Microtubule-targeting-compound PBOX-15 radiosensitizes cancer cells in vitro.
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.
Prostate Molecular Oncology Research Group, Academic Unit of Clinical and Molecular Oncology, St James's Hospital and Trinity College Dublin, Ireland.
James C
JC
Forde
Elaina N
EN
Maginn
Gillian
G
McNamara
Lynn M
LM
Martin
Guiseppe
G
Campiani
D Clive
DC
Williams
Daniela
D
Zisterer
Anthony M
AM
McElligott
Mark
M
Lawler
Thomas H
TH
Lynch
Donal
D
Hollywood
Laure
L
Marignol
D000332:Aerobiosis; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D008870:Microtubules / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D010077:Oxazepines / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000494:pharmacology* / Q000633:toxicity; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000633:toxicity
C514160:4-acetoxy-5-(1-(naphthyl))naphtho(2,3-b)pyrrolo(2,1-d)(1,4)oxazepine; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010077:Oxazepines; D011758:Pyrroles; D011838:Radiation-Sensitizing Agents