Radiosensitization of solid tumors by Z-VAD, a pan-caspase inhibitor.
Despite recent advances in the management of breast and lung cancer, novel treatment strategies are still needed to further improve patient outcome. The targeting of cell death pathways has therefore been proposed to enhance therapeutic ratio in cancer. In this study, we examined the in vitro and in vivo effects of Z-VAD, a broad-spectrum caspase inhibitor, on breast and lung cancer in association with radiation. Using clonogenic assays, we observed that Z-VAD markedly radiosensitized breast and lung cancer cells, with a radiation dose enhancement ratio of 1.31 (P < 0.003). For both models, the enhanced tumor cytotoxicity was associated with induction of autophagy. Furthermore, we found that administration of Z-VAD with radiation in both breast and lung cancer xenograft produced a significant tumor growth delay compared with radiation alone and was well tolerated. Interestingly, Z-VAD also had dramatic antiangiogenic effect when combined with radiation both in vitro and in vivo and thus represents an attractive anticancer therapeutic strategy. In conclusion, this preclinical study supports the therapeutic potential of Z-VAD as a radiosensitizer in breast and lung cancer. This study also suggests caspase inhibition as a promising strategy to enhance the therapeutic ratio of radiation therapy in solid tumors. Therefore, clinical trials are needed to determine the potential of this combination therapy in cancer patients.
Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-5671, USA.
Luigi
L
Moretti
Kwang Woon
KW
Kim
Dae Kwang
DK
Jung
Christopher D
CD
Willey
Bo
B
Lu
D000590:Amino Acid Chloromethyl Ketones / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D011838:Radiation-Sensitizing Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone