A possible mechanism for the cytotoxicity of a polyacetylenic alcohol, panaxytriol: inhibition of mitochondrial respiration

Abstract

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.

Multifaceted cytoprotection by synthetic polyacetylenes inspired by the ginseng-derived natural product, panaxytriol

“…The PXTs and iso-flu were synthesized in-house according to previously reported methods (17,24). In vitro cell growth inhibition was measured by cell counting kit 8 (CCK-8) assay (Dojindo Molecular Technologies Inc.) following a 72-h incubation using a Powerwave XS microplate spectrophotometer (BioTek Instruments, Inc.).…”

“…Toward this end, we took note of the disclosure of a series of biologically active polyacetylene natural products isolated from the P. ginseng root. We were originally drawn, in particular, to (3R, 9R, 10S)-panaxytriol (PXT) (16) on the basis of reports of its in vitro cytotoxic activity against a range of human tumor cells, including breast carcinoma (breast M25-SF) (17) and gastric carcinoma (MK-1) (18). In one in vivo study, PXT was reported to suppress the growth of B16 melanoma cells in mouse models (19).…”

Pharmacodynamics of Ginsenosides: Antioxidant Activities, Activation of Nrf2, and Potential Synergistic Effects of Combinations

“…Many of these compounds have been shown to activate the Nrf2-ARE pathway and many health benefits of ginseng have been reported such as anti-cancer activities. 8-11 Therefore, it appears that ginseng may be a potential cancer preventive agent. 5, 12 In this study, we hypothesized that ginsenosides would activate Nrf2-dependent anti-oxidative stress pathway and with appropriate combinations, ginsenoside Rb1 (Rb1), ginsenoside Rg1 (Rg1) and ginsenoside 20(S)-protopanaxytriol (20S) (Figure 1) could exert synergistic benefits in Nrf2 activation.…”

Anti-cancer and potential chemopreventive actions of ginseng by activating Nrf2 (NFE2L2) anti-oxidative stress/anti-inflammatory pathways

“…Ginseng protects the cardiovascular system, stimulates the central nervous system [1] and possesses anti-cancer activities [2,3] inhibiting human gastric adenocarcinoma [4] and human breast carcinoma [5]. Therefore, ginseng is a potential cancer preventive agent [6].…”