Abstract
Purpose
Tubulysins are natural tetrapeptides that inhibit tubulin polymerisation. Tubulysins are very potent inhibitors of mammalian cancer cell growth, but restricted availability has limited their characterisation and development as anti-cancer compounds. KEMTUB10 was recently developed as a synthetic analogue of natural tubulysins.
Methods
The cell cytotoxicity of KEMTUB10 was studied in cell lines that represent the main breast cancer sub-types. The KEMTUB10 pro-apoptotic mechanism of action was studied in MCF7 and MDAMB231 cells.
Results
KEMTUB10 exerts a potent cytotoxic effect in cells representing the main breast cancer sub-types. KEMTUB10 blocks cells in the G2/M phase of the cell cycle and is a strong stimulator of apoptosis/cell death. KEMTUB10-induced apoptosis involves p53 and Bim, and to some extent Bcl-2 phosphorylation.
Conclusions
KEMTUB10 is a promising new anti-mitotic that exerts a potent cytotoxic effect in breast cancer cells, blocks cells in the G2/M phase of the cell cycle and stimulates apoptosis/cell death. KEMTUB10 has a distinct mode of action to taxol, appears to be sensitive to different molecular factors in cells and is likely subject to different mechanisms of acquired resistance. KEMTUB10 has the potential to be an important addition to the anti-cancer therapeutic armoury.
Tubulysins are natural tetrapeptides that inhibit tubulin polymerisation. Tubulysins are very potent inhibitors of mammalian cancer cell growth, but restricted availability has limited their characterisation and development as anti-cancer compounds. KEMTUB10 was recently developed as a synthetic analogue of natural tubulysins.
Methods
The cell cytotoxicity of KEMTUB10 was studied in cell lines that represent the main breast cancer sub-types. The KEMTUB10 pro-apoptotic mechanism of action was studied in MCF7 and MDAMB231 cells.
Results
KEMTUB10 exerts a potent cytotoxic effect in cells representing the main breast cancer sub-types. KEMTUB10 blocks cells in the G2/M phase of the cell cycle and is a strong stimulator of apoptosis/cell death. KEMTUB10-induced apoptosis involves p53 and Bim, and to some extent Bcl-2 phosphorylation.
Conclusions
KEMTUB10 is a promising new anti-mitotic that exerts a potent cytotoxic effect in breast cancer cells, blocks cells in the G2/M phase of the cell cycle and stimulates apoptosis/cell death. KEMTUB10 has a distinct mode of action to taxol, appears to be sensitive to different molecular factors in cells and is likely subject to different mechanisms of acquired resistance. KEMTUB10 has the potential to be an important addition to the anti-cancer therapeutic armoury.
| Original language | English |
|---|---|
| Pages (from-to) | 1575-1583 |
| Number of pages | 9 |
| Journal | Journal of Cancer Research and Clinical Oncology |
| Volume | 141 |
| Issue number | 9 |
| Early online date | 30 Jan 2015 |
| DOIs | |
| Publication status | Published - Sept 2015 |
Bibliographical note
Acknowledgments We would like to thank Alastair Thompson forproviding the paired MCF7 wt/DD cells, the Aberdeen Flow cytometry
group, for helping to analyse the cell cycle data and Dr. Tim Smith
for invaluable advice with culturing of MCF7 DD cells. We are very
grateful to the NHS Grampian Endowment Fund for providing funding
for this work.
Keywords
- breast cancer
- tubulysin
- anti-mitotic
- apoptosis
- p53
- Bcl-2
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Ian Fleming
- School of Medicine, Medical Sciences & Nutrition, Medical Education - Senior Lecturer (Scholarship)
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Biomedical Imaging Centre
Person: Academic Related - Scholarship