Thermal sensitization through ROS modulation: a strategy to improve the efficacy of hyperthermic intraperitoneal chemotherapy.
BACKGROUND
The purpose of this study was to investigate whether modulation of cellular reactive oxygen species (ROS) provides a synergistic effect with hyperthermia to induce tumor cell death in a colon cancer cell line.


METHODS
HT-29 colon cancer cells were exposed to heat (43 degrees C) in the presence of the ROS-generating drug, 2-2'-azobis-(2-amidinopropane) dihydrochloride (AAPH) for 1 h. Viable cell mass and apoptosis was measured by MTT and annexin V staining, respectively. Oxidative stress was evaluated by DCFH fluorescence. Protein levels were determined by Western blot analysis.


RESULTS
A synergistic effect on cell viability with AAPH was noted under hyperthermic conditions as compared with hyperthermia alone (P < .05). The number of nonviable cells after hyperthermia and AAPH exposure was also significantly increased compared with AAPH at 37 degrees C (42% vs 20%, P < .05). ROS levels were increased modestly with AAPH at 37 degrees C, whereas they increased significantly in a dose-dependent manner with AAPH at 43 degrees C. Transient increases of phosphorylated-p38 and ERK and decreases in phosphorylated-AKT were observed in the cells exposed to AAPH at 43 degrees C. Pretreatment of inhibitors of p38 yielded additional decreases in cell mass when used in combination with AAPH and hyperthermia (P < .05). Increased expression of HSP 27 observed at 43 degrees C was abrogated with AAPH exposure.


CONCLUSIONS
Oxidative stress increased the cytotoxic effects of hyperthermia in colon cancer cells. Thermal sensitization through modulation of cellular ROS may represent a novel approach to increase the efficacy of hyperthermia as an anticancer modality.
Wang
Chia-Chi
CC
Division of Surgical Oncology, UMDNJ--New Jersey Medical School, Newark, NJ 07103, USA.
Chen
Fei
F
Kim
Eugene
E
Harrison
Lawrence E
LE
D000578:Amidines / Q000627:therapeutic use; D018938:Caco-2 Cells; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004358:Drug Therapy / Q000379:methods*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology; D019073:HT29 Cells; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D016877:Oxidants / Q000627:therapeutic use; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D000578:Amidines; D016877:Oxidants; D017382:Reactive Oxygen Species; C046728:2,2'-azobis(2-amidinopropane); D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases