Abstract
The differentiation therapy of breast cancer stem cells (CSCs) represents a significant strategy to treat cancer, but inefficient delivery to CSCs hinders the efficacy of differentiation agents. In this work, we report a type of functional dendrisomes constructed by the synthesized amphiphilic dendrimers, which enhance cellular uptake by breast CSCs, differentiate breast CSCs by carrying all-trans retinoic acid (ATRA), and increase the anticancer efficacy by carrying ATRA and docetaxel (DTX) in vitro and in breast cancer-bearing mice. The study further reveals the mechanism of cellular uptake by breast CSCs and uncovers the differentiation mechanism by analyzing relevant signal molecules, transcription factors, and cell cycle-associated signaling pathways during differentiation therapy in breast CSCs. Hence, this study offers a novel type of functional dendrisomes for differentiation therapy of breast CSCs and has significant clinical implications.
Highlights
Cancer stem cells (CSCs) are initiator cancer cells that possess the capability to generate all types of cells
MCF-7 and MDA-MB-435S breast cancer cells were purchased from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (Beijing, China), and cultured in Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 10% fetal bovine serum (FBS), 100 U/mL penicillin, and 100 μg/mL streptomycin
The results showed that the functional dendrisomes carrying all-trans retinoic acid (ATRA) resulted in a remarkable cell-cycle arrest of cancer stem cells (CSCs) at the G0/G1 phase (CSCs 53.19 ± 0.99% vs. differentiated mature cells (DMCs) 80.97 ± 0.60%), demonstrating that cell-cycle arrest was involved in differentiation
Summary
Cancer stem cells (CSCs) are initiator cancer cells that possess the capability to generate all types of cells. Such cells may give rise to mature cancer cells through selfrenewal and differentiation[1]. CSCs have been identified in breast cancer[2,3] as a subset of cells that cause relapse and metastasis by producing new tumors[4]. CSCs exist in the vicinity or the inside of tumor tissue, often stay at rest, express high levels of ATP-binding cassette transporters (ABC transporters)[5] and have strong DNA repair ability[6], leading to the insensitivity to chemotherapy and radiotherapy[7].
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