KML001 Induces Apoptosis and Autophagic Cell Death in Prostate Cancer Cells via Oxidative Stress Pathway.
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.
Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Dalsan
D
You
Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Yunlim
Y
Kim
Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Myoung Jin
MJ
Jang
Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Chunwoo
C
Lee
Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
In Gab
IG
Jeong
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Yong Mee
YM
Cho
Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Jung Jin
JJ
Hwang
Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Jun Hyuk
JH
Hong
Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Hanjong
H
Ahn
Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Choung-Soo
CS
Kim
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D017670:Sodium Compounds / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000975:Antioxidants; D018053:Arsenites; D017670:Sodium Compounds; C017947:sodium arsenite