A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer.
The chaperone heat shock protein 90 (HSP90) crucially supports the maturation, folding, and stability of a variety of client proteins which are of pivotal importance for the survival and proliferation of cancer cells. Consequently, targeting of HSP90 has emerged as an attractive strategy of anti-cancer therapy, and it appears to be particularly effective in the context of molecular sensitization towards radiotherapy as has been proven in preclinical models of different cancer entities. However, so far the clinical translation has largely been hampered by suboptimal pharmacological properties and serious hepatotoxicity of first- and second-generation HSP90 inhibitors. Here, we report on NW457, a novel radicicol-derived member of the pochoxime family with reduced hepatotoxicity, how it inhibits the DNA damage response and how it synergizes with ionizing irradiation to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer in vitro and in vivo.
Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Linda
L
Kinzel
Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Anne
A
Ernst
Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Michael
M
Orth
Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Valerie
V
Albrecht
Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Roman
R
Hennel
Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Nikko
N
Brix
Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Benjamin
B
Frey
Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Udo S
US
Gaipl
Department of Otorhinolaryngology, Head and Neck Surgery, and Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
Gabriele
G
Zuchtriegel
Department of Otorhinolaryngology, Head and Neck Surgery, and Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
Christoph A
CA
Reichel
Institute of Veterinary Pathology at the Center for Clinical Veterinary Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
Andreas
A
Blutke
Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Daniela
D
Schilling
Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Gabriele
G
Multhoff
Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Minglun
M
Li
Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Maximilian
M
Niyazi
Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Anna A
AA
Friedl
Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva, Geneva, Switzerland.
Nicolas
N
Winssinger
Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Claus
C
Belka
Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
Kirsten
K
Lauber
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000379:methods*; D015179:Colorectal Neoplasms / Q000628:therapy*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D022781:Hepatocytes; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008111:Liver Function Tests; D018942:Macrolides / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D061251:Primary Cell Culture; D059748:Proteolysis / Q000187:drug effects / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000627:therapeutic use*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; D011838:Radiation-Sensitizing Agents; C035359:monorden
DNA damage response; HSP90 inhibition; cell death; colorectal cancer; radiosensitization