- مبلغ: ۸۶,۰۰۰ تومان
- مبلغ: ۹۱,۰۰۰ تومان
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.
Hepatocellular carcinoma (HCC) is one of the most common malignancies, and its incidence appears rapidly increasing worldwide . Although various treatments have been applied in the management of HCC , chemotherapy still remains the top therapeutic choice for most patients. Particularly, doxorubicin (DOX), as the first-line chemotherapeutic agent, shows effective antitumor effects on HCC, and significantly prolongs patient survival. However, its anticancer efficacy is limited due to the frequent emergence of drug resistance during the treatment [3,4]. Therefore, identifying the mechanism of drug resistance developed in tumor may provide a precise strategy for developing effective treatments aimed to fight the therapeutic resistance.
In this work, we have identified that HepG2 tumor spheroids rapidly develop acquired drug resistance during DOX treatment by down-regulating p53, which could be recovered by co-treatment with MDM2 inhibitor MI-773, for the first time. We therefore developed a pH-sensitive liposomal formulation of DOX and MI-773 (LipD/M@CMCS) for overcoming acquired DOX resistance. LipD/M@CMCS converted to cationic liposomes in acidic tumor microenvironment, thereby endowing them with tumor specificity and improved cellular uptake. Particularly, in vivo antitumor studies showed that LipD/M@CMCS improved therapeutic efficacy, overcomed drug resistance and reduced systemic toxicity, in comparison of free DOX with MI-773 and LipD@CMCS. Given these encouraging results, stimuli responsive combination therapy of DOX and MI-773 represents a potent therapeutic strategy for the management of malignant tumors.