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Role of Lipid Peroxidation in Hematoporphyrin Derivative-sensitized Photokilling of Tumor Cells: Protective Effects of Glutathione Peroxidase¹

Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

The ability of cells to detoxify lipid hydroperoxides (LOOHs) generated by hematoporphyrin derivative (HPD)-sensitized photooxidation was investigated for the first time. The general importance of glutathione in cytoprotection was confirmed by showing that murine L1210 cells were more sensitive to the lethal effects of HPD plus red light after being treated with buthionine sulfoximine. The specific role of Se-dependent glutathione peroxidase was investigated by using L1210 cells that were grown in Se-deficient media. Glutathione peroxidase activity of such cells was typically <5% of that exhibited by Se-replete cells. When examined by means of dye exclusion or clonogenic assay, Se-deficient cells were dramatically more sensitive to HPD-mediated photokilling than normal counterparts. Impaired metabolism of hydrogen peroxide was ruled out as a possible cause of enhanced photokilling, since added catalase had no protective effect on Se-deficient cells. Iodometric analysis of lipid extracts from photooxidized cells indicated a significantly greater rate of LOOH accumulation as a result of Se depletion. Moreover, when depleted cells were incubated in the dark after a short period of photoperoxidation, LOOH decay was markedly slower than in controls. Similar results were obtained with human CaSki cells derived from cervical carcinoma. It is apparent from these results that lipid peroxidation plays an important role in tumor cell eradication by HPD/phototherapy, and that glutathione peroxidase serves as a natural protectant against photokilling by catalyzing the reduction of LOOHs.

¹ This project was supported by grants from the National Science Foundation (DCB-8501894), the St. Luke's Foundation (Milwaukee), and the Cancer Center of the Medical College of Wisconsin.

² These studies are based on a dissertation submitted by J. P. Thomas in partial fulfillment of the requirements for the PhD degree in Biochemistry at the Medical College of Wisconsin.

³ To whom requests for reprints should be addressed, at Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226.

Received 8/17/88. Revised 11/16/88. Accepted 12/29/88.