Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Bezafibrate acts as differentiating factor on human tumor cell lines: An intriguing mechanism of action

R Scatena MD 1, I Messana PhD 1, P Bottoni PhD 1, F Vincenzoni PhD 1, G Nocca PhD 1, P De Sole PhD 1, N Maggiano PhD 2, B Giardina PhD 1

1 Istituto Chimica e Chimica Clinica University' Cattolica del Sacro Cuore, Rome, Italy, 2 Istituto Anatomia Patologica, University' Cattolica del Sacro Cuore, Rome, Italy,

AIM: we hypotized that bezafibrate could promote the differentiation of various human cell lines by inducing a significant imbalance in cellular oxidative metabolism that partially results independent from its peroxisome proliferator activity. METHODS: Different human cell lines were cultured for 96 hours with bezafibrate (0.25. 0.5, 1 mmol/l). The following parameters were determined: i) cell growth, cytotoxicity index, apoptosis and morphology (MTT, dye exclusion, and fluorescence an electronic microscopy); ii) lactate, acetate and alanine in supernatant by magnetic resonance; iii) various enzyme activities: catalase, superoxide-dismutase, glutathione-peroxidase, and the mitochondrial respiratory chain enzymes (NADH-cytochrome c reductase, Succinate-cythocrome c reductase, Succinate dehydrogenase-coenzyme Q reductase and Cythocrome oxidase). RESULTS. Our data show that: i) bezafibrate causes a selective derangement of mitochondrial respiratory chain; ii) this derangement determines morphological alterations of mitochondria; iii) metabolic compensatory mechanisms set up (increases of acetate, lactate and alanine); iv) other enzymatic data seem to show an intriguing increase of phosphofructokinase and catalase activities; v) others NMR metabolite analysis using 13C, seem to show a significant increment of anaerobic glucose consumption. CONCLUSION. Bezafibrate induces a derangement of mitochondrial respiratory chain with secondary metabolic perturbations, which appear overlapping to that caused by its peroxisomial proliferator activity. These results could modify some assumptions on the differentating activity of peroxisome proliferators.

KEY WORDS: mitochondria, oxidative stress, cancer.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on differentiation therapy.