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Hydroxamate-type matrix metalloproteinase inhibitor batimastat promotes liver metastasis
1Klinische Forschergruppe der Frauenklinik, Institut für Experimentelle Onkologie und Therapieforschung der Technischen Universität München, Munich, Germany. achim.krueger@lrz.tu-muenchen.de
Abstract:
Overexpression of matrix metalloproteinases (MMPs) facilitates tumor cell invasion. Synthetic MMP inhibitors such as batimastat have been designed to treat cancer. We report that because of batimastat treatment, human breast carcinoma cells metastasized to the liver in nude mice and that an increase of liver metastases of murine T-cell lymphoma cells was observed in syngeneic mice. Batimastat treatment also caused liver-specific overexpression of MMPs-2, -9, and mRNA up-regulation of angiogenesis factors and caspase-1, even in tumor-free animals. Induction of organ-specific side effects need to be taken into account regarding further development and clinical use of synthetic MMP inhibitors.
Insights
Batimastat, a synthetic matrix metalloproteinase (MMP) inhibitor, unexpectedly increased cancer metastasis and liver damage in mice. These findings highlight potential organ-specific side effects of MMP inhibitors in cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Matrix metalloproteinases (MMPs) play a crucial role in tumor cell invasion and metastasis.
- Synthetic MMP inhibitors are being developed as anti-cancer therapeutics.
- The potential for off-target effects of these inhibitors requires thorough investigation.
Purpose of the Study:
- To investigate the effects of batimastat, a synthetic MMP inhibitor, on cancer metastasis and associated molecular changes.
- To evaluate the potential for organ-specific toxicity induced by batimastat treatment.
Main Methods:
- Administration of batimastat to mice bearing human breast carcinoma or murine T-cell lymphoma.
- Assessment of tumor metastasis to the liver.
- Analysis of liver-specific MMP expression (MMP-2, MMP-9) and mRNA levels of angiogenesis factors and caspase-1.
Main Results:
- Batimastat treatment led to increased liver metastasis in both human breast carcinoma and murine T-cell lymphoma models.
- Liver-specific overexpression of MMP-2 and MMP-9 was observed.
- Upregulation of angiogenesis factors and caspase-1 mRNA was detected in the liver, even in tumor-free animals.
Conclusions:
- Batimastat treatment can paradoxically promote cancer metastasis and induce liver-specific overexpression of MMPs.
- The induction of angiogenesis factors and caspase-1 suggests a potential mechanism for organ-specific side effects.
- These findings necessitate careful consideration of organ-specific side effects during the clinical development of synthetic MMP inhibitors.
