A novel approach to the discovery of anti-tumor pharmaceuticals: searching for activators of liponecrosis

Abstract

A recently conducted chemical genetic screen for pharmaceuticals that can extend longevity of the yeast Saccharomyces cerevisiae has identified lithocholic acid as a potent anti-aging molecule. It was found that this hydrophobic bile acid is also a selective anti-tumor chemical compound; it kills different types of cultured cancer cells if used at concentrations that do not compromise the viability of non-cancerous cells. These studies have revealed that yeast can be successfully used as a model organism for high-throughput screens aimed at the discovery of selectively acting anti-tumor small molecules. Two metabolic traits of rapidly proliferating fermenting yeast, namely aerobic glycolysis and lipogenesis, are known to be similar to those of cancer cells. The mechanisms underlying these key metabolic features of cancer cells and fermenting yeast have been established; such mechanisms are discussed in this review. We also suggest how a yeast-based chemical genetic screen can be used for the high-throughput development of selective anti-tumor pharmaceuticals that kill only cancer cells. This screen consists of searching for chemical compounds capable of increasing the abundance of membrane lipids enriched in unsaturated fatty acids that would therefore be toxic only to rapidly proliferating cells, such as cancer cells and fermenting yeast.

Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes

“…Fourth, our ongoing studies indicate that the six longevity-extending PEs also extend longevities of other eukaryotic model organisms, delay the onset of age-related diseases and/or exhibit anti-tumor effects. In this regard, it needs to be mentioned that genetic, dietary and pharmacological interventions known to delay aging in yeast and other eukaryotes have been shown to selectively kill cultured human cancer cells and/or decrease the incidence of cancer [ 29 , 88 , 109 – 120 ]. The challenge for the future is to define mechanisms through which the six geroprotective PEs prolong healthy lifespan and decelerate tumorigenesis.…”

Communications between Mitochondria, the Nucleus, Vacuoles, Peroxisomes, the Endoplasmic Reticulum, the Plasma Membrane, Lipid Droplets, and the Cytosol during Yeast Chronological Aging

“…At the late-life checkpoint 12 in ST phase, the excessive accumulation of free (non-esterified) fatty acids (FFA) and diacylglycerol (DAG) in cellular membranes accelerates yeast chronological aging because it triggers an age-related form of programmed cell death called liponecrosis ( Goldberg et al, 2009a , b ; Arlia-Ciommo et al, 2014a , 2016 ; Richard et al, 2014 ) ( Figure 1 ). ATP, which is produced mainly in mitochondria, slows age-related liponecrosis by providing energy needed for the detoxification of FFA in the ER through the incorporation of FFA into triacylglycerols (TAG) and other neutral lipids ( Arlia-Ciommo et al, 2014a ; Richard et al, 2014 ; Sheibani et al, 2014 ).…”

Lipid metabolism and transport define longevity of the yeast Saccharomyces cerevisiae

“…Lipids are water-insoluble amphiphilic biomolecules; they are structurally diverse and generated by an intricate network of integrated metabolic pathways (1)(2)(3)(4)(5)(6). Lipids are known to play key roles in the organization and function of biological membranes, energy homeostasis, signal transduction, vesicular trafficking, organelle biogenesis, and regulated cell death (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The initial indications that lipids may also modulate the rate of cellular and organismal aging came from observations that longevity-extending mutations in the IGF-1 (insulin/ insulin-like growth factor 1) and TORC1 (target of rapamycin complex 1) signaling pathways elicit an increase in the concentration of storage lipids in the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster and laboratory mice (reviewed in reference 15).…”