Radiation protection of the gastrointestinal tract and growth inhibition of prostate cancer xenografts by a single compound.

Abstract:

:Normal tissue toxicity markedly reduces the therapeutic index of genotoxic anticancer agents, including ionizing radiation. Countermeasures against tissue damage caused by radiation are limited by their potential to also protect malignant cells and tissues. Here, we tested a panel of signal transduction modifiers for selective radioprotection of normal but not tumor tissues. These included three inhibitors of GSK3 (LiCl, SB216763, and SB415286) and two inhibitors of NF-κB (ethyl pyruvate and RTA 408). Among these, the thiol-reactive triterpenoid RTA 408 emerged as a robust and effective protector of multiple organ systems (gastrointestinal, skin, and hemopoietic) against lethal doses of radiation. RTA 408 preserved survival and proliferation of intestinal crypt cells in lethally irradiated mice while reducing apoptosis incidence in crypts and villi. In contrast, RTA 408 uniformly inhibited growth of established CWR22Rv1, LNCaP/C4-2B, PC3, and DU145 xenografts either alone or combined with radiation. Antitumor effects in vivo were associated with reduced proliferation and intratumoral apoptosis and with inhibition of NF-κB-dependent transcription in PC3 cells. Selective protection of normal tissue compartments by RTA 408 critically depended on tissue context and could not be replicated in vitro. Collectively, these data highlight the potential of RTA 408 as a cytoprotective agent that may be safely used in chemoradiation approaches.

journal_name

Mol Cancer Ther

authors

Alexeev V,Lash E,Aguillard A,Corsini L,Bitterman A,Ward K,Dicker AP,Linnenbach A,Rodeck U

doi

10.1158/1535-7163.MCT-14-0354

subject

Has Abstract

pub_date

2014-12-01 00:00:00

pages

2968-77

issue

12

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-14-0354

journal_volume

13

pub_type

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