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Characterization of the Effects of Migrastatic Inhibitors on 3D Tumor Spheroid Invasion by High-resolution Confocal Microscopy
Published on: September 16, 2019
Migrastatin analogues inhibit canine mammary cancer cell migration and invasion
Kinga Majchrzak1, Daniele Lo Re, Małgorzata Gajewska
1Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland ; Department of Animal Environment Biology, Faculty of Animal Sciences, Warsaw University of Life Sciences, Warsaw, Poland.
Background:
Cancer spread to other organs is the main cause of death of oncological patients. Migration of cancer cells from a primary tumour is the crucial step in the complex process of metastasis, therefore blocking this process is currently the main treatment strategy. Metastasis inhibitors derived from natural products, such as, migrastatin, are very promising anticancer agents. Thus, the aim of our study was to investigate the effect of six migrastatin analogues (MGSTA-1 to 6) on migration and invasion of canine mammary adenocarcinoma cell lines isolated from primary tumours and their metastases to the lungs. Canine mammary tumours constitute a valuable tool for studying multiple aspect of human cancer.
Results:
OUR RESULTS SHOWED THAT TWO OF SIX FULLY SYNTHETIC ANALOGUES OF MIGRASTATIN: MGSTA-5 and MGSTA-6 were potent inhibitors of canine mammary cancer cells migration and invasion. These data were obtained using the wound healing test, as well as trans-well migration and invasion assays. Furthermore, the treatment of cancer cells with the most effective compound (MGSTA-6) disturbed binding between filamentous F-actin and fascin1. Confocal microscopy analyses revealed that treatment with MGSTA-6 increased the presence of unbound fascin1 and reduced co-localization of F-actin and fascin1 in canine cancer cells. Most likely, actin filaments were not cross-linked by fascin1 and did not generate the typical filopodial architecture of actin filaments in response to the activity of MGSTA-6. Thus, administration of MGSTA-6 results in decreased formation of filopodia protrusions and stress fibres in canine mammary cancer cells, causing inhibition of cancer migration and invasion.
Conclusion:
Two synthetic migrastatin analogues (MGSTA-5 and MGSTA-6) were shown to be promising compounds for inhibition of cancer metastasis. They may have beneficial therapeutic effects in cancer therapy in dogs, especially in combination with other anticancer drugs. However, further in vivo studies are required to verify this hypothesis.
Insights
Two synthetic migrastatin analogues, MGSTA-5 and MGSTA-6, effectively inhibited canine cancer cell migration and invasion by disrupting actin-fascin interactions. These compounds show promise for cancer metastasis treatment.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Cancer metastasis, the spread of cancer cells, is a primary cause of mortality in oncological patients.
- Inhibiting cancer cell migration is a key therapeutic strategy.
- Migrastatin analogues are promising natural product-derived anticancer agents.
Purpose of the Study:
- To investigate the anti-migratory and anti-invasive effects of six synthetic migrastatin analogues (MGSTA-1 to 6).
- To evaluate these effects on canine mammary adenocarcinoma cell lines from primary tumors and lung metastases.
- To explore the potential of canine mammary tumors as a model for human cancer research.
Main Methods:
- Utilized wound healing assays to assess cell migration.
- Employed trans-well migration and invasion assays.
- Conducted confocal microscopy to analyze F-actin and fascin1 interactions.
Main Results:
- MGSTA-5 and MGSTA-6 significantly inhibited canine mammary cancer cell migration and invasion.
- MGSTA-6 disrupted the binding between filamentous F-actin and fascin1.
- MGSTA-6 treatment reduced filopodia protrusions and stress fiber formation, inhibiting cell movement.
Conclusions:
- MGSTA-5 and MGSTA-6 are promising compounds for inhibiting cancer metastasis.
- These analogues may offer therapeutic benefits in veterinary oncology, potentially in combination therapies.
- Further in vivo studies are necessary to validate these findings for clinical application.
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