Common chemotherapy is unable to eliminate the heterogeneous side population of cancer cells （such as cancer stem-like cells）, resulting in poor prognosis. The heterogeneity of cancer cells causes an extensive multidrug resistance through the aberrantly active Hedgehog （Hh） signaling pathway. Cyclopamine is a chemical compound that can block Hh signaling pathway, and a combination use of cyclopamine with anticancer drug would be beneficial for killing heterogeneous cancer cells. In the present study, we aimed to develop a kind type of fimctional drug liposomes for eliminating heterogeneous cancer, The study was performed on human breast cancer cells. A distearoylphosphoethanolamine polyethylene glycol （DSPE-PEG2000）-cyclopamine conjugate was newly synthesized by a nucleophilic substitution reaction, and confirmed by MALDI-TOF mass. An HPLC method was established and validated for qualification of epirubicin. Functional epimbicin liposomes were successful constructed by modifying with DSPE-PEG2o00-cyclopamine, displaying a particle size in nano-scale （approximately 98 nm） and a high epirubicin encapsulation （〉97%）. The CD44＋/CD24-side population was characterized in defining heterogeneous breast cancer cells. As compared with regular epirubicin liposomes, fimctional epirubicin liposomes exhibited an evidently enhanced cellular drug uptake and a significant killing effect in overall breast cancer cells. In conclusion, the functional epirubicin liposomes could be a useful drug delivery carrier for eliminating heterogeneous breast cancer cells.
A single drug chemotherapy fails to eliminate residual cancer cells due to the existence of the multidrug resistance （MDR）. In the present study, we aimed to develop a compound epirubicin plus quinine injection, to characterize the efficacy in treatment of the drug-resistant breast cancer, and to reveal the involved mechanisms. The HPLC-UV methods were developed for quantifications, and the evaluations were performed on the drug-resistant human breast cancer MCF-7/adr cells using a high content screening system. Results demonstrated that the compound epirubicin plus quinine injection was able to effectively block the drug efflux, exhibiting an evidently overall efficacy in treatment of the resistant breast cancer cells by direct killing effect and by apoptosis-inducing effect. In the formulation, quinine played multiple roles in blocking drug efflux and in inducing the apoptosis of the resistant breast cancer cells. The apoptosis signaling pathways were associated with a cascade of reactions by activating Caspase family and by inhibiting Bcl-2 family. In conclusion, the present study preliminarily revealed the efficacy and mechanism of the compound epirubicin plus quinine formulation in treatment of the drug-resistant breast cancer, and offered a potential strategy to overcome drug resistance in cancer treatments.
