Monotherapy or Combination Therapy of Oleanolic Acid? From Therapeutic Significance and Drug Delivery to Clinical Studies: A Comprehensive Review

Abstract

Oleanolic acid is a pentacyclic triterpenoid molecule widely distributed throughout medicinal plants. This naturally occurring oleanolic acid has attracted considerable interest due to its wide range of pharmacological characteristics, notably its cytotoxic effects on various human cancer cell lines, making it a potential candidate for extensive therapeutic uses. In vivo studies have shown that oleanolic acid possesses hepatoprotective, cardioprotective, anti-inflammatory, and antimicrobial properties. The inherent obstacles of oleanolic acid, such as low permeability, limited bioavailability, and poor water solubility, have restricted its therapeutic applicability. However, recent developments in drug delivery techniques have given oleanolic acid an additional advantage by overcoming issues with its solubility, stability, and bioavailability. This review briefly summarises the signalling pathways involved in the pharmacological activities of oleanolic acid as a monotherapy and in combination with other drugs. The review devotes a substantial portion to explaining the formulation developments, emphasising nanotechnology as a key factor in the improvement of the therapeutic potential of oleanolic acid. Several investigated novel formulations have been discussed, including liposomes, nanoemulsions, phospholipids, and polymeric nanoparticles, emerging synergistically as an efficient delivery of oleanolic acid and several other drugs. Based on our literature evaluation, it can be inferred that combination therapy had a more favourable outcome than using oleanolic acid alone in in vivo trials, primarily due to its synergistic effects. However, it is essential to note that this finding was inconsistent across all investigations. The combination of oleanolic acid with other drugs has not yet been considered for clinical trials. However, it is interesting that neither therapy has obtained approval from the U. S. Food and Drug Administration.

Keywords

oleanolic acid - combination therapy - pharmacological activity - drug delivery

Introduction

Oleanolic acid (OA) is a pentacyclic triterpenoid. It is a potent bioactive phytochemical abundant in many plant species. OA belongs to the most promising members of the triterpenoid groups as per the safety profile, although its dose determination is critical. OA also shows toxicities in certain circumstances like cholestasis. While hepatotoxicity is produced at high doses, low doses show hepato-protective activity. Families of triterpenoids are categorised according to the number of distinct structural isoprene units. Squalene cyclisation often occurs in many plants and is used to synthesise triterpenoids [1]. Typically, OA is found in the different plant parts, such as the leaves, barks, and roots, of more than 120 medicinal plants, including Olea europaea L., Wattakaka volubilis (L. f.). Stapf., Viscum album L., Aralia chinensis l., Eriobotrya japonica Lindl., and Aralia elata Seem [2], [3], [4]. Numerous functional groups serve to provide different important physiological activities of the pentacyclic triterpenes, including protective and therapeutic effects. The protective effects cover major organs/systems like the nervous system (neuroprotective), liver (hepatoprotective), and immunity system (immunoprotective) [5]. In contrast, the anti-inflammatory, antidiabetic, and antitumour [6] therapeutic effects along with in vitro inhibitory activity against breast carcinoma [7] and rectal carcinoma [5] has been observed. OA has been revealed to hinder hepatic carcinoma [8], [9], [10], gallbladder carcinoma [11], and pancreatic ductal adenocarcinoma [12], both in in vitro and in vivo animal models, and is listed as a pharmacotherapeutic effect of OA in various preclinical and clinical studies.

Though OA has marked pharmacotherapeutic potentials, the issue of poor water solubility causes major drawbacks for treatment development. Nanotechnology plays a significant role nowadays by enhancing solubility, steadiness, bioavailability, and delivery of phytochemicals without altering the medicinal activities. Several literatures delineated the anticancer, neuroprotective, and antihyperglycemic properties of OA and its derivatives [13], [14], [15]. However, these evaluations concentrated on advancements in pharmacology. Furthermore, the present review provides a summary of the existing studies on the possibility of OA as a monotherapeutic agent as well as in combination with other drugs in the management of both acute and chronic illnesses, which includes cancer, diabetes, microbial, cardiovascular, inflammation, and hepatic disorders. The article aims to verify whether the monotherapy of this moiety is sufficient or whether a combination is required to address the pressing pathological issues in clinical settings.

Methods

Several databases, including PubMed, Scopus, and Web of Science, were utilised to retrieve original articles and reviews in order to explore the therapeutic importance of OA in monotherapy or combination therapy. The time frame for the search strategy included was from 2004 – 2024. The Boolean functions “and” and “or” were included in the inclusion criteria, which includes “oleanolic acid”, “derivatives”, “pharmacology”, “in vitro”, “in vivo”, “molecular mechanism”, “dosage form”, “monotherapy”, and “combination”. Information on several clinical trials were obtained from the database www.clinicaltrials.gov. All the included articles have illustrated how OA can play a crucial role in the management of cancer, diabetes, microbial, cardiovascular, inflammation, and hepatic disorders.

Property

Chemical properties

The basic structure of the pentacyclic triterpenoids is demonstrated in [Fig. 1]. The activity can be altered by substituting some functional groups in the structure. For example, substituting or moderating the hydroxyl group at C3 (R1 group) results in reduced activity.

Fig. 1 Basic structure of pentacyclic triterpenoids.

Similarly, sugar moiety causes the same reduced activity, whereas the carboxypropionyloxy group can increase activity. Likewise, alteration with methyl hydroxyl or carboxyl group at C4 (R2 group) also decreases the activity. On the other hand, modification by a ketone, methyl, or oxo group at the C11 position (R8) is not beneficial. Another substitution at the C19 (R9) position with the hydroxyl group ultimately causes a lowering of the activity. Carboxylation at C23 and C30 is helpful by improving the activity, whereas esterifications at C30 (R5) is responsible for lowering the activity. Alteration of the carboxyl group at C28 (R3) with ester, alcohol, or amide has no positive action. Modifying the hydroxyl group (R11) attached at C22 ultimately causes more potency of the oleanane group and less of the ursane group.

OA, [(3β)-3-hydroxyolean-12-en-28-oic acid], an essential derivative of these triterpenoids, has the same basic skeleton structure as pentacyclic triterpenoid, where olean-12-en-28-oic acid is replaced at position 3 by a beta-hydroxy group. A number of novel synthetic oleanane triterpenoids have been created by chemically altering OAʼs three “active” components, C-3 hydroxy, C-12-C-13 double bond, and C-28 carboxylic acid [16]. 2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester, CDDO-Me, are the most potent derivatives in this list. The two compounds have an electron-withdrawing nitrile group at the C-2 position in the A-ring and enone functionalities in their A- and C-rings, which have been proven to be crucial for the activity of synthetic triterpenoids [17]. The electron-drawing nitrile group activates the A-ring enone, allowing it to function as a receiver of a Michael addition to covalently but reversibly bind to activated sulfhydryl groups of cysteine residues in protein targets [18].

Physical properties

OA, a natural triterpenoid, is found as an aglycone of saponins [2], sometimes along with UA (Ursolic acid) [19], and also as a free acid. More than 120 plant species (roots and leaves) have been tapped for their OA content, such as O. europaea L., V. album L., and A. chinensis Blume [2]. Physically, OA is a light yellow nonvolatile compound that is hydrophobic. It is poorly soluble in water and organic solvents like ethanol, 2-propanol, methanol, and acetone. OA is more soluble in solvents like 1-butanol and ethyl acetate. Generally, the solubility of OA is directly proportional to the temperature [20], [21]. OA belongs to the BCS class IV drugs and has low bioavailability attributed to its low solubility (< 1 µg/mL), accompanied by low permeation of membranes [22].

Pharmacokinetics

OA shows rapid metabolism, due to which nonspecific distributions and reduced plasma half-life are observed [23], [24], [25], [26]. Some experimental and clinical studies have reported the existence of OA in its exact form within blood compartments, even after a long time has passed since its intake [27], [28], [29]. However, OAʼs oral bioavailability declines because of its hydrophobic character and extensive metabolism by cytochrome P450 isoenzymes (CYP) [30]. Furthermore, Jeong et al. [31] demonstrated that just 0.7% of OA was bioavailable following oral treatment of rats, lending credence to the hypothesis that OA has low bioavailability. The solubility and permeability of OA are being investigated to increase its bioavailability and develop new compounds and formulations [30]. Generally, the bioavailability of any compound or active pharmaceutical ingredient (API) depends mainly on several other factors, like micronutrients and macronutrients found in consumed foods and APIs, along with their physical and chemical properties. These nutrients affect bioavailability and significantly impact the metabolism of API.

In one of investigation, Song et al. [32] used a single-dose 40 mg OA capsule to investigate its pharmacokinetic profile in healthy male volunteers. Data obtained from 18 subjects showed that the distribution of OA beyond the blood compartment or accumulation in tissues accounted for a large portion of the observed mean distribution volume relative to the average total human plasma volume. Rada et al. [33] conducted further pharmacokinetic studies using the same method, administering 30 mg of OA extracted from 70 g of olive pomace oil to each of 9 healthy male volunteers. As a result, the area under the curve and C_max were increased, which may have been due to the enhanced bioavailability of OA. Some of the pharmacokinetic studies are compiled in [Table 1].

Table 1 Pharmacokinetic study of oleanolic acid on humans.

Route	Dose	Cmax	t max	t 1/2	AUC	Ref.
AUC: Area under the Curve, Cmax: Maximum Concentration, tmax: Time to Maximum Concentration, t1/2: Half-life
Oral	40 mg capsule	12.12 ± 6.84 ng/mL	5.2 ± 2.9 h	5.2 ± 2.9 h	124.29 ± 106.77 ng h/mL	[32]
Oral	30 mg dissolved in pomace olive oil	598.2 ± 176.7 ng/mL	3.0 ± 0.8 h	3.0 ± 0.8 h	3181.9 ± 894.3 ng h/mL	[33]
Oral	20 mg tablets/ dispersible tablets	18.9 ± 8 µg/L and 17.8 ± 7.5 µg/L	2.9 ± 1.2 h and 2.5 ± 1:0 h	2.9 ± 1.2 h and 2.5 ± 1:0 h		[136]

Biological source and biosynthesis

Generally, OA is frequently found in different parts (fruits, leaves, stem bark, etc.) of several medicinal and edible plant species [1]. A high amount of OA is generally found in the olive plant, recognised as a primary commercial source of OA [6]. Simultaneously, other medicinal plants, including Lantana camara L. [34], Lisgustrum lucidum W. T.Aiton. [35], Vitis vinifera L. [36], Achyranthes aspera L. [37], Borreria stachydea [38], Monotheca Buxifolia [39], Olea europaea L. [40], Ocimum sanctum L. [41], etc., also showed high OA content and have served as a traditional mode of treatment for different diseases.

2,3-Oxidosqualene, generally synthesised as a by-product from the mevalonate pathway, acts as a precursor of primary sterol metabolism in the natural production of OA. 2,3-Oxidosqualene, with the help of enzyme β-amyrin synthase, is cyclised to β-amyrin, which ultimately produces OA along with erythrodiol using the enzyme cytochrome P450 through a series of three oxidation reactions at the C-28 position. Generally, OA is found in two forms in the plant kingdom, either as a triterpenoid saponin aglycone or in a free form connected with many sugar moieties. Free OA, typically present as cuticular waxes in plants, aids in their responses to biotic and abiotic stress [16].

Pharmacological Activities of Oleanolic Acid as Monotherapy and in Combination

OA has been found to have multiple therapeutic activities as a potential therapeutic agent. Here, various reported pharmacological activities of OA are discussed.

Anti-inflammatory activity

Monotherapy

The role of inflammation in the development and progression of diseases is well established. Thus, the anti-inflammatory activity of any drug is a crucial point in beginning to look for its possible therapeutic potential. The anti-inflammatory effects of OA in human umbilical vein endothelial cells (HUVECs) are due to its ability to reduce the production of high-mobility group box 1 (HMGB1) and cell adhesion molecules (CAMs), both of which are released from the cells in response to lipopolysaccharide (LPS) stimulation [42]. OA reduced the expression of various inflammatory markers, including nuclear factor-kappa B (NF-κB) and TNF-α, thereby diminishing the proinflammatory reactions caused by LPS in HUVECs and mice models [43]. Myocarditis is an inflammation of the heart muscle that can result in chronic cardiac failure. OA reduces the proinflammatory cytokine production, eventually alleviating all the other symptoms of the disease [44]. OA reduced elevated TNF-α, IL-6, and IL-1β levels in a dietary mice model [45]. It was also seen that OA could ameliorate hepatic insulin resistance in mice models by reducing IL-6, TNF-α, and IL-1β in the liver [46]. Anti-inflammatory properties of the OA derivative methyl-3-octanoyloxyiminoolean-12-en-28-oate were demonstrated in a rat model of carrageenan-induced skin inflammation [47]. By reducing inflammation, OA showed a significant anti-arthritic effect in models of adjuvant-induced polyarthritis in rats and mice and formaldehyde-induced arthritis in rats. OA decreased serum transaminase levels elevated by carrageenan. OA also decreased the exudate volume and leucocyte infiltration in rat models of pleurisy [48]. In rat models of adjuvant-induced arthritis and carrageenan-induced paw oedema, OA showed potent anti-inflammatory and complement-inhibitory effects, respectively [49]. In another study, it was seen that OA prevented secretory phospholipase 2 (sPLA2) activities. The anti-inflammatory effects of plants containing OA can be attributed to OAʼs ability to inhibit sPLA2 activity, both in vitro and in vivo [50].

Combination therapy

The anti-inflammatory effects of OA and UA were observed in PC12 cells treated with H₂O₂ or 1-methyl-4-phenylpyridinium. OA and UA exerted their anti-inflammatory effect by augmenting glutathione content and catalase and SOD (Superoxide Dismutase) activities. The combination also decreased lactate dehydrogenase as well as malondialdehyde (MDA) generation, suggesting they may play a crucial role in neurodegenerative disorders [51]. The disruption of the NF-κB, STAT3/6, and Akt/mTOR pathways, individually and together, has been revealed to be the mechanism by which OA and UA exert their anti-inflammatory actions, both in in vitro cell lines and in vivo animal models. Drug delivery systems are being formulated to improve anti-inflammatory properties and bioavailability since these pentacyclic terpenoids lack appropriate hydro solubility and bioavailability ([Fig. 2]) [52].

Fig. 2 Monotherapy and combination therapy involving OA against inflammation. Red arrows indicate inhibition of the inflammatory markers by OA.

Antidiabetic activity

Monotherapy

Diabetes, a chronic condition with several causes that ultimately leads to impaired insulin production and sensitivity [53], is linked to a wide range of metabolic complications that have far-reaching effects on multiple physiological systems [54], [55]. Unlike common antidiabetic therapeutics, OA as a therapeutic agent lacks an adipogenic impact, thus preventing weight gain. It upregulates the glucose transport in the periphery, modulating blood glucose levels without an adipogenic effect [56]. Therefore, it may have an edge over other marketed antidiabetic agents. In insulin-resistant HepG2 cells, treatment with 25 µmol/L OA increased insulin sensitivity by upregulating insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT-4) protein expression [57]. Fructose-induced insulin resistance was attenuated in rats with OA at 25 mg/kg/day. This effect appears mediated through the IRS-1/phosphatidylinositol 3-kinase/Akt pathway [58]. When administered with a dose of 20 mg/kg/day for 14 days in diabetic obese mice, OA prevented insulin resistance, gluconeogenesis, and the loss of body weight and liver and fat weight [46]. OA showed antidiabetic properties in type 1 diabetic rats. A new study on prediabetic Sprague-Dawley rats found that OA with and without dietary intervention dramatically improved glucose homeostasis through decreased caloric intake, body weight, plasma ghrelin levels, and glycated haemoglobin compared to the control [59]. The study indicated that OA improved glucose tolerance, insulin levels, plasma LPS, and hepatic cholesterol and triglyceride (TG) concentrations. OA ameliorates diet-induced obesity in mice via increasing fat preference and reducing inflammation. OA has been found to improve these parameters by modulating the expression of mRNA in the liver and adipose tissue expressing anti-inflammatory cytokines (IL-1β and IL-6) and specific lipogenic genes (PPAR, SREBP1, FAS, ChREBP, and G6Pase) [60]. Castellano et al. [40] reported OAʼs potent inhibitory activity of α-glucosidase. Therefore, it can be summarised that OA can act as a potent antidiabetic agent by targeting multiple biomarkers.

Combination therapy

In recent years, combined therapy for managing type 2 diabetes has been preferred over monotherapy. Metformin, insulin, or a combination of the two, and OA have been tested as a combined therapy for diabetes treatment. In db/db mice, the effects of combining OA (250 mg/kg) with metformin (100 mg/kg) were studied [61]. Compared to monotherapy, the combination therapy dramatically lowered blood glucose and insulin levels and improved liver pathology. When 80 mg/kg of OA was combined with 4 IUs of insulin in a rat model of type 1 diabetes, the ratsʼ blood glucose levels normalised. Enzymes involved in the insulin signalling cascade were activated, attributable to the combination treatment, which improved insulinʼs ability to lower blood glucose [62]. Combination treatment with OA and metformin markedly reduced the levels of glycogen phosphorylase, PGC-1, PEPCK1, and G6Pase while substantially elevating the mRNA expression of glycogen production. Additionally, compared to either drug used alone, the combination treatment enhanced the phosphorylation of Akt, PI3K, AMPK, and ACC, lowering the protein expressions of G6Pase, PEPCK1, and TORCs in diabetic mice. The synergic treatment also decreased the phosphorylation of mTOR and CREB. Therefore, the findings imply that OA and metformin have synergistic benefits through enhancing glucose and insulin homeostasis [61]. It has been shown that integrating lipid-lowering ketones with nanosized OA may delay the rate of weight gain in rats, lowers fasting blood sugar levels, decreases the levels of nitric oxide and TG in serum, and boosts SOD and CAT (catalase) activity. The combined use of these drugs in pregnant rats may slow the formation of lipids, reduce oxidative stress, and decrease glucose metabolism, all of which are beneficial for treating type 2 diabetes ([Fig. 3]) [63].

Fig. 3 Monotherapy and combination therapy involving OA against diabetes. Red arrows indicate inhibition, while blue arrows designate activation the markers involved in diabetes by OA.

Cardioprotective activity

Monotherapy

Hypertension is a prevalent noncommunicable disease in both the global south and north. It is characterised by a sustained increase in systemic arterial pressure over a normal range. Since synthetic antihypertensive drugs present in the market often carry severe adverse effects, alternative plants or other therapy sources are regularly encouraged [64]. However, there is evidence indicating the potential role of OA in reducing hypertension. In one study, 60 mg/kg OA exhibited a preventive effect in glucocorticoid-induced hypertensive rats [65]. Treatment with OA dramatically reduced the incidence of high systolic blood pressure and cardiac lipid peroxidation. However, glucocorticoid therapy had no detectable effect on total body or thymus mass. To explore nitric oxide (NO) release, Nω-nitro-L-arginine methyl ester (L-NAME) was used to induce hypertension in rats, and the vasodilatory effect of OA was observed [66]. According to the results of one investigation, both the methyl ester of OA and brominated OA displayed vasodilatory effects through endothelium-dependent and endothelium-independent pathways that require COX (cyclooxygenase) and vascular muscle K⁺ channels [67]. The mRNA and protein levels of sPLA2 and FAS (Fatty Acid Synthase) were recently discovered to be downregulated after OA treatment in SHRs (Spontaneously Hypertensive Rats). Treatment with OA in hypertensive rats significantly improved blood pressure and related irregularities in the lipid metabolites, suggesting that OAʼs antihypertensive effect is mediated through the downregulation of sPLA2 and FAS in SHRs [68]. In another study, OA therapy dramatically changed metabolites related to tyrosine and glutamate metabolism in hypertensive rats, among other pathways, confirming the presence of 18 neurotransmitters. It suggested that region-specific metabolomics in the brain might be an effective approach for learning more about the probable mechanism of OA in essential hypertension (EH). As such, OA in EH provides a potent tool for further research into the probable mechanism of OA in EH [69]. In one study, OA reduced plasma levels of ANP (atrial natriuretic peptide), renin activity, aldosterone, and intrarenal levels of renin and angiotensin II type 1 receptor expression while increasing expression of the angiotensin II type 2 receptor in hypertensive rats. These results imply that OAʼs functions in the renin-angiotensin and cardiac natriuretic hormone systems are directly related to its favourable effects on the cardiorenal system [70]. An investigation using a cell model of atherosclerosis examined the impacts and potential underlying mechanisms of OA in atherosclerosis. To create an atherosclerosis cell model, oxidised low-density lipoprotein (ox-LDL, 100 µg/mL) was applied to HUVECs for 24 h. Next, using the CCK-8 test and ELISA kits, cell viability and cytokine expression (ANG [Angiogenin], NO [Nitric Oxide], eNOS [endothelial Nitric Oxide Synthase], IL-1β, TNF-α, and IL-6) were assessed. Flow cytometry was used to examine cell apoptosis and cell cycle distribution in the atherosclerotic cell model. Treatment with OA or ANG reversed the effects of ox-LDL-induced anti-proliferation, cytokine changes, and cell death. Subsequent investigations revealed that in the ox-LDL-induced HUVECs atherosclerosis model, OA upregulated the levels of FXR (Farnesoid X Receptor), which in turn elevated the production of ANG [71]. By affecting the hepatic buildup of lipids, arterial intimal thickening, and serum lipid levels, OA prevented the development of atherosclerosis in C57BL/6 J mice. Additionally, PPARγ, AdipoR1, and AdipoR2 genes involved in lipid metabolism may have a role in the fundamental mechanism of OA influencing atherosclerosis [72]. The effects of ox-LDL on the expression of genes, reactive oxygen species (ROS) production, and cell survival were eliminated by LOX-1 (Lectin-like Oxidized Low-Density Lipoprotein Receptor-1) silencing. HFD (high fat diet)-induced atherosclerosis in quail and ox-LDL-induced cytotoxicity in HUVECs may be mitigated by OA; the possible mechanism entails modification of LOX-1 activity, including the upregulation of nrf2 and ho-1 expression and downregulation of NADPH (Nicotinamide Adenine Dinucleotide Phosphate in reduced form) oxidase module expression ([Fig. 4]) [73].

Fig. 4 Monotherapy involving OA against cardiovascular disorder. Red arrows indicate inhibition, while blue arrows designate activation of the various cardiovascular markers by OA.

Hepatoprotective activity

Monotherapy

It is understood that OA can shield the liver against toxins [74]. Administration of OA reversed the ethanol-induced increase in serum marker enzyme levels in rat livers [75]. One study demonstrated that the OAʼs hepatoprotective effect of adult male Kunming mice against carbon tetrachloride-induced liver injury was greatly improved by pretreatment with OA nanosuspensions. This effect was evidenced by decreased serum alanine aminotransferase activity and the liver MDA level [76]. OA retarded the development of high-fructose-induced NAFLD (Non-Alcoholic Fatty Liver Disease) by decreasing lipid accumulation and providing hepatoprotection in non-alcoholic fatty liver disease. This also decreased the chances of developing hepatic steatosis, which diminished hepatic inflammation. Furthermore, OA elevated GPx (Glutathione Peroxidase) and SOD antioxidants and decreased MDA levels to regulate hepatic oxidative stress in various in vitro cell lines and in vivo animal models [77]. Another study used hepatotoxicants to damage the livers of mice and rats before performing RT-PCR. The expression of hepatic metallothionein (Mt), nuclear factor E2-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (Nqo1), heme oxygenase-1 (Hmox1), and glutamate-cysteine ligases (Gclc and Gclm) was significantly elevated after treatment with OA at a hepatoprotective dose of 50 µmol/kg for 4 days. It is to be noted that there was a 60-fold increase in hepatic Mt protein and a 15-fold increase in mice livers [78]. Various OA derivatives showed that essential amino acids (lysine) could effectively enhance OA hydrophilicity, alkalinity, and hepatoprotective activity, both in vitro and in vivo [79]. Recent studies have found that OAʼs antiapoptotic and anti-autophagic effects in Con A-induced acute liver damage may be linked to OAʼs inhibition of PPAR and upregulation of JNK (c-Jun N-terminal Kinase) signalling in Balb/C mice [80]. However, another recent study showed that while OA at low doses is hepatoprotective, at larger doses or with prolonged usage, it might cause liver impairment, characterised by the occurrence of cholestasis. Therefore, it is critical to comprehend how OA exerts hepatotoxicity and guides the liver to defend against hepatotoxic compounds [81].

Combination therapy

The impact of OA in combination therapy with UA on antitubercular drug-induced liver damage was studied by Gutiérrez-Rebolledo et al. [82]. The antitubercular drug-induced steatosis was averted by administering either 100 or 200 mg/kg/day of the OA and UA combination in male Balb/C mice. The lower dose (100 mg/kg/day) was found to have a more pronounced impact. OAʼs ability to protect mice against carbon tetrachloride-induced hepatotoxicity may be due to, at least in part, its ability to suppress the expression and activity of P450 2E1 ([Fig. 5]) [83].

Fig. 5 Monotherapy and combination therapy involving OA as hepatoprotective. Red arrows indicate inhibition, while blue arrows designate activation of the several hepatic markers by OA.

Anticancer activity

Monotherapy

Numerous studies suggest that OA may have antitumour and anticancer effects. One particular study showed that OA suppresses the development of transplanted tumours in mice by upregulating the tumour protein p53 and a COX-2-mediated activation of the mitochondrial apoptotic pathway and cell cycle arrest [84], [85]. Exposing lung cancer cells such as A549, NCI-H460, and NCI-H1299 with 60 µg/mL of OA for 8 h increased the expression of miR-122, which has been shown to possess a tumour-suppressing effect [86]. Furthermore, OA reduced cancer cell growth by downregulating glycolytic enzyme expression, which subsequently causes a reduction in MDA-MB-231 breast cancer cell proliferation [87]. When human bladder cancer T24 cells were treated with 50 µM OA, they showed a reduced proliferation and increased apoptosis, owing to the inhibition of the Akt/mTOR/S6K and ERK1/2 pathways [88]. A derivative of OA, oleanolic acid methyl ester, also showed cytotoxic effects on human cervical cancer cells (HeLa) by the concentration- and time-dependent induction of apoptosis and ROS generation [89]. In addition, a study demonstrated that ovarian cancer A2780 cells were induced to undergo apoptosis by a gold (I) complex containing an OA derivative through the activation of endoplasmic reticulum stress (ERS) [90]. OA decreased prostatic cell proliferation in a testosterone-induced animal model of benign prostate hyperplasia (BPH) via reducing PCNA (proliferating cell nuclear antigen) and cell cycle marker expressions. OA was more effective than finasteride in treating the condition in an animal model of BPH [91]. OA may reduce the growth and spread of gastric cancer, with high incidence and mortality. One study found that OA decreased the production of cyclin A and cyclin-dependent kinase 2, reducing the viability and proliferation of gastric cancer MKN-45 and SGC-7901 cells. Moreover, OA decreased the yes-associated protein (YAP) nuclear abundance in gastric tumour cells [92]. Further, in prostate cancer cell lines of prostatic cancer xenograft in mice, OA promoted p53-dependent apoptosis via the ERK/JNK/Akt pathway [93]. Aridanin, a naturally occurring N-acetyl glycoside of OA, was tested for its cytotoxic effects on various cancer cell lines. Aridaninʼs IC₅₀ values were much lower than doxorubicinʼs (Dox) when tested against multidrug-resistant CEM/ADR5000 cells and melanoma cell lines. Aridanin also triggered apoptosis in CCRF-CEM human T cell leukaemia cells by increasing ROS levels, breaking down MMPs (Matrix Metalloproteinases), and, to a lesser extent, activating caspases [94].

However, in contrast to these observations, recent research has focused on OAʼs function as a cytoprotective agent. By increasing SIRT1 expression and decreasing p65 acetylation, OA has been shown to attenuate NMDA (N-Methyl-D-Aspartate)-induced apoptosis in lung epithelial MLE-12 cells [95]. Another study exhibited that OA suppressed cisplatin-induced ERK1/2, STAT-3, and NF-κB activation in mice kidneys, reduced renal expression of apoptotic and autophagic proteins, and decreased renal expression of oxidative stress and proinflammatory markers ([Fig. 6]) [96].

Fig. 6 Monotherapy and combination therapy involving OA against cancer. Red arrows indicate inhibition, while blue arrows designate activation of markers involved in carcinogenesis by OA.

Combination therapy

A recent study based on breast cancer brain metastasis (BCBM) found that OA nanoparticles can penetrate the brain and act on cancer cells. Thus, a combination of paclitaxel (PTX) and OA nanoparticles was formed, effectively inhibiting BCBMs in mouse xenografts [97]. Adding OA nanoparticles to cisplatin (CDDP) showed a synergistic and hepatoprotective effect. The combination downregulated the P13K/AKT/mTOR pathway and upregulated the p53 proapoptotic pathway, promoting apoptosis by increasing proapoptotic protein expression [98], [99], [100]. Reducing the production of proteins like XIAP (X-linked inhibitor of apoptosis protein) and Bcl-2 (B-cell lymphoma 2) through the NF-κB pathway was one method in which OA aided CDDP in breaking through its resistance. Decreased alanine transaminase levels and histochemical assessment showed that OA significantly mitigated CDDP-induced hepatotoxicity in HepG2 cells. All of these pointed to the synergistic and hepatoprotective effects of the combination of OA and CDDP [101]. A study involving OA and glycyrrhetinic acid (GA) derivatives showed selective toxicity against HeLa and MCF-7 cell lines [102]. Combining OA and UA with CPT-11 improved the anti-tumourigenic properties and showed higher anticancer effects in two colon cancer lines: HT-29 and SW 620. The uPA/uPAR-dependent MMP pathway was downregulated to cause migration-limiting action [103]. Combining OA with 5-fluorouracil (5-FU) synergistically boosted the proapoptotic and necrotic responses in Panc-28 cells. OA and 5-FU exhibited significant expression on apoptotic markers, such as caspase-3 activation, Bcl-2/Bax, survivin, and NF-κB. Therefore, using OA and 5-FU together might be a cutting-edge approach to treat pancreatic cancer [104]. In the case of BCBMs, OA was employed to produce NPs (nanoparticles) that effectively entered the brain. A synergistic chemotherapeutic approach was introduced by formulating PTX into OA nanoparticles. The formulated PTX-OA NPs significantly inhibited the primary breast cancer and BCBMs in mice xenografts. Overall, this study suggests a novel combination approach for treating primary breast cancer and BCBMs [97]. OA and olaparib decreased HIF-1, Glut-1, and VEGF in MDA-MB-231 cells, suggesting an intriguing progressive combination for successfully treating triple-negative breast cancer patients [105]. The concurrent administration of PD98059, a specific inhibitor of the MEK/ERK pathway, and OA resulted in a reduction in p-ERK and p-JNK levels in DU145 cells, as distinguished from the levels seen after administration with PD98059 alone. The levels of p-ERK, p-AKT, and p-JNK expression in U87 cells subjected to a combination of PD98059 and OA were shown to be comparatively reduced than those detected in U87 cells treated just with PD98059 [93]. It has been reported that OA prevents hepatocellular carcinoma from undergoing epithelial-mesenchymal transition by increasing dimerisation of inducible nitric oxide synthase (iNOS) [106]. A study on a rhodamine B-conjugated oleanolic acid derivative (RhodOA) revealed its potential as an anticancer agent on various cell lines [107]. Marked HepG2 cell growth inhibitory action was found in several of the ionic derivatives of OA and UA, accompanied by increased solubility [108].

Antimicrobial activity

Monotherapy

Isolated from the medicinal food plant Akebia trifoliate, OA showed modest efficacy against Staphylococcus aureus and Bacillus thuringiensis at 62.5 µg/mL and against Escherichia coli, Salmonella enterica, and Shigella dysenteriae at 31.2 µg/mL [109]. Disrupting their cell membranes also showed antibacterial activity against the bacteria Listeria monocytogenes, Enterococcus faecalis, and Enterococcus faecium [110].

Combination therapy

Tuberculosis is still a significant cause of mortality globally, as it has become resistant to several drugs formerly used to treat it. In light of this, research and treatment frequently favour natural products and new combinations of therapeutic agents. Mycobacterium tuberculosis H37Rv and a drug-resistant clinical strain (MDR) were selected to check the antibacterial activity of OA and UA in macrophage cell lines and tuberculosis-infested BALB/C mice. Interferon-gamma (IFN-γ), TNF-α, and iNOS expression levels were measured, as were lung bacilli burdens. A substantial decrease in pulmonary bacilli burden was seen in infected BALB/c mice following treatment with either drug [111]. The antimycobacterial effects of the combination of OA with isoniazid (INH), rifampicin (RMP), or ethambutol (EMB) were shown to be synergistic and beneficial in the six drug-resistant strains that were examined. When sub-inhibitory amounts of OA were added, the MICs (Minimum Inhibitory Concentration) of INH, RMP, and EMB decreased by a range of 4-fold to 16-fold. The fractional inhibitory concentration index (FICI) values for INH ranged from 0.121 to 0.347, RMP ranged from 0.113 to 0.168, and EMB ranged from 0.093 to 0.266. The MICs of OA against all mycobacterial strains were lowered to less than 25 µg/mL for each combination [112]. The concurrent administration of OA and β-lactams demonstrated a noteworthy synergistic impact in the management of β-lactamase-producing bacteria. This was substantiated by the observed elevated overall survival rate of mice infected with S. aureus or E. coli, which spiked from 25.0 to 75.0% or from 44.4 to 61.1%, respectively, when compared to the intervention with β-lactams alone. While using OA alone demonstrated defence against S. aureus-infected mice by targeting α-hemolysin (Hla), a more favourable therapeutic outcome was obtained when the combination therapy was used [113].

Recently developed formulations of oleanolic acid

Monotherapy

Gao and his team modified the ethanol injection method, combining sonication to prepare PEGylated liposomal oleanolic acid. Further, native and PEGylated liposomes of OA were investigated for their anticancer activities in the HeLa cell line using the MTT test [114]. Justo and Moraes [115] used the ethanol injection technique using natural phospholipids in the formulations, which provided excellent stability, biocompatibility, and production of oxidation-resistant lipid vesicles. This markedly reduced the liposomal formulation cost compared to preparations containing synthetic phospholipids. Concerning the stability of the preparation, the liposomal formulation demonstrated better steadiness in vitro than native OA. The PEGylated liposomes could be a choice to serve as an influential transport medium of OA for oncological treatment [116].

Multivesicular liposome (MVL) aims to overcome the poor solubility of OA and prolong the therapeutic level of drugs in circulation to augment antineoplastic activity in hepatic cancer. Luo and the team used the double emulsion technique to prepare OA-encapsulated multivesicular liposomes (OA-MVLs). OA-MVLs prolonged the survival rate in tumour-bearing mice by suppressing the development of murine H22 hepatoma [117]. Alvarado et al. [118] developed polymeric nanoparticles for an ophthalmic delivery system, using polydl-lactide glycolide acid nanoparticles to carry OA in a controlled distribution system for optical use. The solvothermal approach effectively synthesised the hollow metal-organic frameworks (MOFs). OA was introduced into the hollow framework via the process of physical adsorption subsequent to its characterisation analysis. The SK-OV-3 cell line, derived from human ovarian cancer, was chosen as the experimental model to investigate the drug loading method, assess cytotoxicity, and examine cellular absorption. The use of hollow MOFs enhanced the drug loading capacity, leading to a more optimal sustained release action of the drug OA [119]. The study showcased the application of self-nanoemulsifying drug delivery systems (SNEDDS) for the oral administration of OA. The surfactant to cosurfactant weight ratio significantly impacted the effective self-emulsion area and emulsification rate of the resulting nanoemulsion systems. The SNEDDS exhibited an enhanced release of OA in both aqueous media and digestive fluid. Additionally, it enhanced the oral bioavailability of OA by extending the duration of OA present in rat plasma [120].

Combination therapy

Zhang et al. [121] developed NLCs (nanostructured lipid carriers) combining gentiopicrin and OA to improve their hepatoprotective action. The film-ultrasonic technique was used to formulate NLCs of gentiopicrin and OA to enhance the entrapment efficiency of gentiopicrin and OA. The film-ultrasonic technique was applied where an oil state composed of oleic acid, gentiopicrin, and OA was melted in absolute ethyl alcohol, and an aqueous phase of surfactant poloxamer 188 was prepared. In vivo pharmacokinetic studies showed a significantly prolonged half-life and occupancy period in the body of the optimised NLCs and a sustained release effect, improving drug bioavailability. ELISA results showed that the NLCs also altered ALT (Alanine Aminotransferase) and AST (Aspartate Aminotransferase) levels in the rat model of carbon tetrachloride-induced hepatic impairment.

The combination chemotherapy of OA and Dox delivered via nanomedicine was formulated by producing micelles of the co-polymer methoxy-poly(ethylene glycol)-poly (D, l-lactide) mPEG-PLA-OA, in which mPEG-PLA was associated with OA and the PLA chain. These micelles comprised Dox. The OA-conjugated micelles enabled the entrapment of Dox within the micelle core. Compared to free Dox, the combination of nanomedicine was very effective in triggering apoptosis ROS production. As a result, the combination therapy using Dox-OA-micelles may provide solid tumour patients with a potential therapeutic alternative in FaDu HTB-43 cells [122]. Again, Dox and OA-loaded liposomes inhibited cardiotoxicity and tumour growth by inducing apoptosis, thereby suggesting the anticancer effect of the combination delivery [123]. pH-responsive nanoplatforms built on CC NPs (calcium carbonate nanoparticles) were used to load two drugs simultaneously (CDDP and OA) for an effective combination treatment against hepatocellular carcinoma in HepG2 cells. The pH-sensitive lipid-coated nanoparticles (CDDP/OA-LC-NPs) demonstrated amazing site-specific tumour targeting, considerable anticancer activity in vivo Balb/c nude mice, and good drug release profiles. Kidney-protecting effects of OA on CDDP/OA-LC-NPs dramatically decreased CDDP-induced renal damage [124].

Transdermal administration of an OA patch or a chloroquine combination (CHQ-OA) patch substantially decreased blood sugar levels without affecting insulin levels. Whether administered as a monotherapy or in conjunction with CHQ, transdermal OA can eradicate and eliminate malaria parasites in rats infected with Plasmodium berghei despite having a detrimental impact on glucose homeostasis [125]. Mesoporous silica nanoparticles (Nsi) were co-loaded with CDDP and OA to create CDDP/OA-Nsi and overcome CDDP resistance in lung cancer treatment. Cytotoxicity of CDDP/OA-Nsi was considerably more significant than that of free CDDP in CDDP-resistant A549/DDP cells. The intracellular investigation found that the CDDP/OA-Nsi groupʼs CDDP level was greater than that of the free CDDP and CDDP-Nsi groups. The most significant anticancer effect was shown by CDDP/OA-Nsi in an A549/DDP xenograft tumour model. These findings suggest that CDDP/OA-Nsi seems to be a potential drug delivery method to address MDR in lung cancer treatment [126]. The thermosensitive poly(N-vinylcaprolactam) (PNVCL), chitosan (CS), and functionalised cell-penetrating peptide (H6R6) make up the nanocomposite. The nanocomposite (H6R6-CS-g-PNVCL) is loaded with Dox and OA. The combination of loaded drugs exhibited better anticancer activity than the individual drugs [126].

Another study developed a novel OA nanoparticle (OA-NP) loaded with a lactoferrin (Lf) nano delivery system to enhance OA dissolution in vitro and enhance absorption and bioavailability. OA-NPs were developed with the help of NP albumin-bound technology. The developed OA-NPs (OA : Lf = 1 : 6, w/w %) showed spherical morphology, a particle size of 202.2 ± 8.3 nm, ζ potential of + 27.1 ± 0.32 mV, encapsulation efficiency of 92.59 ± 3.24%, and appropriate in vitro release. After oral absorption in Sprague-Dawley rats, an efficient bioavailability of 340.59% was obtained in comparison to the free drug. The OA and LF combination-based nanodelivery vehicle improved the dissolution rate, absorption in the intestine, and bioavailability, suggesting that Lf NPs could be used to improve poorly soluble and absorbed drug in terms of better oral absorption, which eventually improves bioavailability [22].

Recent Developments in Oleanolic Acidʼs Therapeutic Potential

Most studies have focused on OAʼs anticancer and antitumour properties, although additional therapeutic benefits have also been discovered. Every year, the possibility of a new therapy for OA is investigated. For example, a recent study showed OAʼs potential to improve intestinal health by adjusting gut microbiota and modifying the immunological activity of intestinal epithelial cells [127]. Liver transplantation, hepatectomy, and haemorrhagic shock cause hepatic ischemia-reperfusion (IR) damage, a clinical issue for decades. Preconditioning with OA has been shown to reduce liver damage dramatically. HMGB1 and TNF-α are downregulated, while alanine and aspartate aminotransferase levels are reduced in hepatic IR mice, among other benefits. To further regulate apoptosis and autophagy, OA downregulated caspase-3, caspase-9, Bax, Beclin 1, and LC3 while upregulating Bcl-2 [128].

In addition, UA and OA derivatives have shown impressive anticholinesterase action lately. This point is noteworthy, as anticholinesterase agents are often used as therapeutic agents in Alzheimerʼs and Myasthenia Gravis [129]. A recent investigation demonstrated that OA might mitigate Aβ25 – 35-induced neuronal damage and synapse alterations in Alzheimerʼs disease. Protein expressions for CaMKII, PKC, NMDAR2B, BDNF, TrkB, and CREB were all considerably higher in the OA group compared to the model group, suggesting that OA was able to prevent synaptic plasticity loss in the hippocampus of rats exposed to Alzheimerʼs disease [130].

Findings from studies on the role of OA in neuroprotection–including the BBB (blood brain barrier)-indicate that OA can block the activation of p38 mitogen-activated protein kinase and the subsequent upregulation of VEGF (vascular endothelial growth factor). The p38MAPK/VEGF/Src signalling pathway, which contributes to the BBB breakdown after SAH (subarachnoid haemorrhage), is also downregulated. OA might be crucial in managing vasogenic cerebral oedema following SAH in male Sprague-Dawley rats [131]. Furthermore, OA inhibited apoptosis and inflammation in mice with spinal cord damage by blocking p38, JNK, and MAPKs (Mitogen-Activated Protein Kinase) [132].

Oleanolic Acid and Its Derivatives in Clinical Trials

Like synthetic or semisynthetic drug molecules, OA and its derivatives have been part of different human studies investigating their safety, proper dose, utility, and adverse effects. A list of clinical trials involving OA are mentioned in [Table 2].

Table 2 Clinical trials of oleanolic acid.

OA or its derivative	Clinical trial phase	Pharmacological application	Molecular targets	NCT No.	Refs
OA: Oleanolic acid, NA: Not Applicable, TG: Triglyceride
OA	Phase 1	Gastrointestinal satiation peptide secretion	TGR5 and GLP-1	NCT01674946	https://classic.clinicaltrials.gov/ct2/show/NCT01674946
OA	NA	Identification and quantification of the OA present in TG-rich lipoproteins	GLP-1	NCT05529953	https://clinicaltrials.gov/study/NCT05529953?intr=oleanolic%20acid&rank=2
OA	NA	Preventing insulin resistance with OA	NA	NCT05049304	https://clinicaltrials.gov/study/NCT05049304?intr=oleanolic%20acid&rank=3
OA-enriched olive oil (equivalent dose 30 mg OA)	NA	Antidiabetic	apo B48 and B100, serum insulin, C-peptide and GLP-1	NCT05529953	https://classic.clinicaltrials.gov/ct2/show/study/NCT05529953?term=oleanolic+acid&draw=2&rank=1
OA-enriched functional olive oil	Phase 2	Type 2 diabetes mellitus	NA	NCT06030544	https://classic.clinicaltrials.gov/ct2/show/study/NCT06 030 544

Bardoxolone methyl (CDDO-Me), the most active derivative of OA, was part of a clinical trial among 47 volunteers in phase I with solid tumours and lymphomas at an advanced stage, where zero life risks were found linked with OA as an adverse effect. The increased estimated glomerular filtration rate (eGFR) of participating volunteers indicated good or improved renal function, which denotes that it can be used for chronic kidney disease [133]. In phase II, the study was performed for 52 weeks in 227 patients with type 2 diabetes-induced chronic kidney disease (CKD). The result of the study exhibited an improved eGFR rate with reduced swelling and CKD-induced oxidative stress. Though some adverse effects like cramps, slightly increased alanine aminotransferase levels, and gastrointestinal consequences were observed, they were not life-long or life-threatening adverse events and were terminated while continuing the drug [134]. Participants reported experiencing cardiac-related adverse effects, prompting the phase III studyʼs early termination; this raised concerns about the safety of the OA derivative CDDO-Me [135].

Conclusion

Both monotherapy including derivatives and combination therapy of OA have demonstrated significant therapeutic potential across various pathological conditions through various mechanisms in both in vivo and in vitro studies. Predictable delivery of OA and its derivatives has been the subject of several published in vitro reports on nanometric techniques, including formulations like liposomes, nanoemulsions, and magnetic and polymeric nanoparticles. OAʼs efficacy as a monotherapy and combination therapy is evident, as it addresses liver disorder, cancer, cardiovascular disorders, and antimicrobial activities. The article emphasises incidents when combination treatment, particularly with OA, has synergistic effects that improve therapeutic results. This is especially apparent in the treatment of diabetes, cancer, antimicrobial agents, and hepatoprotectants when used with other medications. In in vivo research, the combination of OA and metformin mitigated type 2 diabetes more effectively than either agent used alone [62]. The major takeaway of this review is that combination OA had superior efficacy compared to OA alone in in vivo investigations, which was attributed to synergism, although this was seen in select studies. Remarkably, such combinations of OA have not yet been evaluated in clinical studies. This article, though, covered both monotherapy and combination therapy of OA, yet, surprisingly, none of the forms of OA (monotherapy/combination therapy) has reached the U. S. Food and Drug Administrationʼs approval level. Several accounts of OAʼs synthetic counterparts are used to search for more effective and less hazardous compounds. Some adverse effects have been observed in clinical trials, particularly with the most active OA derivative bardoxolone methyl, which disappeared after continuing the drug. However, the overall safety profile of OA appears promising, especially in its natural form. A comparative study involving OA/OA derivatives alone and in combination is warranted in clinical trials.

Contributorsʼ Statement

Data collection: Md. A. Shaharyar, M. Sengupta, T. Banerjee; Design of the study: Md. A. Shaharyar, T. Banerjee, R. Bhowmik; Analysis and interpretation: S. I. Alzarea, N. Ghosh, J. Akhtar, I. Kazmi, S. Karmakar; Drafting the manuscript: T. Banerjee, Md. A. Shaharyar, M. Sengupta, R. Bhowmik, A. Sarkar, N. Ghosh, S. Karmakar; Critical revision of the manuscript: I. Kazmi, S. Karmakar, N. Ghosh.

Conflict of Interest

The authors declare that they have no conflict of interest.

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