Targeting cancer cells in acidosis with conjugates between the carnitine palmitoyltransferase 1 inhibitor etomoxir and pH (low) insertion peptides.

Targeting enzymes involved in tumor metabolism is a promising way to tackle cancer progression. The inhibition of carnitine palmitoyltransferase 1 (CPT1) by etomoxir (Eto) efficiently slows down the growth of various cancers. Unfortunately, the clinical use of this drug was abandoned because of hepatotoxic effects. We report the development of pH-sensitive peptide (pHLIP)-drug conjugate to deliver Eto selectively to cancer cells exposed to acidic microenvironmental conditions. A newly designed sequence for the pHLIP peptide, named pHLIPd, was compared with a previously published reference pHLIP peptide, named pHLIPr. We showed that the conjugate between pHLIPd and Eto has a better pH-dependent insertion and structuration than the pHLIPr-based conjugate inside POPC vesicles. We observed antiproliferative effects when applied on acid-adapted cancer cells, reaching a larger inhibitory activity than Eto alone. In conclusion, this study brings the first evidence that pHLIP-based conjugates with a CPT1 inhibitor has the potential to specifically target the tumor acidic compartment and exert anticancer effects while sparing healthy tissues.

Punicic Acid Triggers Ferroptotic Cell Death in Carcinoma Cells.

Plant-derived conjugated linolenic acids (CLnA) have been widely studied for their preventive and therapeutic properties against diverse diseases such as cancer. In particular, punicic acid (PunA), a conjugated linolenic acid isomer (C18:3 c9t11c13) present at up to 83% in pomegranate seed oil, has been shown to exert anti-cancer effects, although the mechanism behind its cytotoxicity remains unclear. Ferroptosis, a cell death triggered by an overwhelming accumulation of lipid peroxides, has recently arisen as a potential mechanism underlying CLnA cytotoxicity. In the present study, we show that PunA is highly cytotoxic to HCT-116 colorectal and FaDu hypopharyngeal carcinoma cells grown either in monolayers or as three-dimensional spheroids. Moreover, our data indicate that PunA triggers ferroptosis in carcinoma cells. It induces significant lipid peroxidation and its effects are prevented by the addition of ferroptosis inhibitors. A combination with docosahexaenoic acid (DHA), a known polyunsaturated fatty acid with anticancer properties, synergistically increases PunA cytotoxicity. Our findings highlight the potential of using PunA as a ferroptosis-sensitizing phytochemical for the prevention and treatment of cancer.

Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects.

Tumor acidosis promotes disease progression through a stimulation of fatty acid (FA) metabolism in cancer cells. Instead of blocking the use of FAs by acidic cancer cells, we examined whether excess uptake of specific FAs could lead to antitumor effects. We found that n-3 but also remarkably n-6 polyunsaturated FA (PUFA) selectively induced ferroptosis in cancer cells under ambient acidosis. Upon exceeding buffering capacity of triglyceride storage into lipid droplets, n-3 and n-6 PUFA peroxidation led to cytotoxic effects in proportion to the number of double bonds and even more so in the presence of diacylglycerol acyltransferase inhibitors (DGATi). Finally, an n-3 long-chain PUFA-rich diet significantly delayed mouse tumor growth when compared with a monounsaturated FA-rich diet, an effect further accentuated by administration of DGATi or ferroptosis inducers. These data point out dietary PUFA as a selective adjuvant antitumor modality that may efficiently complement pharmacological approaches.

Cancer diets for cancer patients: Lessons from mouse studies and new insights from the study of fatty acid metabolism in tumors.

Specific diets for cancer patients have the potential to offer an adjuvant modality to conventional anticancer therapy. If the concept of starving cancer cells from nutrients to inhibit tumor growth is quite simple, the translation into the clinics is not straightforward. Several diets have been described including the Calorie-restricted diet based on a reduction in carbohydrate intake and the Ketogenic diet wherein the low carbohydrate content is compensated by a high fat intake. As for other diets that deviate from normal composition only by one or two amino acids, these diets most often revealed a reduction in tumor growth in mice, in particular when associated with chemo- or radiotherapy. By contrast, in cancer patients, the interest of these diets is almost exclusively supported by case reports precluding any conclusions on their real capacity to influence disease outcome. In parallel, the field of tumor lipid metabolism has emerged in the last decade offering a better understanding of how fatty acids are captured, synthesized or stored as lipid droplets in cancers. Fatty acids participate to cancer cell survival in the hypoxic and acidic tumor microenvironment and also support proliferation and invasiveness. Interestingly, while such addiction for fatty acids may account for cancer progression associated with high fat diet, it could also represent an Achilles heel for tumors. In particular n-3 polyunsaturated fatty acids represent a class of lipids that can exert potent cytotoxic effects in tumors and therefore represent an attractive diet supplementation to improve cancer patient outcomes.

TGFß2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells.

Acidosis, a common characteristic of the tumor microenvironment, is associated with alterations in metabolic preferences of cancer cells and progression of the disease. Here we identify the TGF-ß2 isoform at the interface between these observations. We document that acidic pH promotes autocrine TGF-ß2 signaling, which in turn favors the formation of lipid droplets (LD) that represent energy stores readily available to support anoikis resistance and cancer cell invasiveness. We find that, in cancer cells of various origins, acidosis-induced TGF-ß2 activation promotes both partial epithelial-to-mesenchymal transition (EMT) and fatty acid metabolism, the latter supporting Smad2 acetylation. We show that upon TGF-ß2 stimulation, PKC-zeta-mediated translocation of CD36 facilitates the uptake of fatty acids that are either stored as triglycerides in LD through DGAT1 or oxidized to generate ATP to fulfill immediate cellular needs. We also address how, by preventing fatty acid mobilization from LD, distant metastatic spreading may be inhibited.

Dealing with saturated and unsaturated fatty acid metabolism for anticancer therapy.

PURPOSE OF REVIEW: Although saturated fatty acid (FA) (SFA) and monounsaturated FA (MUFA) are synthesized in cancer cells from acetyl-CoA, polyunsaturated FAs (PUFAs) are necessarily obtained from diet. Depending on concentrations and metabolism, these different FAs may support tumor proliferation but also exert growth inhibitory effects. The mutual interplay between them also requires to integrate the FA oxidation component that may be concomitant with FA synthesis is cancer cells. RECENT FINDINGS: New molecular mechanisms driving FA synthesis, lipotoxicity and anti-inflammatory activity of eicosanoids in mouse and human cancers were recently elicited. To block or take advantage of the above represent attractive perspectives of treatments to fight cancer progression. SUMMARY: The various enzymatic reactions leading to SFA synthesis represent as many targets to prevent tumor growth. Ironically excess SFAs are per-se toxic for cancer cells and the introduction of a double bound to form MUFA is actually limiting lipotoxicity in cancer cells. Blocking stearoyl-CoA desaturase therefore represents another attractive modality. By contrast, dietary PUFAs may exert direct cytotoxic effects by promoting apoptosis or by generating anti-inflammatory eicosanoids. Altogether, these data point out the intricate relationship between SFA, MUFA and PUFA at the heart of the metabolism of proliferating cancer cells.