Nanoparticle-facilitated autophagy inhibition promotes the efficacy of chemotherapeutics against breast cancer stem cells

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• 作者：Rong Sun^a ; ¹ ; Song Shen^b ; ¹ ; Yun-Jiao Zhang^a ; Cong-Fei Xu^a ; Zhi-Ting Cao^a ; Long-Ping Wen^a ; Jun Wang^a ; ^b ; ^c ; ^d ; ^{jwang699@ustc.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cancer stem cells ; Autophagy inhibition ; Chemotherapeutics ; Combination therapy ; Nanoparticles ; Breast cancer
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：103
• 期：Complete
• 页码：44-55
• 全文大小：2062 K

文摘

Cancer stem cells (CSCs) have garnered increasing attention over the past decade, as they are believed to play a crucial role in tumor initiation, progression and metastasis, relapse and drug resistance. Therapeutic strategies which simultaneously exterminate both bulk tumor cells and the rare CSC subpopulation may produce striking response and result in long-term tumor remission. Accumulating evidence provides insight into the function of autophagy in maintenance, plasticity and survival of CSCs. The role of autophagy in the susceptibility of breast CSCs to chemotherapeutics was investigated in the present work, reduced ‘stemness’ and increased susceptibility to chemotherapy drugs (doxorubicin, DOX and docetaxel, DTXL) were observed after chloroquine (CQ)-mediated autophagy inhibition in sorted ALDH^hi cells of breast cancer cell line MDA-MB-231. We further proved that nanoparticle-mediated autophagy inhibition promoted the efficacy of chemotherapeutics against ALDH^hi MDA-MB-231 cells in vitro. Administration of drug delivery systems significantly prolonged the circulation half-life and augmented enrichment of two different drugs in tumor tissues and ALDH^hi cells. More importantly, compared with single treatment, the combined delivery systems NP_CQ/NP_DOX and NP_CQ/DOX (NP_CQ/NP_DTXL and NP_CQ/DTXL) showed most effective and persistent tumor growth inhibitory effect by eliminating bulk tumor cells as well as CSCs (p < 0.01) in an MDA-MB-231 orthotopic tumor murine model. Therefore, our research provides new insights into the nanoparticle-facilitated combination of autophagy inhibition and chemotherapy for effective therapy of breast cancer.