAC5, BIRC5, and SP1, which are hot therapeutic targets for cancer in vitro. Notably, pLMNPpSur125a also downregulated the expression of TDO2 in the human KB cervical carcinoma cells. PLMNPpSur125a decreased the viability of various BIRC5expressing cancer cells, regardless of the tissue origin or the expression of ABCB1, but not of the human BIRC5nonexpressing HMEC1 endothelial cells. In vivo, pLMNPpSur125a exhibited potent antitumor growth effects, but without inducing liver toxicity, in various zebrafish humanABCB1expressing and ABCB1nonexpressing tumor xenograft models. In conclusion, pLMNPpSur125a is an easytoprepare and a promising polypharmacological anticancer nanodrug that has the potential to manage numerous malignancies, particularly for patients with BIRC5/ABCB1related drug resistance after prolonged chemotherapeutic treatments.