Caffeic acid phenethyl ester preferentially sensitizes CT26 colorectal adenocarcinoma to ionizing radiation without affecting bone marrow radioresponse.
OBJECTIVE
Caffeic acid phenethyl ester (CAPE), a component of propolis, was reported capable of depleting glutathione (GSH). We subsequently examined the radiosensitizing effect of CAPE and its toxicity.


METHODS
The effects of CAPE on GSH level, GSH metabolism enzyme activities, NF-kappaB activity, and radiosensitivity in mouse CT26 colorectal adenocarcinoma cells were determined. BALB/c mouse with CT26 cells implantation was used as a syngeneic in vivo model for evaluation of treatment and toxicity end points.


RESULTS
CAPE entered CT26 cells rapidly and depleted intracellular GSH in CT26 cells, but not in bone marrow cells. Pretreatment with nontoxic doses of CAPE significantly enhanced cell killing by ionizing radiation (IR) with sensitizer enhancement ratios up to 2.2. Pretreatment of CT26 cells with N-acetyl-L-cysteine reversed the GSH depletion activity and partially blocked the radiosensitizing effect of CAPE. CAPE treatment in CT26 cells increased glutathione peroxidase, decreased glutathione reductase, and did not affect glutathione S-transferase or gamma-glutamyl transpeptidase activity. Radiation activated NF-kappaB was reversed by CAPE pretreatment. In vivo study revealed that pretreatment with CAPE before IR resulted in greater inhibition of tumor growth and prolongation of survival in comparison with IR alone. Pretreatment with CAPE neither affected body weights nor produced hepatic, renal, or hematopoietic toxicity.


CONCLUSIONS
CAPE sensitizes CT26 colorectal adenocarcinoma to IR, which may be via depleting GSH and inhibiting NF-kappaB activity, without toxicity to bone marrow, liver, and kidney.
Chen
Yu-Jen
YJ
Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan.
Liao
Hui-Fen
HF
Tsai
Tung-Hu
TH
Wang
Sheng-Yuan
SY
Shiao
Ming-Shi
MS
D000230:Adenocarcinoma / Q000378:metabolism / Q000532:radiotherapy*; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000528:radiation effects*; D002109:Caffeic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D004260:DNA Repair / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D002109:Caffeic Acids; D016328:NF-kappa B; D011838:Radiation-Sensitizing Agents; D005979:Glutathione Peroxidase; D005723:gamma-Glutamyltransferase; C055494:caffeic acid phenethyl ester; D005978:Glutathione; D010626:Phenylethyl Alcohol