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首页> 外文期刊>Molecular cancer therapeutics >Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling
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Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling

机译：氯喹通过抑制CXCR4和刺猬信号靶向胰腺癌干细胞

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Pancreaticductal adenocarcinoma is one of the deadliest carcinomas andis 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 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, 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. (C) 2014 AACR.
机译：胰腺导管腺癌是最致命的癌症之一，其特征是高度致瘤性和转移性癌干细胞（CSC）。 CSC逃避了现有的疗法，这些疗法优先针对高度增殖且分化程度更高的子代，从而使CSC成为疾病复发的推定来源。因此，为了确定潜在的更有效的治疗方案，我们筛选了既定的和新的化合物消除体外原发性胰腺癌（stem）细胞中CSC的能力以及体内消除患者相应的胰腺癌组织异种移植物的能力。有趣的是，我们发现抗疟药氯喹的体外治疗显着降低了CSCs，转化为大量胰腺癌的体内致瘤性和侵袭性降低。与吉西他滨联用的体内治疗能够更有效地消除已建立的肿瘤并改善总生存期。氯喹的抑制作用与抑制自噬无关，而是由于抑制CXCL12 / CXCR4信号传导，导致ERK和STAT3的磷酸化降低。此外，氯喹通过减少平滑化的产生而显示出对刺猬信号的有效抑制，这转化为声波刺猬诱导的趋化性的显着降低以及CSCs和周围基质中下游靶标的下调。我们的研究表明，迄今为止，氯喹是迄今未曾报道的疗效，是化疗的有效辅助疗法，可更有效地消除肿瘤并提高治愈率。在临床上应进一步探索氯喹，因为其成功可能有助于更快地改善胰腺癌患者的不良预后。 （C）2014 AACR。

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