The marine compound spongistatin 1 targets pancreatic tumor progression and metastasis.
Treatment of pancreatic cancer remains a major challenge and new anticancer drugs are urgently required. Our study presents the marine natural compound spongistatin 1 as a promising experimental drug. Spongistatin 1 was applied in an orthotopic in vivo model of human pancreatic cancer. Spongistatin 1 significantly reduced tumor growth, which correlates with a strong apoptosis induction (DNA-fragmentation) and long-term effects on clonogenic survival of pancreatic tumor cells (L3.6pl) in vitro. In addition, the formation of metastasis was reduced in spongistatin 1-treated mice, which is in line with a diminished MMP-9 activity in tumor tissue determined by zymography. Based on the pronounced efficacy of spongistatin 1, the underlying mechanisms were studied in more detail. In vitro adhesion, as well as migration, and invasion assays showed spongistatin 1 to influence these critical steps in the metastatic cascade. Furthermore, spongistatin 1 induced anoikis in L3.6pl cells. Exposure to spongistatin 1 leads to phosphorylation, and thus inactivation of the antiapoptotic protein Bcl-2 in pancreatic tumor cells. siRNA experiments silencing Bcl-2 suggest a role of Bcl-2 in anoikis and cell migration. Taken together, spongistatin 1 not only proved to be a potent experimental drug but also served as a chemical tool to examine the role of the antiapoptotic protein Bcl-2 in pancreas carcinoma, thereby supporting the hypothesis of a link between apoptosis signaling and metastasis.
Department of Pharmacy, Center for Drug Research, University of Munich, Munich, Germany.
Andrea S
AS
Rothmeier
Uta M
UM
Schneiders
Romina M
RM
Wiedmann
Ivan
I
Ischenko
Christiane J
CJ
Bruns
Anita
A
Rudy
Stefan
S
Zahler
Angelika M
AM
Vollmar
D000818:Animals; D023102:Anoikis / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D005260:Female; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050257:Tubulin Modulators / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000095702:Polyether Toxins
D018942:Macrolides; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D050257:Tubulin Modulators; C083856:spongistatin 1; D000095702:Polyether Toxins