Microtubule-targeting-compound PBOX-15 radiosensitizes cancer cells in vitro

James C Forde, Elaina N Maginn, Gillian McNamara, Lynn M Martin, Guiseppe Campiani, D Clive Williams, Daniela Zisterer, Anthony M McElligott, Mark Lawler, Thomas H Lynch, Donal Hollywood, Laure Marignol, Mark Lawler

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

BACKGROUND: We proposed to investigate the radiosensitizing properties of PBOX-15, a novel microtubule-disrupting agent, in a panel of cancer cell lines.

RESULTS: PBOX-15 treatment was associated with significant cell kill and increased radiosensitivity in all three cell lines tested. The number of surviving cells in response to the combined treatment was significantly less than PBOX -15 alone in 22Rv1 cells. In these cells, radiosensitisation correlated with induction of G2/M cell cycle arrest by PBOX-15. The compound sustained its activity and increased HIF-1Α expression under hypoxic conditions. PBOX-15 prevented onset of hypoxia-induced radioresistance in hypoxic prostate cells and reduced the surviving fraction of irradiated hypoxic cells to levels similar to those achieved under aerobic conditions.

METHODS: Clonogenic assays were used to determine sensitivity of a panel of cancer cell lines (22Rv1, A549, U87) to PBOX-15 alone or in combination with a single 2Gy dose fraction. Induction of cell cycle arrest and apoptosis was investigated in 22Rv1 prostate cancer cells. The cytotoxic properties of the compound under hypoxic conditions were correlated with Hypoxia Inducible Factor 1 alpha (HIF-1Α) gene and protein expression levels and its radiosensitisation potential was investigated in hypoxic 22Rv1 using clonogenic assays.

CONCLUSIONS: This preliminary data identifies the potential of PBOX-15 as a novel radiosensitising agent for the management of solid tumours and eradication of hypoxic cells.

Original languageEnglish
Pages (from-to)421-8
Number of pages8
JournalCANCER BIOLOGY & THERAPY
Volume11
Issue number4
Publication statusPublished - 15 Feb 2011

Keywords

  • Aerobiosis
  • Anoxia
  • Apoptosis
  • Cell Cycle
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Male
  • Microtubules
  • Neoplasms
  • Oxazepines
  • Pyrroles
  • Radiation Tolerance
  • Radiation-Sensitizing Agents

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