A POSSIBLE MECHANISM FOR THE CYTOTOXICITY OF A POLYACETYLENIC ALCOHOL, PANAXYTRIOL - INHIBITION OF MITOCHONDRIAL RESPIRATION

A polyacetylenic alcohol, panaxytriol, isolated from Panax ginseng C. A. Meyer inhibits both tumor cell growth in vitro and the growth of B1 6 melanoma transplanted into mice. Our preliminary studies indicated t hat panaxytriol localizes to the mitochondria in human breast carcinom a cells (Breast M25-SF). This study focused on the effects of panaxytr iol on mitochondrial structures and function in Breast M25-SF. The res ults indicate that panaxytriol rapidly inhibits cellular respiration a nd disrupts cellular energy balance in Breast M25-SF. At concentration s between 11.3 and 180 mu M, panaxytriol causes a dose-dependent inhib ition of the conversion of the tetrazolium (MTT assay) by mitochondria l dehydrogenase within 2 h. A l-h treatment with 180 mu M panaxytriol causes a significant loss of rhodamine-123 from cells with mitochondri a prestained with rhodamine-123 (by flow cytometry). Specific toxic ch anges were observed by electron microscopy in the mitochondria of Brea st M25-SF within 1 h after treatment with more than 180 mu M panaxytri ol. These data indicate that 180 mu M panaxytriol rapidly disrupts cel lular energy balance and respiration in Breast M25-SF and suggest that panaxytriol may lower cellular ATP concentrations. After treatment wi th 180 mu M panaxytriol, cellular ATP levels were 40% of those in cont rol cells after 1 h. ATP depletion preceded the loss of cellular viabi lity. Neither ATP depletion nor cytolysis was found in human erythrocy tes that have no mitochondria. Thus, ATP depletion resulting from a di rect inhibition of mitochondrial respiration is a critical early event in the cytotoxicity of panaxytriol.