New Insight Into Hyperthermic Intraperitoneal Chemotherapy Induction of Oxidative Stress Dramatically Enhanced Tumor Killing in In Vitro and In Vivo Models

Background: The aim of hyperthermic intraperitoneal chemotherapy (HIPEC) is to eradicate microscopic residual tumor after radical surgical tumor excision in patients with peritoneal carcinomatosis. The common use of antineoplastic agents such as mitomycin C, doxorubicin, or oxaliplatin with hyperthermia fails to eradicate tumors in a significant subset of patients, and alternative approaches to target chemoresistant cells are needed. The induction of reactive oxygen species (ROS) by inhibiting the critical detoxification enzyme superoxide dismutase (SOD) during hyperthermia is an appealing approach to induce death of residual cancer cells. Methods: Human and murine colon cancer cell lines were subjected to mild hyperthermia (40-42 degrees C), and treated with chemotherapy, similar to clinical protocols. ROS were induced by the SOD inhibitor diethyldithiocarbamate (DDC), a metabolite of the drug disulfiram. In mice, peritoneal carcinomatosis use C57Bl/6 was induced in C57Bl/6 by intraperitoneal injection of syngenic tumor cells (MC38). Results: Hyperthermia alone failed to kill cells but induced intracellular ROS and activated protective mechanisms. Chemotherapy conferred inconsistent cytotoxicity depending on the cell line and dose. In contrast, induction of ROS by DDC consistently activated apoptotic pathways, with increased cell death in combination with mild hyperthermia. In vivo, combined treatment with DDC and hyperthermia significantly delayed tumor progression in tumor-bearing mice. In addition, hyperthermic combined treatment with chemotherapy and DDC significantly improved animal survival compared with chemotherapy alone. Conclusions: Addition of DDC improves the efficacy of existing HIPEC protocols in a safe way and may open the door to a more effective, multimodal HIPEC.