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

Pancreaticductal adenocarcinoma isoneof thedeadliest carcinomasand is characterizedbyhighly 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 potentiallymore effective treatment regimens,we screened established and new compounds for their ability to eliminateCSCs inprimarypancreatic cancer (stem) cells in vitro and correspondingpatient-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 inva-siveness in a large panel of pancreatic cancers. In vivo treatment in combinationwith gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloro-quinewasnot related to inhibitionofautophagy,butwasdue to inhibitionofCXCL12/CXCR4signaling, resulting in reducedphosphorylationofERKand STAT3. Furthermore, chloroquine showedpotent inhibition of hedgehog signaling bydecreasing theproductionof Smoothened, translating into a significant reduction in sonic hedgehog-induced 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, offeringmore efficient tumor elimination and improved cure rates. Chloroquine shouldbe 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. 2014 AACR