Bisht KS, Bradbury CM, Mattson D, Kaushal A, Sowers A, Markovina
S, Ortiz KL, Sieck LK, Isaacs JS, Brechbiel MW, Mitchell JB,
Neckers LM, Gius D.Geldanamycin and
17-allylamino-17-demethoxygeldanamycin potentiate the in vitro
and in vivo radiation response of cervical tumor cells via the
heat shock protein 90-mediated intracellular signaling and
cytotoxicity.
Cancer Res. 2003 Dec 15;63(24):8984-95.
Radiation Oncology Branch and. Radiation Biology Branch,
Center for Cancer Research, National Cancer Institute, NIH,
Bethesda, Maryland 20892-1002, USA.
Ansamycin antibiotics inhibit function of the heat shock
protein (HSP) 90, causing selective degradation of several
intracellular proteins regulating such processes as
proliferation, cell cycle regulation, and prosurvival signaling
cascades. HSP90 has been identified previously as a molecular
target for anticancer agents, including ionizing radiation (IR).
Therefore, we hypothesized that the ansamycin geldanamycin and
its 17-allylamino-17-demethoxy analog (17-AAG), which inhibit
HSP90, would enhance tumor cell susceptibility to the
cytotoxicity of IR. Treatment of two human cervical carcinoma
cell lines (HeLa and SiHa) with geldanamycin and 17-AAG resulted
in cytotoxicity and, when combined with IR, enhanced the
radiation response, each effect with a temporal range from 6 to
48 h after drug exposure. In addition, mouse in vivo models
using 17-AAG at clinically achievable concentrations yielded
results that paralleled the in vitro radiosensitization studies
of both single and fractioned courses of irradiation. The
increase in IR-induced cell death appears to be attributable to
a combination of both programmed and nonprogrammed cell death.
We also measured total levels of several prosurvival and
apoptotic signaling proteins. Akt1, extracellular
signal-regulated kinase-1, Glut-1, HER-2/neu, Lyn, cAMP-dependent
protein kinase, Raf-1, and vascular endothelial growth factor
expression were down-regulated in 17-AAG-treated cells,
identifying these factors as molecular markers and potential
therapeutic targets. Finally, a series of immortalized and human
papillomavirus-transformed cell lines were used to demonstrate
that the radiosensitizing effects of 17-AAG were limited to
transformed cells, suggesting a possible differential cytotoxic
effect. This work shows that altered HSP90 function induces
significant tumor cytotoxicity and radiosensitization,
suggesting a potential therapeutic utility.
PMID: 14695217 |
