Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics

Abstract

Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics.

Saponin-Rich Extracts and Their Acid Hydrolysates Differentially Target Colorectal Cancer Metabolism in the Frame of Precision Nutrition

“…As far as our knowledge goes, no previous studies have been performed in which the cell bioenergetics have been assessed with extracts where saponins and sapogenins are within the major bioactive components or with fenugreek extracts in general. Only a couple studies have very recently the steroid saponin gracillin as a mitochondria-targeting antitumor drug, thanks to its ability to induce a dose-dependent decrease of mitochondrial respiration and the inhibition of aerobic glycolysis [ 45 , 46 ].…”

Structures and Bioactivities of Steroidal Saponins Isolated from the Genera Dracaena and Sansevieria

“…In addition to antiproliferative activities, saponins 20 , 21 , 85 , 112 , 124 also exhibited significantly cytotoxic properties [ 28 , 32 , 55 ] and some mechanisms of action have been clarified. For example, the potent anticancer agent gracillin ( 85 ) showed significant inhibitory effect on mitochondrial complex II-mediated energy production in non-small cell lung cancer, and it inhibited glycolysis and oxidative phosphorylation-mediated bioenergetics [ 74 ].…”

The multifaceted roles of mitochondria at the crossroads of cell life and death in cancer

“…Gracillin, a natural product-derived steroidal saponin, is another mitochondria-targeting natural compound. By means of in vitro and in vivo studies, it was reported that, in NSCLC (non-small cell lung cancer) and breast cancer cells, gracillin inhibits the OXPHOS-mediated bioenergetics through the dysruption of the mitochondrial complex II-mediated energy production, resulting in ROS overproduction and cell death; the glycolytic pathway was also found to be reduced by this compound [349,350]. Similarly, a mixture of bergamot-derived polyphenols (brutieridin and melitidin) and the catechin-enriched matcha green teawere shown to inhibit the breast cancer stem cell propagation by targeting mitochondrial respiration and fatty acid oxidation [351,352].…”