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Effect of microtubule inhibitors on malignant invasion in vitro
Abstract:
The malignant C3H/3T3 mouse cells MO4 invaded embryonic chick heart fragments in an organotypic coculture system on semisolid medium, which mimicked malignant invasion. In this system, at a dose of 1 microgram/ml, the microtubule inhibitors colchicine, demecolcine, vincristine sulfate, vinblastine sulfate, or methyl[5-(2-thienylcarbonyl)-1H-benzimidazol-1-yl]-carbamate (Nocodazole) totally inhibited malignant invasion. At the same dose the drugs were also mitostatic, which was apparent from C-mitoses and from the absence of postmetaphase figures. At a mitostatic dose of 10 microgram/ml, 5-fluorouracil (FUra), cytosine arabinoside, or bleomycin did not interfere with malignant invasion. Combined treatment of the cocultures with the antimetabolite FUra (10 microgram/ml) plus the microtubule inhibitor Nocodazole (1 microgram/ml) completely inhibited invasion. These cocultures also showed the effective inhibition of mitosis by FUra, because Nocodazole-induced C-mitoses were absent. The reversibility of the anti-invasive effect of 4-day treatment with Nocodazole (1 microgram/ml) was demonstrated in shaker cocultures with the use of fluid medium. Our in vitro experiments indicated that cytoplasmic microtubules were involved in malignant invasion and that cell division and invasion constituted separate characteristics of malignant cells.
Insights
Microtubule inhibitors effectively block cancer cell invasion in vitro, demonstrating that cell division and invasion are distinct malignant traits. This research highlights microtubules
Area of Science:
- Cell Biology
- Cancer Research
- Biochemistry
Background:
- Malignant cells exhibit invasive properties crucial for metastasis.
- Understanding the mechanisms of cancer cell invasion is vital for developing targeted therapies.
Purpose of the Study:
- To investigate the role of microtubules in malignant cell invasion.
- To determine if inhibiting cell division also inhibits invasion.
Main Methods:
- Organotypic coculture system using C3H/3T3 mouse cells and embryonic chick heart fragments.
- Treatment with microtubule inhibitors (colchicine, demecolcine, vincristine sulfate, vinblastine sulfate, Nocodazole) and antimetabolites (5-fluorouracil, cytosine arabinoside, bleomycin).
- Assessment of invasion inhibition and mitostatic effects (C-mitoses).
Main Results:
- Microtubule inhibitors at 1 µg/ml completely inhibited malignant invasion and were mitostatic.
- Antimetabolites (5-FUra, cytosine arabinoside, bleomycin) at 10 µg/ml did not inhibit invasion.
- Combined treatment with 5-FUra and Nocodazole inhibited invasion, with Nocodazole preventing FUra-induced C-mitoses.
- The anti-invasive effect of Nocodazole was reversible.
Conclusions:
- Cytoplasmic microtubules are involved in malignant invasion.
- Cell division and invasion are separate characteristics of malignant cells.
- Targeting microtubules offers a potential strategy to inhibit cancer cell invasion.