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 B16 melanoma transplanted into mice. Our preliminary studies indicated that panaxytriol localizes to the mitochondria in human breast carcinoma cells (Breast M25-SF). This study focused on the effects of panaxytriol on mitochondrial structures and function in Breast M25-SF. The results indicate that panaxytriol rapidly inhibits cellular respiration and disrupts cellular energy balance in Breast M25-SF. At concentrations between 11.3 and 180 microM, panaxytriol causes a dose-dependent inhibition of the conversion of the tetrazolium (MTT assay) by mitochondrial dehydrogenase within 2 h. A 1-h treatment with 180 microM panaxytriol causes a significant loss of rhodamine-123 from cells with mitochondria prestained with rhodamine-123 (by flow cytometry). Specific toxic changes were observed by electron microscopy in the mitochondria of Breast M25-SF within 1 h after treatment with more than 180 microM panaxytriol. These data indicate that 180 microM panxytriol rapidly disrupts cellular energy balance and respiration in Breast M25-SF and suggest that panaxytriol may lower cellular ATP concentrations. After treatment with 180 microM panaxytriol, cellular ATP levels were 40% of those in control cells after 1 h. ATP depletion preceded the loss of cellular viability. Neither ATP depletion nor cytolysis was found in human erythrocytes that have no mitochondria. Thus, ATP depletion resulting from a direct inhibition of mitochondrial respiration is a critical early event in the cytotoxicity of panaxytriol.
Matsunaga
H
H
Hospital Pharmacy, Saga Medical School, Japan.
Saita
T
T
Nagumo
F
F
Mori
M
M
Katano
M
M
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000480:Alkynes; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D053281:Enediynes; D005233:Fatty Alcohols / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010100:Oxygen / Q000378:metabolism*; D012235:Rhodamines; D013778:Tetrazolium Salts; D013844:Thiazoles; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000480:Alkynes; D000972:Antineoplastic Agents, Phytogenic; D053281:Enediynes; D005233:Fatty Alcohols; D012235:Rhodamines; D013778:Tetrazolium Salts; D013844:Thiazoles; D000244:Adenosine Diphosphate; C057682:panaxytriol; D000255:Adenosine Triphosphate; C022616:thiazolyl blue; D010100:Oxygen