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Review

Alkali Salts of Microbial Lipids with Anticancer Potential

by
Georgios Kalampounias
* and
Panagiotis Katsoris
Division of Genetics, Cell Biology and Development, Department of Biology, School of Natural Sciences, University of Patras, 26504 Patras, Greece
*
Author to whom correspondence should be addressed.
Lipidology 2025, 2(2), 12; https://doi.org/10.3390/lipidology2020012
Submission received: 4 April 2025 / Revised: 1 June 2025 / Accepted: 11 June 2025 / Published: 13 June 2025
Versions Notes

Abstract

Microbial lipids are substances of high added value produced by single-cell organisms grown on simple substrates. These lipids, depending on the producing organism, may contain rare fatty acids, whose isolation and purification from non-microbial sources usually is an inefficient and costly procedure. Such fatty acids mostly include members of the omega-3 and omega-6 families of polyunsaturated fatty acids, which are credited with potential anticancer, anti-inflammatory, cardioprotective, and neuroprotective actions. However, their poor solubility in aqueous solutions often restricts their potential applications, as routes other than dietary consumption are unavailable. A promising approach for administering them is their conversion into alkali salts, mostly with lithium or potassium, which are water-soluble and bio-assimilable. In this article, all studies investigating the potential anticancer effects of alkali salts of fatty acids isolated from microorganisms were reviewed in an attempt to sum up existing knowledge and encourage further research.

1. Introduction

Fatty acids are molecules essential to all living organisms, as they are credited with diverse roles that transcend their basic utility as energy sources [1]. Their long carbon chains not only pack several dense bonds whose hydrolysis releases usable energy to the cells but also act as structural components of cellular membranes and organelles [2]. The existence of unsaturated bonds in the molecules changes their properties drastically, resulting in lipids of varying reactivity, stored energy, and flexibility [3,4]. Unsaturated fatty acids, and especially those with multiple double bonds (polyunsaturated fatty acids, PUFAs), form distinctive groups within the umbrella term PUFA, depending on the position of each bond [5,6]. Besides their main and universal function as energy sources, each group has distinguishable biological roles, as all living organisms have evolved mechanisms to better exploit them and take advantage of their characteristics [4,6]. Lipid saturation greatly affects their biological functions, and each fatty acid type has a different metabolic route and lifecycle when incorporated by a cell [6]. PUFAs are vital for the membrane’s ability to function correctly (affecting stability, fluidity, permeability, and binding of molecules), and each cell or tissue type has a different lipid profile depending on the cell needs and microenvironment [7,8]. Moreover, certain fatty acids have been reported to interfere with or regulate cell signaling cascades, promote or inhibit cell death pathways, control inflammatory reactions, and have beneficial or detrimental effects on the function of the cardiovascular and neural systems [6]. Therefore, their repeated correlation as prognostic and therapeutic agents to various diseases (like many types of cancer, cardiovascular problems, as well as neurodegenerative and autoimmune diseases) has drawn much research attention over the years while their availability has fallen behind the demand [9,10,11,12,13,14,15].
A huge drawback of several fatty acids, limiting research and possible applications, used to be their scarcity or expensive isolation and purification processes. The ‘conventional’ sources of lipids like gamma-linolenic acid (GLA) used to be plants and marine organisms, which produce such rare fatty acids in small quantities [16,17]. The fractionation process and production of pure fatty acids demanded vast quantities of raw materials, and the final yield could not be adequate to fulfill nutritional, pharmaceutical, and research purposes [18,19]. However, everything in lipid research changed when biotechnology started replacing conventional sources with oleaginous fungi, microorganisms that inherently produce and accumulate lipids [20,21,22,23]. Each oleaginous organism can produce fats of varying composition, depending on its genotype, substrate, and culture conditions [22,23]. All these parameters can be set and monitored, resulting in lipids of specific, reproducible composition, which can be isolated after cell lysis [23]. A significant discovery in this field was the fact that fatty acids that used to be rare in conventional food sources are abundant in certain microorganisms that can be easily cultured and that grow on simple substrates [23]. This led to a giant breakthrough, as for the first time, the therapeutic potential of various lipids as parts of dietary or pharmaceutical products could be explored [24].
This study thoroughly reviews articles where fatty acid lithium salts (FALSs) from microbial oils were used instead of purified fatty acids, as this novel approach has recently renewed the interest around rare fatty acids and new potential applications. Most of the data centers around GLA, a fatty acid that has been reported to exhibit anticancer actions through several proposed mechanisms. The transformation of GLA into lithium gamma linolenate (LiGLA) significantly improves its solubility, bioavailability, and stability, thus improving many parameters of pharmaceutical interest. Therefore, in order to categorize this knowledge and promote further research interest, the existing literature was searched in a systematic manner to gather and discuss all related articles.

2. Biological Actions of Fatty Acid Alkali Salts of Non-Microbial Origin

Over the years, several studies have been published where fatty acids were examined for their biological actions on both in vitro and in vivo systems. Transformation of fatty acids into lithium salts was a relatively popular notion during the late 1990s, when several studies were conducted. The majority of these articles focused on GLA and LiGLA due to the multiple cytotoxic/anticancer properties attributed to them [25,26,27,28,29,30,31,32,33,34].

2.1. Data from In Vitro Studies

De Antueno et al. in 1997 investigated the metabolism of LiGLA in both in vitro and in vivo settings [26]. Pancreatic, prostatic, and mammary cancer cell lines were treated with radiolabeled LiGLA, and in the study, it is stated that administered LiGLA was found to be transformed into di-homo-gamma-linolenic acid (DGLA) and arachidonic acid (AA) (Table 1). The administration method includes a mixture of radiolabeled GLA or LiGLA, diluted in non-radiolabeled fatty acids, that was ultimately added to the culture plates as an ethanolic solution. The final concentration of fatty acids was set at 66 μM. Following 72 h of incubation, the cells were washed to remove excessive, extracellular radiolabeled fatty acids (as part of the medium) and impurities, and cell lysis was performed. The cellular lipids were extracted using the Folch method [35], and HPLC coupled with both a UV–VIS and a radioisotope detector was used to analyze and quantify intracellular radiolabeled lipids, derivatives of LiGLA. The authors did not observe significant cell death in the first 72 h following LiGLA administration, and cell viability was as high as 90%. Intracellularly, it was shown that LiGLA and GLA did not have significant differences regarding their metabolic transformations. GLA, either in its pure form or as lithium salt, was transformed into DGLA and AA in all three cancer types; however, the metabolite’s relative abundance was dependent on the cancer type. Pancreatic cancer cells transformed most of the GLA into DGLA compared with AA, while human mammary cancer cells accumulated mostly AA compared with DGLA and GLA. Finally, prostatic carcinoma cells were found to have intermediate concentrations.
Ravichandran et al. in 1998 studied the effects of LiGLA on pancreatic cancer cell lines [27]. MIA PaCa-2 and Panc-1 cells were used as models of human pancreatic cancer, and the non-cancerous human fibroblast cell line HFF-5 was used as a model of normal cells (Table 1). Cytotoxicity assays using the MTT assay revealed that the IC50 of MIA PaCa-2 cells following 24 h of incubation was 10.7 μM, and for the Panc-1 cells, the IC50 was 12.6 μM. The fibroblast had an IC50 of 110.8 μM, indicating the high susceptibility of pancreatic cells to LiGLA. The authors also monitored whether the observed cytotoxicity was a result of lithium instead of the fatty acids and found that it had no significant contribution. In the same study, it was investigated whether albumin can act synergistically with LiGLA on cell viability or affect LiGLA uptake. Viability was found to be higher when albumin was added while LiGLA doses remained stable. At a molar ratio of albumin:LiGLA of 8:1, the cytostatic/cytotoxic effects of LiGLA were found to be non-significant. LiGLA uptake was also assessed, and it was shown that albumin affected its absorption in a dose-dependent manner. Finally, the authors introduced iron in the medium to study possible synergy. Iron in the form of ferric chloride acted synergistically with LiGLA and negatively affected cell viability, while transferrin-bound iron indicated no synergistic effects. The authors proposed that albumin, through binding to LiGLA, decreased its uptake and the subsequent cytotoxic activity, while iron had the opposite effect through its oxidizing effects. Ferric ions are known to cause peroxidation, and GLA can act as a substrate to produce free radicals. Transferrin-bound iron did not increase cytotoxicity as it is bound to the protein and thus cannot participate in the Fenton reactions required for peroxidation cycles.
Jiang et al. in 1998 investigated the effects of various n-3 and n-6 PUFAs on human colon carcinoma (HT115) and triple-negative breast cancer (MDA MB 231) cell lines [36]. These types of cancer are among the most aggressive and highly metastatic, and the authors focused on the nm-23 tumor suppressor gene. The authors assessed the effects of pure AA, linolenic acid (LA), eicosipentanoic acid (EPA), GLA, and LiGLA (Table 1). Cytotoxicity was assessed using the DNA stain Hoechst, and the authors stated that the concentration of PUFAs used in the study was adequate to regulate nm-23 expression; however, no effects on cell viability were documented. GLA and LiGLA were both found to induce the expression of nm-23 at concentrations as low as 10 μM, and a peak in expression was documented 12 h following treatment. On the contrary, the other fatty acids, EPA, LA, and AA, were found to downregulate nm-23 expression. The study concluded that high doses of GLA or LiGLA may lead to cell death through peroxidation propagation; however, low GLA concentrations may be crucial for regulating cell adhesion and motility signaling.
Seegers et al. in 1998 assessed the effects of AA, GLA, and LiGLA on esophageal cancer cells (WHCO3) and on primary embryonic equine lung cells [34]. Both cell types were incubated with lipids or LiGLA (a stable dose of 50 μg/mL for 24 h) and were subsequently analyzed using flow cytometry to assess the distribution of the cell cycle phases. The authors reported that LiGLA caused a significant induction of an apoptosis peak (starting as fast as 6 h following treatment) in treated cancer cells (Table 1). LiGLA was more potent compared with the effect caused by GLA or AA (both of which mostly caused S-phase blockage). Normal cells (of equine origin) have slower cell cycle progression rates; therefore, the authors reported that effects were observed only after 24 h. However, susceptibility to LiGLA was greater than that to GLA or AA. In the same study, TK-6 lymphoblastic cells were used to assess apoptosis caused by LiGLA and GLA using the Hoechst assay (Table 1). LiGLA was demonstrated to be more cytotoxic than GLA, and the authors attributed this to lithium through the inhibition of endogenous inositol recycling. However, they did not conclude whether lithium and GLA act independently or synergistically to induce apoptosis.
Ilc et al. in 1999 studied the effects of LiGLA and meglumine gamma-linolenate (MeGLA) on human glioma cell lines [29]. The authors used A172 and U373MG as cancer cell models and tested cell viability after exposure to LiGLA or MeGLA (10−5 to 2 × 10−4 M) for 24 to 216 h by using the MTT assay (Table 1). They reported cytotoxicity following 4 days of exposure and proceeded to calculate the IC50 values. MeGLA was more potent as it had an IC50 of 47 μM for A172 cells following 4 days of exposure and 52 μM for U373MG cells. LiGLA had a four-day IC50 value of 73 μM for A172 cells and 86 μM for U373MG cells, respectively. Besides assessing the salts IC50 values as parts of monotherapy, the authors also co-administered LiGLA/MeGLA with fotemustine. Fotemustine is an anticancer drug that belongs to the nitrosourea family and exhibits antiproliferative effects by binding to DNA. Fotemustine is investigated as an anti-glioma agent due to its ability to cross the blood–brain barrier. In Ilc et al., it was shown that fotemustine and LiGLA/MeGLA exhibited slight antagonistic interactions [29]. The authors concluded that GLA assisted the formation of free radicals (acting as a substrate for peroxidation) that ultimately increased the expression of the O6-alkylguanine-DNA acyltransferase, which increases the cell’s ability to tolerate nitrosoureas.

2.2. Data from In Vivo Experiments

De Antueno et al. in 1997 also studied the in vivo effects of both GLA and LiGLA using athymic CD1BR (nu/nu) mice [26]. Xenografts of pancreatic cancer cells or prostatic cancer cells (PC-3) were created using 5 × 106 cells for each injection in the interscapular region. GLA or LiGLA was administered using a modified protocol initially developed by Fearon et al. in 1996 [30]; radiolabeled fatty acids were injected in the mice (through the tail vein) in a solution containing 200 IU/kg heparin, 14 μCi Li [1-14C]GLA, and 0.9% NaCl. To study the subjects, the mice were euthanized at key time points (0, 24, 48, 96 h) and perfusion was performed. The tissues were analyzed to study radioactivity distribution, and it was found that the organs incorporating most of LiGLA were the liver, the spleen, and the pancreas. The authors also studied the metabolic products of LiGLA/GLA, which were found to be mostly transformed into AA in most tissues (Table 1). In the blood plasma and in tumor cells, the ratio of GLA+DGLA:AA was found to be significantly higher and was about 2- to 4-fold higher in tumor tissues compared with normal tissues. The authors attributed this trait to low (but present) Δ5-desaturase activity detected in pancreatic and prostatic cancer cells, and these characteristics demonstrated that incorporated GLA:LiGLA had increased half-time inside cancer cells compared with normal tissues.
Ravichandran et al. in 1998 used BALB/c nude mice to study the effects of LiGLA on pancreatic tumors [28]. The tumors were created by subcutaneously injecting MIA PaCa-2 cells into the animals’ left flank or by transplanting tumors already grown on another BALB/c xenograft of MIA PaCa-2 cells (Table 1). The administration of LiGLA was performed by exploiting three different routes: intraperitoneal injection of ethanolic LiGLA (140 mg/mL in 12.75% ethanol; total dose: 0.5 mg/g of body weight), intravenous injection with galactosomal LiGLA (1.5% w/v and 10% oat galactolipids; total dose: 1 mg/g of body weight), and intratumoral injection of ethanolic LiGLA (140 mg/mL in 12.75% ethanol). All doses were dispensed as 10 daily injections. The tumors were monitored, and the subjects were euthanized to study the lipid composition of the various tissues pre- and post-treatment. Intraperitoneal injection of LiGLA was found to be toxic in doses of 1 mg/g of body weight and led to chemical peritonitis-related deaths. The lower dose of 0.5 mg/g of body weight was tolerated; however, neither dose led to tumor shrinkage. The tumor remained unchanged during intravenous injection as well; nonetheless, intratumoral injection of LiGLA led to a significant reduction in tumor size following 3–4 weeks of administration. Lipid composition analysis did not reveal any changes in the accumulation of n-6 fatty acids either in phospholipids or in the total lipids fraction. The authors attributed GLA’s inability to cause tumor shrinkage when administered intraperitoneally or intravenously to many factors. Low penetration ability and thus reduced intake by the tumor was theorized as the principal cause, along with albumin binding of the injected LiGLA and the activity of antioxidants, as has been shown in other studies [27].

2.3. Clinical Data

In 1996, Fearon et al. studied whether LiGLA could be effective against inoperable pancreatic cancer by carrying out an open-label phase I/II dose escalation clinical study [30]. For this purpose, an infusion method was developed, and LiGLA’s efficacy was investigated on 48 patients with pancreatic cancer (Table 1). The doses were adjusted to a range between 7 and 77 g per patient, which were cumulatively delivered over 2–12 days. Following survival analysis, the authors reported that higher LiGLA doses were correlated with longer survival time. Additionally, they mention that no significant side effects were recorded and that peripheral venous infusion should be avoided to reduce the risk of thrombophlebitis. To address those side effects, the authors suggested a protocol that includes infusion via a central vein and appropriate heparinization. Thus, encouraging clinical data was produced for the first time.
In 2001, Johnson et al. [31] carried out a randomized, dose-finding phase III trial, further expanding the preliminary data of Fearon et al. [30]. LiGLA was administered to 278 patients with advanced pancreatic adenocarcinoma in order to determine the suitability of LiGLA as a clinical agent per se [31]. The patients were treated either orally (a daily dose of 700 mg for 15 days) or with a low-dose (0.28 g/kg of body weight) or a high-dose (0.84 g/kg of body weight) intravenous LiGLA injection. Rapid infusions were documented to cause hemolysis, and the subgroup of patients with this side effect were documented to have a significantly increased survival time (Table 1). Oral and low-dose treatments were not found to be remarkably effective (129 days of survival for oral treatment, 121 days for low-dose intravenous injection), leading to survival times similar to those of other treatments for pancreatic cancer. On the other hand, high-dose-treated patients had an even lower survival time (94 days), and the therapy was discouraged due to serious side effects. The treatment was not toxic, as no signs of toxicity were reported; however, it was poorly tolerated, and the clinical study was not expanded.
In another clinical study, Kairemo et al. in 1999 reported that five patients with pancreatic cancer received LiGLA, and the response was compared with conventional regimens [32]. Two patients received two-dose intravenous injections of 0.28 g/kg of body weight each, and one patient received a higher dose of 0.84 g/kg of body weight. Finally, another two patients were administered LiGLA orally, with a single dose of 10.5 g. They subsequently used 99Tc-MIBI and observed that its half-life in the liver and pancreas had increased following LiGLA treatment, while in other organs, such as the kidneys or the spleen, no significant changes were observed (Table 1). In general, oral administration was less potent compared with intravenous injections; nevertheless, all patients had a significantly better response compared with conventional therapies. The authors documented tumor stabilization following treatment with LiGLA and changes in CA 19-9 values. The study had been published as a letter to the editor and concluded that more research was warranted; however, LiGLA treatment was found to increase blood flow in the pancreas and the liver and, in general, produced encouraging results, regardless of the very small patient sample.

3. Biological Actions of Alkali Salts from Microbial Lipids

The encouraging results from the late 1990s, which credited GLA and its soluble form, LiGLA, with multiple potential anticancer actions, were not widely adopted due to the high cost of GLA availability at the time. GLA used to be isolated principally from evening primrose (Oenothera biennis) and borage (Borago officinalis), in which GLA is found at concentrations of 8–22% wt/wt; nonetheless, the isolation and purification process is a costly and time-consuming process. However, recent advances in biotechnology allowed for a revival in fatty acid anticancer research. In the last ten years, GLA as part of microbial lipid formulations has been investigated for potential nutraceutical applications. This review focuses on applications in cancer research, and following a systematic search, only a limited number of publications were found, being the first of their kind in this category [17,37,38,39].

3.1. Leukemia

Alakhras et al. in 2015 investigated for the first time whole microbial lipids transformed into FALSs as anticancer agents [37]. The study describes a method where Cunninghamella echinulata was used as a microbial oil producer due to the organism’s ability to synthesize and accumulate GLA. Briefly, per 1 g of lipids, saponification is performed using 10 mL of 1 N KOH ethanol solution (95% vol/vol) at reflux for 105 min. At this stage, lipids break down and free fatty acids (FFAs) are released. To reduce FFA solubility, 10 mL of 4 N HCl and 5 mL of hexane are added in the mixture to form an organic phase. Following three cycles of hexane addition (5 mL each) and distilled water washing, the organic phase is collected and the FFAs are isolated using vacuum evaporation of the hexane under reduced nitrogen atmosphere and in the absence of light to avoid photodegradation. During the process, the temperature is maintained at 8 °C. Finally, isolated FFAs are transformed into FALSs. Per 1 g of FFA (diluted in an ethanol:diethyl ether 1:1 solution), 1 N LiOH is added until the pH reaches a value of 9.0. As a final step, the solvent mixture is evaporated under vacuum at a temperature of 50 °C, and the final solution is neutralized by adding 0.2 N H3PO4 until the pH reaches a value of 7.0. The mixture is then diluted at a final volume of 10 mL using distilled water, resulting in a stick solution of 10% wt/vol lipid extract [37].
In this study, as a cancer model, the HL-60 promyelocytic leukemia cell line was selected (Table 2) [37]. The microbial oils collected from C. echinulata contained about 12.9% wt/wt GLA and were used to assess the cytotoxic, genotoxic, and oxidative effects on the leukemia cells. Cell toxicity was determined using the trypan blue assay using FALS concentrations ranging from 5 to 20 μg/mL and exposure times as fast as 20 min. Their findings demonstrate a linear dose–response manner of action, and the FALS cytotoxicity was shown to act synergistically with H2O2. Similar FALS concentrations co-administrated with H2O2 were used to assess the effects of the salts on DNA fragmentation using the comet assay [40]. Doses as low as 15–20 μg/mL were found to significantly enhance the fragmentation caused by H2O2 as GLA and other PUFAs acted as peroxidation substrates that allowed the propagation of free radical production.

3.2. Prostate Cancer

Regarding prostate cancer, only two in vitro studies have been conducted so far. In a 2024 study by Kalampounias et al., FALSs from Cunninghamella elegans were used to study multiple biological effects on prostate cancer cell lines [38]. FALSs from C. elegans were rich in oleic acid (OA, C18:1) (48.8%, wt/wt), linoleic acid (LA, C18:2n-6) (11.9%, wt/wt), palmitic acid (PA, C16:0) (21.4%, wt/wt), and GLA (C18:3n-6) (9.5%, wt/wt). Both models of the study (PC-3 and DU-145) were incubated with FALSs containing mostly LiGLA, and the IC50 values following 48 h of treatment were determined. PC-3 had an IC50 of 59.2 μg/mL, while DU-145 had an IC50 of 60.7 μg/mL. FALSs were also documented to significantly impair the cancer cells’ ability to migrate (Table 2). Wound healing assays revealed that the healing rate of incubated cells was significantly lower compared with untreated cells, an effect appearing as fast as 24 h following treatment. Boyden chambers revealed that the cells’ ability to migrate was decreased and the ability to move towards chemoattractants was diminished following incubation with FALS for 24 h. Besides cytotoxicity and migration, the oxidative stress of the cells was also evaluated. Using H2DCFDA, which is an assay that detects hydroxyl radicals, the intracellular oxidative stress lipid levels were determined and found to be significantly elevated in treated cells. Oxidative stress was increased in a time-dependent and dose-dependent manner, showing a strong correlation to the presence of lipids in the medium. Additionally, cellular death was also assessed using annexin V (apoptosis marker) and propidium iodide (necrosis marker). Even though reports of late cell death activation exist, probably due to activation of apoptosis, in this study, cell death was documented as fast as 24–48 h following treatment, and as most cells were negative for annexin V, the response was either necrotic (PI-positive) or ferroptotic. This study was also the first of its kind because it describes a methodology to visualize and quantify lipid accumulation following FALS treatment in cell cultures [38]. Nile red and BODIPY 515 stains were used, and the cells were visualized using both wide-field and confocal fluorescence microscopy. Using that method, the lipid droplets inside incubated cells were found to be brightly stained compared with the dim staining of non-treated cells, as indicated by the Nile red staining. Additionally, Nile red was also used in flow cytometry to perform an estimate on lipid accumulation. Using different fluorescent channels and the fact that Nile red emits photons of longer wavelengths when it is bound to phospholipids, in Kalampounias et al., both neutral lipids and phospholipids were studied. Following 24 h of incubation, the phospholipids remained stable; however, neutral lipids had increased significantly, validating the absorption of the lipids.
In a second study published in 2025 by Kalampounias et al., FALSs derived from two organisms, Thamnidium elegans CCF 1465 and Mortierella alpina CBS 343.66, were assessed for their main biological actions on prostate cancer cell lines [39]. Regarding T. elegans FALSs, they were high in OA (29.7%, wt/wt), PA (23.3%, wt/wt), and LA (22.1%, wt/wt). These are generally considered well tolerated, and both cancerous and normal cells exhibit relatively high IC50 values. However, T. elegans is also able to synthesize and accumulate GLA, which, according to Kalampounias et al., was present in a relatively high concentration in the isolated lipids (19.4%, wt/wt). Regarding M. alpina, its lipids were rich in PA (C16:0) (32.2%, wt/wt), gondoic acid (C20:1n-9) (19.8%, wt/wt), and OA (18.0%, wt/wt). However, besides these, DGLA (C20:3n-6) (4.5%, wt/wt), AA (3.5%, wt/wt), and GLA (2.9%, wt/wt) were also present in the mixture. As stated by de Antueno et al., DGLA and AA are the main metabolites of GLA in normal cells, while in prostate cancer cells, GLA is catabolized more slowly due to lower enzymatic activity [26]. In the study by Kalampounias et al., the lipids from the two fungi are compared with the biological effects of FALSs derived from olive oil (complete lack of GLA), which constitute a mixture of lipids well tolerated by the cells, as well as FALSs derived from fish oil [39]. Fish oil FALSs are rich in EPA and were found to have very high cytotoxic and anti-migratory activity (Table 2). The study concludes that FALSs from these two organisms have an intermediate cytotoxicity between olive oil and fish oil FALS. M. alpina lipids are more potent than T. elegans; however, both lipid formulations are cytotoxic agents and cost-effective sources of GLA.

3.3. Thyroid Cancer

In thyroid cancer, limited data exists, only from an article by Kalampounias et al. in 2024 [38]. In the aforementioned study, the papillary thyroid carcinoma cell lines K1 and TPC-1 were used, and as a control, the Nthy-ori 3-1 normal thyroid cell line (Table 2). In general, the three cell lines did not exhibit significant differences; however, Nthy-ori 3-1 cells, despite expressing most thyroid markers and being able to be used to adequately mimic thyrocyte hormone excretion and phenotypical characteristics, with respect to metabolism, they are not ideal models [41]. This happens mainly due to the fact that cell lines are immortalized and engineered to divide endlessly, while under physiological conditions, normal thyrocytes remain in the G0 phase and do not divide. The IC50 for each cell line was determined following 48 h of treatment with FALSs from C. elegans. K1 had an IC50 of 57.9 μg/mL, TPC-1 had an IC50 of 58.6 μg/mL, and Nthy-ori 3-1 had an IC50 of 58.1 μg/mL.

3.4. Breast Cancer

In Sayegh et al., lipids from Thamnidium elegans CCF 1465 and Nannochloropsis salina were used to assess potential antimicrobial and anticancer effects [17]. The lipids were transformed into fatty acid potassium salts (FAPSs), and as a cancer model, the MCF-7 breast cancer cell line was used. The cells were incubated with various FAPS concentrations for 24 h, and their viability was subsequently assessed using the trypan blue assay. As controls, FAPSs derived from olive oil (low cytotoxicity) and from evening primrose oil (conventional GLA source) were used. T. elegans FAPSs contained 6.8% wt/wt GLA, 16.3% wt/wt LA, 44.1% wt/wt OA, and 19% wt/wt PA. The reported IC50 was 0.3 μg/mL, while the reported IC50 for olive oil FAPSs was 0.4 μg/mL (Table 2). Similar data was reported on evening primrose oil, which had an IC50 value of 0.4 μg/mL. N. salina FAPSs were rich in EPA (29.7% wt/wt), palmitoleic acid (C16:1, 19.5% wt/wt), and PA (20.0% wt/wt). The exhibited IC50 was 0.45 μg/mL. The authors also stated that both formulations caused morphological alterations typical of apoptosis.

4. Current Limitations and Future Directions

The aforementioned studies are pioneers in this cell biology and biotechnology joint area of study. Given the encouraging findings, it is important to mention certain aspects of the experimental design that need further refinement and standardization to allow for greater repeatability, translational interest, and scientific soundness. FALSs and FAPSs were employed as means to introduce lipophilic substances in an aqueous solution like culture medium; however, the role of the alkali moiety of the molecule (potassium or lithium) needs to be studied further. Potassium in its ionic form is a very common food ingredient being present in almost all food sources [42]. Its concentration in the blood plasma, inside the cells, or in different tissues is regulated by several homeostatic mechanisms, relying heavily on specialized proteinic pumps [42]. On the other hand, lithium is a much more rare element in the food chain and human organism [43]. The biological actions are not fully understood up to this day [43]; however, lithium salts are used as psychiatric medications, specialized in the treatment of bipolar disorder and major depression [44]. Additionally, lithium-based medications are used as second-line antipsychotic drugs, used to treat schizophrenia [44].
In general, lithium comes with several side effects, interacting with sodium homeostasis and also affecting the function of the thyroid, the kidneys, and the neural system. Lithium overdose (or lithium toxicity) can be acute or chronic, depending on the exposure duration and the magnitude of the dose [45]. Acute toxicity has effects mostly on the gastroesophageal system, while chronic toxicity affects mainly the muscle and the neural system [45]. Regarding cancer, lithium (in the form of lithium salts) is also being investigated as a potential anticancer agent [46]. Lithium acetoacetate, lithium chloride, lithium carbonate, lithium citrate, and lithium gamma-linolenate are the main forms of lithium whose anticancer actions are under investigation [26,29,38,39,46]. Inhibitory effects have been observed regarding the growth and multiplication of tumor cells, and key cellular functions have been shown to be suppressed by lithium compounds [38,46]. A significant observation is that lithium can act synergistically with other chemotherapies, thus underscoring its role as a possible therapeutic agent [46,47]. Therefore, besides its present as solubilizing agent in FALSs, it can exhibit its own anticancer actions, which need further investigation. Except for a 2024 study by Kalampounias et al., so far, microbial FALSs have not been assessed with standard lithium salts solutions in parallel [38]. It is of paramount importance to further investigate whether lithium accounts for the majority of the cytostatic effects caused by microbials FALSs or whether the fatty acid part is the more significant moiety. Lithium dosage must be seriously under consideration when lithium-based pharmaceuticals are designed, as lithium toxicity can be a major burden. Therefore, studies addressing this issue should be considered.
Another major parameter to be taken into consideration is the use of appropriate models and administration strategies. Microbial lipids have only been investigated in vitro, which significantly narrows down our ability to extrapolate on their systemic effects. Older studies have shown that the lithium salts of gamma-linolenate can exhibit differential results regarding the administration site and method of administration [26,30,31,32]. These papers are quite old compared with recent advances in drug delivery systems; therefore, coupling FALSs with state-of-the-art drug vectors could create powerful tumoricidal formulations [48,49,50,51]. In vitro assessments so far have been conducted on the cell cultures of immortalized cells; however, it is very important to study the effects of microbial FALSs on primary cancer cells. Each cancer type is unique (regarding its intracellular dynamics and activated pathways) and requires a different approach. Therefore, high-throughput methods should be developed to study key molecular and biochemical effects observed in cancer cells [52].
Finally, it is important to mention that using alkali salts of single cell oils can have another benefit. The rapid advancement of biotechnology makes possible the production of a wide variety of rare lipids and even more rare lipid mixtures that are uncommon in the human diet and until recently relatively limited in their pure form. From that point of view, FALS/FAPS could act as tool for a rapid assessment of anticancer potential when studying undefined, under-studied lipids of microbial, plant, or even synthetic origin [53,54,55,56,57,58,59]. Transforming a novel oil into a lithium or potassium salt is a relatively easy solubilization process (compared with complex chemical, mechanical, or biological process), which can be used as a rapid screening method. The use of standard fatty acids (instead of microbial oils containing mixtures of them) will provide the required internal standards needed to chart the effects of each individual fatty acid and also consider the synergy among them. Therefore, future studies employing FALS/FAPS could be based on a more mechanistic approach, able to correlate specific ingredients of the total microbial extract to their respective effects on key cell functions.

5. Conclusions

Alkali salts of fatty acids have been demonstrated to exhibit multiple cytotoxic actions that can be used to target cancer cells. Several studies were conducted in the past in which purified fatty acids, or their salt form, were administered and tumoricidal properties were recorded. As the most potent fatty acid, GLA emerges, as does its water-soluble and bio-assimilable lithium salt. Given the recent advances in biotechnology, GLA and other fatty acids of high pharmaceutical interest may now be available in vast quantities by exploiting cost-effective substrates. Therefore, research on fatty acids as nutraceutical formulations could also experience a significant revival. Up to this day, limited data exists on whether microbial lipids could undergo minor chemical transformations and be exploited as agents of high pharmaceutical value. Recent studies indicate that microbial lipids rich in GLA can still exhibit anticancer activity without the need for GLA isolation, purification, and encapsulation in sophisticated drug carriers. It is of paramount importance to further investigate more fatty acids, combinations, and potential microorganisms that could produce such products of high added value. The existing studies contain a significant amount of information regarding GLA’s and other lipids’ mechanisms of action; however, there are important aspects of their biological actions that are still obscure. PUFAs in great quantities are known for their ability to propagate peroxidation reactions, producing peroxides detrimental to the cellular metabolism, signaling, and membrane integrity, thus leading to apoptotic or ferroptotic death. However, small amounts of certain PUFAs (such as GLA, AA, and EPA), also have a significant role in regulating intracellular processes like autophagy, metabolic pathways, cell proliferation, and migration. Different mixtures, doses, and treatment durations are responsible for the varying results reported in the existing literature, thus emphasizing the need for further research. Future studies should direct their attention to the mechanistic part of the observed effects as this could shed light to the exact pathways affected by FALS/FAPS, thus expanding current understanding of their tumoricidal properties. Last but not least, the current data underscores the role of alkali salts of (microbial) oils as a rapid screening tool for novel lipids or lipid mixtures. Further refinement of the described techniques and standardization of future protocols to apply both on in vitro and in vivo models could provide a sound methodology for the screening of extracts of microbial and non-microbial origin for their anticancer potential.

Author Contributions

Conceptualization and investigation, G.K.; data curation, G.K.; writing—original draft preparation, G.K.; writing—review and editing, G.K. and P.K.; visualization, G.K.; supervision, P.K.; project administration, P.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AAArachidonic acid
DGLADi-homo gamma linolenic acid
DOAJDirectory of Open Access Journals
EPAEicosipentanoic acid
FALSFatty acid lithium salt
FAPSFatty acid potassium salt
FFAFree fatty acid
GLAGamma linolenic acid
HPLCHigh-performance liquid chromatography
LiGLALithium gamma linolenate
MDPIMultidisciplinary Digital Publishing Institute
MeGLAMeglumine gamma linolenate
OAOleic acid
PAPalmitic acid
PUFAPolyunsaturated fatty acid

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Table 1. Studies investigating the anticancer potential of alkali salts of fatty acids.
Table 1. Studies investigating the anticancer potential of alkali salts of fatty acids.
SubstancesModels or Clinical Study ParticipantsMain Outcomes of the StudyRef.
In vitro
LiGLA 1, GLAPancreatic, prostate, and mammary cancer cell lines.GLA/LiGLA was transformed into DGLA and AA. Pancreatic cancer cells turned GLA mostly into DGLA; human mammary cancer cells turned most GLA into AA. Prostate cancer cells were found with intermediate concentrations.[26]
LiGLAPancreatic cancer (MIA PaCa-2 and Panc-1) and non-cancerous fibroblast (HFF-5) cell lines.Pancreatic cells are more susceptible to LiGLA than normal cells. The inhibitory effects were attributed to the fatty acid moiety. Albumin, through binding to LiGLA, decreases its uptake and cytotoxicity, while iron has the opposite effect through peroxidation synergy.[27]
AA, LA, EPA, GLA, and LiGLAHuman colon carcinoma (HT115) and triple-negative breast cancer (MDA MB 231) cell lines.GLA and LiGLA induce the expression of nm-23 at concentrations as low as 10 μM. EPA, LA, and AA downregulate nm-23 expression. High doses of GLA or LiGLA may lead to cell death through peroxidation propagation. Low doses of GLA may be crucial to cell adhesion and motility.[36]
AA, GLA, and LiGLAEsophageal cancer cells (WHCO3), lymphoblastic cells (TK-6), and primary embryonic equine lung cells.LiGLA causes a significant induction of an apoptosis peak in cancer cells. LiGLA is more potent compared to GLA or AA.[34]
LiGLA, MeGLA, FotemunstineHuman glioma cells lines (A172 and U373MG).MeGLA is more cytotoxic than LiGLA. Fotemustine and LiGLA/MeGLA exhibit slight antagonistic interactions.[29]
In vivo
LiGLA, GLAPC-3 xenografts in athymic CD1BR (nu/nu) mice.The organs incorporating most of LiGLA are the liver, the spleen, and the pancreas. LiGLA/GLA, are transformed into AA in most tissues.[26]
LiGLAMia PaCa-2 xenografts in BALB/c mice.Intraperitoneal injections of LiGLA did not lead to tumor shrinkage. The tumor remained unchanged during intravenous injections as well; nonetheless, intratumoral injection of LiGLA led to a significant reduction in tumor size following 3–4 weeks of administration.[28]
Clinical trials
LiGLA48 patients with inoperable pancreatic cancer.Higher LiGLA doses were correlated with longer survival time.[30]
LiGLA278 patients with advanced pancreatic adenocarcinoma.Rapid infusions caused hemolysis but the subgroup of patients with this side effect had a significantly increased survival time. Oral and low-dose treatments were not found to be remarkably effective (129 days of survival for oral treatment, 121 days for low-dose intravenous injection), leading to survival times similar to those of other treatments for pancreatic cancer. High-dose-treated patients had an even lower survival time (94 days). The therapy was discouraged due to serious side effects. The treatment was not toxic, as no signs of toxicity were reported; however, it was poorly tolerated.[31]
LiGLA5 patients with pancreatic cancer.The half-life of 99Tc-MIBI in the liver and pancreas increased following LiGLA treatment. Treatment with LiGLA stabilized the tumor and changed CA 19-9 values.[32]
1 Notes: LiGLA: lithium gamma-linolenate; GLA: gamma linolenate; AA: arachidonic acid; LA: linolenic acid; EPA: eicosipentanoic acid; MeGLA: meglumine gamma-linolenate.
Table 2. Studies investigating the anticancer potential of alkali salts of microbial fatty acids.
Table 2. Studies investigating the anticancer potential of alkali salts of microbial fatty acids.
SubstancesModels or Clinical Study ParticipantsMain Outcomes of the StudyRef.
FALS from Cunninghamella echinulata.Human promyelocytic leukemia cells (HL-60).FALS act in a linear dose–response manner of action. FALS cytotoxicity acts synergistically with H2O2. Doses as low as 15–20 μg/mL significantly enhance DNA fragmentation caused by H2O2.[37]
FAPS from (a) Thamnidium elegans CCF 1465, (b) Nannochloropsis salina, (c) olive oil, and (d) evening primrose oil.Human breast cancer cells (MCF-7).T. elegans FAPS have a lower IC50 (0.3 μg/mL) than both olive oil (0.4 μg/mL) and evening primrose oil FAPS (0.4 μg/mL).[17]
FALS from Cunninghamella elegans.Human pancreatic cancer (PC-3 and DU-145), papillary thyroid carcinoma (K1, TPC-1), and normal thyrocyte (Nthy-ori 3-1) cell lines.FALS suppress the cells’ ability to multiply and migrate. Intracellular ROS levels rise. Apoptosis and ferroptosis are induced. Lipids from the FALS are accumulated intracellularly inside lipid droplets.[38]
FALS from (a) Thamnidium elegans CCF 1465, (b) Mortierella alpina CBS 343.66, (c) olive oil, and (d) fish oil.Human pancreatic cancer (PC-3 and DU-145).Fish oil FALS have the highest cytotoxic and anti-migratory activity. Microbial FALS from these two organisms have an intermediate cytotoxicity between olive oil and fish oil FALS. M. alpina lipids are more potent than T. elegans; however, both lipid formulations are cytotoxic agents and cost-effective sources of GLA.[39]
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Kalampounias, G.; Katsoris, P. Alkali Salts of Microbial Lipids with Anticancer Potential. Lipidology 2025, 2, 12. https://doi.org/10.3390/lipidology2020012

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Kalampounias G, Katsoris P. Alkali Salts of Microbial Lipids with Anticancer Potential. Lipidology. 2025; 2(2):12. https://doi.org/10.3390/lipidology2020012

Chicago/Turabian Style

Kalampounias, Georgios, and Panagiotis Katsoris. 2025. "Alkali Salts of Microbial Lipids with Anticancer Potential" Lipidology 2, no. 2: 12. https://doi.org/10.3390/lipidology2020012

APA Style

Kalampounias, G., & Katsoris, P. (2025). Alkali Salts of Microbial Lipids with Anticancer Potential. Lipidology, 2(2), 12. https://doi.org/10.3390/lipidology2020012

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