Radiation protection of the gastrointestinal tract and growth inhibition of prostate cancer xenografts by a single compound.
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.
Department of Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Vitali
V
Alexeev
Department of Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Elizabeth
E
Lash
Department of Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania.
April
A
Aguillard
Department of Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Laura
L
Corsini
Department of Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Avi
A
Bitterman
REATA Pharmaceuticals, Irving, Texas.
Keith
K
Ward
Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Adam P
AP
Dicker
Department of Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Alban
A
Linnenbach
Department of Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania. ulrich.rodeck@jefferson.edu.
Ulrich
U
Rodeck
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000473:pathology* / Q000528:radiation effects; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D014916:Whole-Body Irradiation; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D016328:NF-kappa B; D011837:Radiation-Protective Agents; D014315:Triterpenes; D038362:Glycogen Synthase Kinase 3; C000589490:omaveloxolone