Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling

Abstract

Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehoginduced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer. Mol Cancer Ther; 13(7); 1758-71. Ó2014 AACR.

Abrogation of Autophagy by Chloroquine Alone or in Combination with mTOR Inhibitors Induces Apoptosis in Neuroendocrine Tumor Cells

“…Since CQ was reported to have pleiotropic effects on cells [15,38,39,40,41], our results further suggest that, in this NET cell model, cell apoptosis is related to the inhibitory effect of CQ on autophagy, and not to an alternative effect of CQ on the cells. …”

“…Considering that autophagy may function as a stress-activated prosurvival mechanism in a NET cell model, we hypothesized that inhibition of autophagy by lysosomal inhibitors could promote cell death and enhance the antitumorigenic effects of PI3K/Akt/mTOR pathway inhibitors. As CQ is known to have pleiotropic effects on cells (not only by inhibiting autophagosome degradation) [15,38,39,40,41], we used both pharmacological and genetic approaches to inhibit autophagy. We show for the first time that treatment with CQ alone or together with mTORi exerts robust inhibitory effects on pancreatic NET cell proliferation and survival.…”

New insights into pancreatic cancer stem cells

“…Pancreatic cancer progression was inhibited by sulforaphane, green tea catechins and quercetin by inducing let7a miRNA and inhibiting Kras and ALDH1 activity [82] . The 3-Bromopyruvate, a glycolysis inhibitor blocked CSC signaling in PC cell lines and the spheroids derived from patients [83] . Also, chloroquine (antimalarial agent) decreased CSCs in vitro and in vivo in combination with gemcitabine by inhibiting the hedgehog signaling [84] .…”

Chloroquine affects autophagy to achieve an anticancer effect in EC109 esophageal carcinoma cells in�vitro

“…As an inhibitor of autophagy, a number of studies have suggested CQ as a promising approach for cancer therapy as it is relatively safe and inexpensive (7,22,23). However, the specific anti-tumor mechanisms of CQ remain uncharacterized.…”