Cancer Metabolism: Fasting Reset, the Keto-Paradox and Drugs for Undoing

Abstract

In tumor cells, ketolysis "via" succinyl-CoA: 3-oxoacid-CoAtransferase (SCOT) and acetyl-CoA acetyltransferase 1 (ACAT1) is a major source of mitochondrial acetyl-CoA. Active ACAT1 tetramers stabilize by tyrosine phosphorylation, which facilitates the SCOT reaction and ketolysis. Tyrosine phosphorylation of pyruvate kinase PK M2 has the opposite effect, stabilizing inactive dimers, while pyruvate dehydrogenase (PDH), which is already inhibited by phosphorylation, is acetylated by ACAT1 and is doubly locked. This closes the glycolytic supply of acetyl-CoA. In addition, since tumor cells must synthesize fatty acids to create new membranes, they automatically turn off the degradation of fatty acids into acetyl-CoA ("via" the malonyl-CoA brake for the fatty acid carnityl transporter). Thus, inhibiting SCOT the specific ketolytic enzyme and ACAT1 should hold back tumor progression. However, tumor cells are still able to take up external acetate and convert it into acetyl-CoA in their cytosol "via" an acetyl-CoA synthetase, which feeds the lipogenic pathway; additionally, inhibiting this enzyme would make it difficult for tumor cells to form new lipid membrane and survive.

Keywords: SCOT-ACAT1 inhibitions; acetohydroxamates; butenolides; karrikins; siderophores; tumor ketolysis.

Figure 1

Ketolytic dependent tumor cells. Inhibitions by phosphorylation, of Pyruvate kinase PK M2, and Pyruvate dehydrogenase PDH, cut the glycolytic supply of acetyl-CoA to mitochondria, lactic acid release occurs through MCT monocarboxylate transporters. Moreover, an acetylation of PDH by ACAT1 thiolase further increases the inhibition of PDH. Since tumors must synthesize fatty acid to create new membranes, this automatically turns off the fatty acid mitochondrial carnityl transporter and the fatty acid supply of acetyl-CoA. The carnityl transporter is inhibited by malonyl-CoA, the product of Acetyl CoA carboxylase (ACC), starting the lipogenic pathway in the cytosol. Hence, ketone bodies and beta-hydroxybutyrate, (BHB) become an essential source of acetyl-CoA in tumors, via SCOT the specific ketolytic enzyme and ACAT1. Then, citrate exits the mitochondria and feeds lipogenesis via ATP citrate lyase (ACL) and acetyl-CoA carboxylase (ACC). By blocking the MCT transporters with indicated compounds, one would affect the lactate release, the influx of beta-hydroxybutyrate (BHB) and the supply of acetoacetate to SCOT. We indicate possible inhibitors for SCOT: Lithostat or other Siderophores, Ferrichrome, Phycocyanin, Febrifugine or even Melatonin. As for ACT1, Butenolides, vitamin C and others are indicated; this should starve the tumor. We suggest inhibiting the citrate condensation and supply to the lipogenic pathway using lipoic acid and hydroxycitrate, as indicated. Moreover, Allicine would cut the direct conversion of acetate into acetyl-CoA in the cytosol. An essential key is that AMP kinase will inhibit ACC, which merits stimulation by acetogenin, and to inhibit AMP deaminase with Docosahexaenoic acid (DHA) or Galega officinalis, or metformin. By inhibiting the entry of BHB, one also stops the stimulation of NFkB-mediated transcription, a hallmark of cancer, and cancels the inhibition of histone deacetylase (HDAC) caused by BHB. Upstream of ketolysis, one may use octreotide (a somatostatin analog) to decrease the ketogenic supply. There is, however, a paradox, since the signaling action of extracellular BHB on HCA2, a Gi coupled receptor, is to preserve (it inhibits NFkB transcription). A prostaglandin messenger is involved; it can be strengthened with Andrographolite. Niacin is another agonist for HCA2, which may help when using octreotide for decreasing ketogenesis. Green arrows: HCA2 signaling. Red arrows: BHB influx through MCT and effects.