Environmentally relevant concentration of arsenic trioxide and humic acid promoted tumor progression of human cervical cancer cells: In vivo and in vitro studies.
In a previous study, treatment at higher concentrations of arsenic trioxide or co-exposure to arsenic trioxide and humic acid was found to be inhibited cell growth of cervical cancer cells (SiHa cells) by reactive oxygen species generation. However, treatment at lower concentrations slightly increased cell viability. Here, we investigate the enhancement of progression effects of environmentally relevant concentration of humic acid and arsenic trioxide in SiHa cell lines in vitro and in vivo by measuring cell proliferation, migration, invasion, and the carcinogenesis-related protein (MMP-2, MMP-9, and VEGF-A) expressions. SiHa cells treated with low concentrations of humic acid and arsenic trioxide alone or in co-exposure significantly increased reactive oxygen species, glutathione levels, cell proliferation, scratch wound-healing activities, migration abilities, and MMP-2 expression as compared to the untreated control. In vivo the tumor volume of either single drug (humic acid or arsenic trioxide) or combined drug-treated group was significantly larger than that of the control for an additional 45 days after tumor cell injection on the back of NOD/SCID mice. Levels of MMP-2, MMP-9, and VEGF-A, also significantly increased compared to the control. Histopathologic effects of all tumor cells appeared round in cell shape with high mitosis, focal hyperkeratosis and epidermal hyperplasia in the skin, and some tumor growth in the muscle were observed. Our results may indicate that exposure to low concentrations of arsenic trioxide and humic acid is associated with the progression of cervical cancer. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1121-1132, 2016.
Institute of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan.|Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, 402, Taiwan.
Min-Ling
ML
Tsai
Department of Occupational Safety and Health, College of Health Care and Management, Chung Shan Medical University, Taichung, 402, Taiwan.|Department of Occupational Medicine, Chung Shan Medical University Hospital, Taichung, 402, Taiwan.
Cheng-Chieh
CC
Yen
Institute of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan.
Fung-Jou
FJ
Lu
Department of Early Childhood Educare, TransWorld University, Yun-lin, 640, Taiwan.
Hung-Chih
HC
Ting
Institute of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan.|Division of Nephrology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, 402, Taiwan.
Horng-Rong
HR
Chang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006812:Humic Substances / Q000633:toxicity*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008938:Mitosis / Q000187:drug effects; D010087:Oxides / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014183:Transplantation, Heterologous; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A
D001152:Arsenicals; D006812:Humic Substances; D010087:Oxides; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D005978:Glutathione; D000077237:Arsenic Trioxide
arsenic trioxide; human cervical cancer cells; humic acid; tumor progression