AI Article Synopsis
- Drug resistance in cancer treatment, specifically to the drug doxorubicin (DOX), is primarily due to MDM2-mediated degradation of the p53 protein, which can be reversed using the MDM2 inhibitor MI-773.
- A pH-sensitive liposomal formulation combining DOX and MI-773 (LipD/M@CMCS) was created to specifically target hepatocellular carcinoma by stabilizing in normal conditions and becoming active in the acidic tumor environment.
- LipD/M@CMCS effectively induced cancer cell death in HepG2 tumor spheroids and significantly inhibited tumor growth while minimizing side effects, suggesting that targeted regulation of MDM2 could illuminate new pathways for managing drug resistance in malignant tumors.
Article Abstract
Drug resistance is a major hindrance in the anticancer treatment, which encourages the development of effective therapeutic strategies. For the first time, MDM2-mediated p53 degradation was identified as a critical factor for developing acquired resistance of doxorubicin (DOX) in HepG2 tumor spheroids, which could be effectively reversed by MDM2 inhibitor MI-773, thereby improving anticancer effects. Therefore, a pH-sensitive liposomal formulation of DOX and MI-773 (LipD/M@CMCS) were developed for recovering p53-mediated DOX resistance in hepatocellular carcinoma. LipD/M@CMCS were composed of cationic liposomes covered with carboxymethyl chitosan (pI = 6.8), and were stable in the physiological condition (pH 7.4), but rapidly converted to cationic liposomes in tumor acidic microenvironment (pH 6.5), endowing them with tumor specificity and enhanced cellular uptake. We showed that LipD/M@CMCS could not only effectively induce cell apoptosis in HepG2 tumor spheroids, but significantly inhibit tumor growth with minimal adverse effects. In summary, selective regulation of MDM2 in cancer cells is a promising strategy to overcome DOX resistance, and may provide a perspective on the management of malignant tumors.
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| http://dx.doi.org/10.1016/j.msec.2019.110403 | DOI Listing |
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