Induction of Cell Death in Pancreatic Tumors by Zinc and Its Fluorescence Chelator TSQ.

Abstract

Pancreatic ductal adenocarcinoma is a devastating cancer and is the fourth-leading cause of cancer death in the USA. Zinc is abundant in the pancreas, but its role in pancreatic cancer remains elusive. The aim of this study is to determine effects of zinc chelators in pancreatic cancer. Pdx1Cre and LSL-KrasG12D mice expressing an oncogenic mutation of KRAS develop pancreatic intraepithelial neoplasia in the pancreas. We found that EPCAM + tumors developed in the mouse pancreas store zinc that is detectable by fluorescence-activated cell sorting using N-(6-methoxy-8-quinolyl)-p-toluenesulfonamide (TSQ), a fluorescence chelator. EPCAM + TSQ + tumor cells isolated from the mouse pancreas formed organoids in matrigel. Upon treatment with N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN), a zinc chelator, the organoids degenerated and its negative effect was rescued by co-treatment with zinc, indicating that zinc is necessary for the growth and survival of tumor organoids. Different from TPEN, TSQ treatment did not affect the organoid growth and survival. Interestingly, co-treatment with TSQ and zinc resulted in strong emission of TSQ fluorescence in the organoid and its degeneration. The combination of zinc with TSQ, but not with TPEN, also induced cell death in PANC-1, a human pancreatic cancer cell line. These results suggest that a TSQ-zinc complex formed in pancreatic tumors induces cell death if zinc is overloaded.