The tubulysin analogue KEMTUB10 induces apoptosis in breast cancer cells via p53, Bim and Bcl-2

Oluwafunmilayo Lamidi, Monica Sani, Paolo Lazzari, Matteo Zanda, Ian Neil Fleming

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1575-1583
Number of pages9
JournalJournal of Cancer Research and Clinical Oncology
Volume141
Issue number9
Early online date30 Jan 2015
DOIs
Publication statusPublished - Sep 2015

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Apoptosis
Breast Neoplasms
G2 Phase
Cell Division
Cell Cycle
Cell Death
Neoplasms
MCF-7 Cells
Tubulin
Paclitaxel
Polymerization
Phosphorylation
Cell Line
Growth
Therapeutics

Keywords

  • breast cancer
  • tubulysin
  • anti-mitotic
  • apoptosis
  • p53
  • Bcl-2

Cite this

The tubulysin analogue KEMTUB10 induces apoptosis in breast cancer cells via p53, Bim and Bcl-2. / Lamidi, Oluwafunmilayo; Sani, Monica; Lazzari, Paolo; Zanda, Matteo; Fleming, Ian Neil.

In: Journal of Cancer Research and Clinical Oncology, Vol. 141, No. 9, 09.2015, p. 1575-1583.

Research output: Contribution to journalArticle

Lamidi, Oluwafunmilayo ; Sani, Monica ; Lazzari, Paolo ; Zanda, Matteo ; Fleming, Ian Neil. / The tubulysin analogue KEMTUB10 induces apoptosis in breast cancer cells via p53, Bim and Bcl-2. In: Journal of Cancer Research and Clinical Oncology. 2015 ; Vol. 141, No. 9. pp. 1575-1583.
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abstract = "PurposeTubulysins 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.MethodsThe 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.ResultsKEMTUB10 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.ConclusionsKEMTUB10 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.",
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author = "Oluwafunmilayo Lamidi and Monica Sani and Paolo Lazzari and Matteo Zanda and Fleming, {Ian Neil}",
note = "Acknowledgments We would like to thank Alastair Thompson for providing 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.",
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T1 - The tubulysin analogue KEMTUB10 induces apoptosis in breast cancer cells via p53, Bim and Bcl-2

AU - Lamidi, Oluwafunmilayo

AU - Sani, Monica

AU - Lazzari, Paolo

AU - Zanda, Matteo

AU - Fleming, Ian Neil

N1 - Acknowledgments We would like to thank Alastair Thompson for providing 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.

PY - 2015/9

Y1 - 2015/9

N2 - PurposeTubulysins 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.MethodsThe 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.ResultsKEMTUB10 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.ConclusionsKEMTUB10 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.

AB - PurposeTubulysins 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.MethodsThe 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.ResultsKEMTUB10 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.ConclusionsKEMTUB10 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.

KW - breast cancer

KW - tubulysin

KW - anti-mitotic

KW - apoptosis

KW - p53

KW - Bcl-2

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DO - 10.1007/s00432-015-1921-6

M3 - Article

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SP - 1575

EP - 1583

JO - Journal of Cancer Research and Clinical Oncology

JF - Journal of Cancer Research and Clinical Oncology

SN - 0171-5216

IS - 9

ER -