Chloroquine Eliminates Cancer Stem Cells Through Deregulation of Jak2 and DNMT1

Abstract

Triple negative breast cancer (TNBC) is known to contain a high percentage of CD44+/CD24−/low cancer stem cells (CSC), corresponding with a poor prognosis despite systemic chemotherapy. Chloroquine (CQ), an anti-malarial drug, is a lysotropic reagent which inhibits autophagy. CQ was identified as a potential CSC inhibitor through in silico gene expression signature analysis of the CD44+/CD24−/low CSC population. Autophagy plays a critical role in adaptation to stress conditions in cancer cells, and is related with drug resistance and CSC maintenance. Thus the objectives of this study were to examine the potential enhanced efficacy arising from addition of chloroquine (CQ) to standard chemotherapy (paclitaxel) in TNBC and to identify the mechanism by which CQ eliminates CSCs in TNBCs. Herein, we report that CQ sensitizes TNBC cells to paclitaxel through inhibition of autophagy and reduces the CD44+/CD24−/low CSC population in both preclinical and clinical settings. Also, we are the first to report a mechanism by which CQ regulates the CSCs in TNBC through inhibition of the Janus-activated kinase 2 (Jak2) - Signal transducer and activator of transcription 3 (STAT3) signaling pathway by reducing the expression of Jak2 and DNA methyltransferase 1 (DNMT1).

Identifying and targeting tumor-initiating cells in the treatment of breast cancer

“…Consistent with these data, a recent study showed that the anti-malarial drug chloroquine inhibits Jak2/STAT3 signaling, decreases the MSFE in a number of TN breast cancer cell lines, and decreases the TIC frequency in MDA231 xenograft tumors (Choi, et al 2014). Importantly, it has also been shown that breast TIC-derived IL-6 recruits mesenchymal stem cells, which communicate with breast TICs by secreting additional cytokines and chemokines, creating a breast TIC-promoting microenvironment (Liu, et al 2011).…”

Chloroquine exerts antitumor effects on NB4 acute promyelocytic leukemia cells and functions synergistically with arsenic trioxide

“…Previous studies have demonstrated that the potential mechanisms for the antitumor effects of CQ may include the inhibition of autophagy (22), the induction of apoptosis (23,24), the elimination of cancer stem cells (25), the normalization of vasculature (26), the enhancement of the immune response (27) and the arrest of cell cycle progression (22). The focus of the present study was primarily on the apoptosis, cell cycle distribution and autophagy induced by CQ treatment.…”

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

“…In order to verify whether modulation of 4 autophagy could reduce the 'stemness' or induce apoptosis of CSCs, we treated ALDH hi cells with 5 CQ, a well-known autophagy inhibitor which can impair endosomal acidification, block endosome 6 and autophagosome fusion with lysosomes, and result in accumulation of LC3-II and p62 proteins 7 (p62 is an adaptor protein that delivers specific ribosomal and bulk ubiquitinated cytosolic 8 proteins to autolysosomes, eventually being delivered to lysosomes for degradation) [38][39]. As 9 shown in Fig.…”