Abstract
We investigated the effects of KML001 (NaAsO2, sodium metaarsenite, Kominox), an orally bioavailable arsenic compound, on the growth and death of human prostate cancer cells and its mechanism of action. Growth inhibition was assessed by cytotoxicity assays in the presence or absence of inhibitor of apoptosis, inhibitor of autophagy or antioxidant N-Acetyl-L-cysteine to study mechanism of cell death induced by KML001 in PC3, DU145 and LNCaP prostate cancer cell lines. Electron microscopy, flow cytometry and Western blotting were used to study apoptotic and autophagic mechanisms. The DU145 xenograft model was used to determine the efficacy of KML001 in vivo. KML001 decreased the viability of cells and increased the percentage of annexin V-positive cells dose-dependently in prostate cancer cells, and LNCaP cells were more sensitive to KML001 than PC3 or DU145 cells. Electron microscopy revealed typical apoptotic characters and autophagic vacuoles in cells treated with KML001. Exposure to KML001 in prostate cancer cells induced apoptosis and autophagy in a time- and dose-dependent manner. KML001 induced dose-dependent accumulation of reactive oxygen species, and scavenging the reactive oxygen species with N-Acetyl-L-cysteine reduced LC3 and cleaved poly (ADP-ribose) polymerase. KML001 significantly inhibited tumor growth in the DU145 xenograft model. In addition, significant decrease of proliferation and significant increases of apoptosis and autophagy were observed in KML001-treated tumors than in vehicle-treated tumors. Exposure of human prostate cancer cells to KML001 induced both apoptosis and autophagic cell death via oxidative stress pathway. And KML001 had an antiproliferative effect on DU145 cells in xenograft mice.
Highlights
While arsenic compounds are widely known as carcinogens that induce cancers in many human tissues, arsenic trioxide (As2O3, ATO) has been demonstrated clinically to be an effective therapeutic agent for the treatment of acute promyelocytic leukemia [1,2]
To determine whether treatment with KML001 (10 μM) induces apoptosis, the ultrastructure of KML001-treated PC3 cells was analyzed by electron microscopy
PC3 cells treated with KML001 showed typical apoptotic characters, including a smaller nucleus, more concentrated cytoplasm, crumpled nuclear membrane, and chromosomes condensed into a semilunar shape with attachments to the nuclear and cellular membranes
Summary
While arsenic compounds are widely known as carcinogens that induce cancers in many human tissues, arsenic trioxide (As2O3, ATO) has been demonstrated clinically to be an effective therapeutic agent for the treatment of acute promyelocytic leukemia [1,2]. Its anticancer mechanism of action is not well understood, ATO has been found to regulate various biological functions, including cell proliferation, apoptosis, differentiation, and angiogenesis in various cell lines [3]. Because ATO was successful in treating acute promyelocytic leukemia [1,2,4], arsenicals are experiencing a revival in modern cancer medicine [5]. Trivalent arsenicals, including KML001 (NaAsO2, sodium metaarsenite, Kominox) and ATO, inhibit many enzymes by reacting with biological ligands that have free sulfur groups [3,6]. The mechanism of action of ATO is well-known [7,8,9,10,11,12], that of KML001 is still under investigation [13,14]
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