Anti-Tumor Effects of Cardiac Glycosides on Human Lung Cancer Cells and Lung Tumorspheres.
Lung cancer is a leading cause of cancer-related death in the United States. Although several drugs have been developed that target individual biomarkers, their success has been limited due to intrinsic or acquired resistance for the specific targets of such drugs. A more effective approach is to target multiple pathways that dictate cancer progression. Cardiac glycosides demonstrate such multimodal effects on cancer cell survival, and our aim was to evaluate the effect of two naturally occurring monosaccaridic cardiac glycosides-Convallatoxin and Peruvoside on lung cancer cells. Although both drugs had significant anti-proliferative effects on H460 and Calu-3 lung cancer cells, Convallatoxin demonstrated twofold higher activity as compared to Peruvoside using both viability and colony forming assays, suggesting a role for the aglycone region in dictating drug potency. The tumor suppressor p53 was found to be important for action of both drugs-p53-underexpressing cells were less sensitive as compared to p53-positive H460 cells. Further, assessment of p53-underexpressing H460 cells showed that drugs were able to arrest cells in the G0/G1 phase of the cell cycle in a dose-dependent manner. Both drugs significantly inhibited migration and invasion of cancer cells and decreased the viability of floating tumorspheres. An assessment of intracellular pathways indicated that both drugs were able to modulate proteins that are involved in apoptosis, autophagy, cell cycle, proliferation, and EMT. Our data suggest, a promising role for cardiac glycosides in lung cancer treatment, and provides impetus for further investigation of the anti-cancer potential of this class of drugs. J. Cell. Physiol. 232: 2497-2507, 2017. © 2016 Wiley Periodicals, Inc.
Department of Pharmaceutical Sciences, Hampton University School of Pharmacy, Hampton, Virginia.
Vivek
V
Kaushik
Department of Pharmaceutical Sciences, Hampton University School of Pharmacy, Hampton, Virginia.
Juan Sebastian
JS
Yakisich
Department of Pharmaceutical Sciences, Hampton University School of Pharmacy, Hampton, Virginia.
Neelam
N
Azad
Department of Pharmaceutical Sciences, Hampton University School of Pharmacy, Hampton, Virginia.
Yogesh
Y
Kulkarni
Department of Pharmaceutical Sciences, Hampton University School of Pharmacy, Hampton, Virginia.
Rajkumar
R
Venkatadri
Department of Pharmaceutical Sciences, Hampton University School of Pharmacy, Hampton, Virginia.
Clayton
C
Wright
Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia.
Yon
Y
Rojanasakul
Department of Pharmaceutical Sciences, Hampton University School of Pharmacy, Hampton, Virginia.
Anand Krishnan V
AKV
Iyer
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002298:Cardenolides / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D018874:Spheroids, Cellular; D013328:Strophanthins / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D002298:Cardenolides; D013328:Strophanthins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C100098:cannogenin thevetoside; C000505:convallatoxin