Cysteamine suppresses invasion, metastasis and prolongs survival by inhibiting matrix metalloproteinases in a mouse model of human pancreatic cancer.

Abstract

BACKGROUND:

Cysteamine, an anti-oxidant aminothiol, is the treatment of choice for nephropathic cystinosis, a rare lysosomal storage disease. Cysteamine is a chemo-sensitization and radioprotection agent and its antitumor effects have been investigated in various tumor cell lines and chemical induced carcinogenesis. Here, we investigated whether cysteamine has anti-tumor and anti-metastatic effects in transplantable human pancreatic cancer, an aggressive metastatic disease.

METHODOLOGY/PRINCIPAL FINDINGS:

Cysteamine's anti-invasion effects were studied by matrigel invasion and cell migration assays in 10 pancreatic cancer cell lines. To study mechanism of action, we examined cell viability and matrix metalloproteinases (MMPs) activity in the cysteamine-treated cells. We also examined cysteamine's anti-metastasis effect in two orthotopic murine models of human pancreatic cancer by measuring peritoneal metastasis and survival of animals. Cysteamine inhibited both migration and invasion of all ten pancreatic cancer cell lines at concentrations (<25 mM) that caused no toxicity to cells. It significantly decreased MMPs activity (IC(50) 38-460 µM) and zymographic gelatinase activity in a dose dependent manner in vitro and in vivo; while mRNA and protein levels of MMP-9, MMP-12 and MMP-14 were slightly increased using the highest cysteamine concentration. In vivo, cysteamine significantly decreased metastasis in two established pancreatic tumor models, although it did not affect the size of primary tumors. Additionally, cysteamine prolonged survival of mice in a dose-dependent manner without causing any toxicity. Similar to the in vitro results, MMP activity was significantly decreased in animal tumors treated with cysteamine. Cysteamine had no clinical or preclinical adverse effects in the host even at the highest dose.

CONCLUSIONS/SIGNIFICANCE:

Our results suggest that cysteamine, an agent with a proven safety profile, may be useful for inhibition of metastasis and prolonging the survival of a host with pancreatic cancer.

• Authors: Toshio Fujisawa, Benjamin Rubin, Akiko Suzuki, Prabhudas S Patel, William A Gahl, Bharat H Joshi, Raj K Puri
• Journal: PloS one (PLoS One) Vol. 7 Issue 4 Pg. e34437 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22532830 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Matrix Metalloproteinase Inhibitors
• Cysteamine
• Matrix Metalloproteinases

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Cysteamine (pharmacology, therapeutic use)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinases (metabolism)
• Mice
• Neoplasm Metastasis
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured