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The Marine Natural Product Manzamine A Targets Vacuolar ATPases and Inhibits Autophagy in Pancreatic Cancer Cells
Marine Biomedical and Biotechnology Research Program, Harbor Branch Oceanographic Institute, Florida Atlantic University, 5600 US 1 North, Fort Pierce, FL 34946, USA
Novartis Institutes for BioMedical Research, Developmental & Molecular Pathways, Novartis Pharma AG, WSJ-355.1.051.21, Fabrikstrasse 22, Basel CH-4056, Switzerland
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 1 August 2013; in revised form: 31 August 2013 / Accepted: 3 September 2013 / Published: 17 September 2013
Abstract: Manzamine A, a member of the manzamine alkaloids, was originally isolated from marine sponges of the genus Haliclona. It was recently shown to have activity against pancreatic cancer cells, but the precise mechanism of action remained unclear. To further our understanding of the mechanism of action of manzamine A, chemogenomic profiling in the yeast S. cerevisiae was performed, suggesting that manzamine A is an uncoupler of vacuolar ATPases. Fluorescence microscopy confirmed this effect on yeast vacuoles, where manzamine A produced a phenotype very similar to that of the established v-ATPase inhibitor bafilomycin A1. In pancreatic cancer cells, 10 µM manzamine A affected vacuolar ATPase activity and significantly increased the level of autophagosome marker LC3-II and p62/SQSTM1 as observed by western blot analysis. Treatment with manzamine A in combination with bafilomycin A1 (inhibitor of autophagosome-lysosome fusion) did not change the levels of LC3-II when compared to cells treated with bafilomycin A1 alone, suggesting that manzamine A is a potential inhibitor of autophagy by preventing autophagosome turnover. As autophagy is essential for pancreatic tumor growth, blocking this pathway with manzamine A suggests a promising strategy for the treatment of pancreatic cancer.
Keywords: manzamine A; vacuolar ATPase; lysosome; autophagy; pancreatic cancer
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MDPI and ACS Style
Kallifatidis, G.; Hoepfner, D.; Jaeg, T.; Guzmán, E.A.; Wright, A.E. The Marine Natural Product Manzamine A Targets Vacuolar ATPases and Inhibits Autophagy in Pancreatic Cancer Cells. Mar. Drugs 2013, 11, 3500-3516.
Kallifatidis G, Hoepfner D, Jaeg T, Guzmán EA, Wright AE. The Marine Natural Product Manzamine A Targets Vacuolar ATPases and Inhibits Autophagy in Pancreatic Cancer Cells. Marine Drugs. 2013; 11(9):3500-3516.
Kallifatidis, Georgios; Hoepfner, Dominic; Jaeg, Tiphaine; Guzmán, Esther A.; Wright, Amy E. 2013. "The Marine Natural Product Manzamine A Targets Vacuolar ATPases and Inhibits Autophagy in Pancreatic Cancer Cells." Mar. Drugs 11, no. 9: 3500-3516.