1. INTRODUCTION:

Angiogenesis is the process by which new blood vessels form from existing ones. This process is crucial in various biological functions such as embryonic development, wound healing, and the female reproductive cycle¹. However, when angiogenesis is not properly regulated, it can contribute to numerous diseases. For instance, excessive or insufficient angiogenesis is a key factor in conditions like cancer, inflammatory diseases, diabetic retinopathy, and cardiovascular issues. Because of this, controlling angiogenesis has become an important therapeutic strategy for treating these diseases^2-4.

Researchers have shown a growing interest in natural compounds derived from medicinal plants as potential regulators of angiogenesis. These natural products are appealing because they have diverse chemical structures and biological activities^5–7. One such plant, Boswellia serrata, commonly used in traditional Ayurvedic medicine, has garnered attention for its potential antiangiogenic properties. B. serrata extract has been found to inhibit angiogenesis, making it a promising candidate for treating various angiogenesis-related diseases⁸. The bioactive compounds in B. serrata, especially boswellic acids (BAs), have been extensively studied for their ability to block the formation of new blood vessels. This plant is known for its medicinal properties in traditional practices and has been the focus of significant research. By targeting abnormal blood vessel growth, B. serrata extract could potentially intervene in conditions dependent on angiogenesis. Preclinical and clinical studies have demonstrated its capacity to inhibit tumor growth, reduce inflammation, alleviate symptoms of diabetic retinopathy, and lower the risk of cardiovascular problems. Therefore, the antiangiogenic properties of B. serrata extract present an exciting avenue for developing new treatments aimed at improving patient outcomes in these diseases^9,10.

This review aims to provide a comprehensive understanding of the phytochemistry, crucial features, and mechanisms of action behind the antiangiogenic effects of B. serrata extracts. Additionally, it will highlight the potential therapeutic applications of B. serrata in managing diseases related to abnormal angiogenesis, including cancer, diabetic retinopathy, inflammatory disorders, and cardiovascular diseases.

2. Pharmacognostical Characteristics of Boswellia serrata:

B. serrata is a deciduous tree that typically grows to a height of 4 to 5 meters. It belongs to the botanical family Burseraceae. The tree's trunk has a circumference of about 2.4 meters, which is roughly equivalent to 1.5 meters, making it comparable to other medium to large-sized trees with branches. The bark of B. serrata is thin and can easily be peeled off. It changes color from greenish-grey to yellow or reddish before turning ashy. The bark can be completely removed^11,12.

When the papery bark is peeled or cut, it releases sticky oleoresin in the form of translucent lumps, tears, or drips. This oleoresin varies in color from white to yellow, has a bitter taste, and smells like balsamic vinegar. The leaves of the tree are pinnate and notable for their structure. They are 30 to 45cm long, without stipules, and composed of several leaflets. These leaflets are clustered at the tips of the branches¹³.

The number of leaflets per leaf ranges from 8 to 15. Each leaflet measures between 2.5 to 6.3cm in length and 1.2 to 3.0cm in width. They are elongated or oval-lanceolate with a rounded base and nearly stalkless, with finely toothed edges. Most leaflets are covered in fine hairs.

The tree produces small, hermaphroditic white flowers, often found in clusters or on side branches at the very tips of the stems. Each flower has a small calyx with 5-6 lobes. The petals are a mix of white and pink and measure 0.5 to 0.8cm in length. The fruits are cotyledonous, trifed, about 1.25cm long, trigonous, and obovoid¹⁴. The seeds are compact, heart-shaped, and hang from the inner corner of the fruit. Various parts of B. serrata have been shown in Figure 1.

Figure 1. Boswellia serrata: Various parts of plants A. Leaves. B. Flowers. C&D. Seeds. E. Bark.

3. Phytochemistry:

3.1. Chemical Composition of Boswellia Resin:

The oleo-gum-resin mixture produced by various Boswellia species contains about 200 different phytochemicals. These include essential oils, pure resin, and mucus. The quantity and composition of the oleo-gum-resin can vary between species due to factors like the tree's age, the quality of the resin, and geographical conditions^12,15.

3.2. Key Components of Boswellia Resin:

The primary constituents of Boswellia resins are pentacyclic triterpenes and tetracyclic triterpenes, which belong to a class of compounds known as higher terpenoids. Among these, the pentacyclic triterpenes are considered the main contributors to the significant pharmacological effects of Boswellia resin. One of the key pentacyclic triterpenes is boswellic acid (BA), with the chemical formula three-hydroxyurs-12-ene-23-oic acid ¹⁶.

3.1.1. Main Types of Boswellic Acids:

All Boswellia species contain similar chemical compounds known as BAs. The main types of BAs found in these species include:

1. Alpha and beta-Boswellic Acids (BA, 10–21%)

2. Acetylated alpha and beta-Boswellic Acids (ABA, 0.05–6%)

3. 11-keto-beta-Boswellic Acid (KBA, 2.5–7.5%)

4. 3-O-acetyl-11-keto-beta-Boswellic Acid (AKBA, 0.1–3%)

While these are present in all Boswellia species, their concentrations can vary ¹⁷. Major chemical constituents of B. serrata have been presented in Figure 2.

3.1.2. Boswellic Acids in Standardized Extracts:

Standardized extracts of Boswellia available for purchase typically contain between 37.5% and 65% BAs. One of the primary components, 3-O-acetyl-11-keto-beta-boswellic acid (AKBA), exists as a crystalline powder with a maximum particle size of 250 nanometers. AKBA is soluble in chloroform and methanol but nearly insoluble in water. Among the various BAs, AKBA and 11-keto-beta-boswellic acid (KBA) are the most potent and promising for their anti-inflammatory properties.

Boswellia contains a variety of BAs, including 9,11-dehydro-alpha-Boswellic acid and its isomer 9,11-dehydro-beta-Boswellic acid, Acetylated forms such as Acetyl-9,11-dehydro-alpha-Boswellic and Acetyl-9,11-dehydro-beta-Boswellic acids. Other chemical constituents found in Boswellia include: Lupeolic acid and Acetyl-Lupeolic acid, Incensole acetate, Incensole oxide, and Isoincensole oxide, In addition, research has identified a pentacyclic triterpenediol mixture in the crude extract, which contains: 3a,24-dihydroxyurs-12-ene, 3a,24-dihydroxyolean-12-ene, Serratol, Alpha-Thujene, Tirucall-8,24-dien-21-oic acids, Oilbanumols DG, Alpha-pinene, Octyl acetate.

Figure 2. Major chemical constituents Boswellia serrata. A. Structure of α-boswellic acid (Planer&3D). B. Structure of β-boswellic acid (Planer&3D). C. Structure of 11-keto-β-boswellic acid (Planer&3D).

3.3. Essential Oil Composition:

The essential oil of Boswellia, also known as Salai guggal, primarily comprises monoterpenoids, including Alpha-pinene (73.3% of the total), Cis-verbenol, Trans-pinocarveol, Borneol, Myrcene

Phellandrene, Cadinene, Verbenone, Limonene, Thuja-2,4(10)-diene, P-cymene. Additionally, it contains a small amount of diterpenes. The high content of alpha-pinene is particularly notable for its significant presence in the essential oil¹⁸.

3.4. Structure-Activity Relationship of Boswellic Acids:

The effectiveness of BAs, particularly in their anti-inflammatory role, is influenced by their chemical structure. The presence of an 11-keto group is critical for their activity. For example, the conversion of the 11-keto group to an 11-methylene group reduces the inhibition of the enzyme 5-lipoxygenase (5-LO). Removing the acetyl group or converting the 11-keto group to an alcohol in AKBA slightly decreases 5-LO inhibitory activity. These findings indicate that the pentacyclic triterpene backbone, along with the 11-keto group, is essential for binding to the receptor site to exert anti-inflammatory effects¹⁹.

4. Pharmacokinetics of Boswellic Acids:

Both 11-keto-beta-boswellic acid (KBA) and 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) have a high potential for retention in the body due to their lipophilic nature. This lipophilicity, however, results in restricted absorption via the gastrointestinal tract (GIT). The elimination half-life of KBA is approximately six hours, so to maintain optimal plasma levels, BAs should be taken orally every six hours. Additionally, consuming BAs with a high-fat meal significantly boosts their plasma concentration²⁰.

4.1. Enhancing Absorption and Bioavailability:

Studies have shown that delivering Boswellia extract in a lecithin-based form increases the plasma levels of BAs, leading to greater tissue accumulation. Using a phospholipid-based delivery method has been found to improve absorption while reducing variability. Researchers like Sharma et al. have used complexation techniques to enhance the pharmacokinetic profile of BAs. Specifically, combining BAs with phosphatidylcholine has been shown to increase absorption^21,22.

An ex-vivo study using an everted intestinal sac method demonstrated that the complex BAs and phosphatidylcholine had significantly better absorption compared to simple BAs. This amphiphilic complex also showed superior anti-inflammatory and hypolipidemic effects due to improved pharmacokinetics and higher absorption rates²³.

4.2. Metabolic Pathways and Efficacy:

Six main BAs—alpha-boswellic acid, beta-boswellic acid, acetyl-alpha-boswellic acid, acetyl-beta-boswellic acid, 11-keto-beta-boswellic acid, and 3-O-acetyl-11-keto-beta-boswellic acid—have been detected in rat tissues following oral administration of Boswellia at a dose of 240 mg/kg. This dose is equivalent to 86.97 mg/kg of total BAs. When administered to living organisms, BAs undergo significant metabolic processes, limiting their effectiveness.

The primary mechanism for the metabolism of KBA, alpha-BA, and beta-BA is Phase I metabolism in the liver, producing monohydroxylated or polyhydroxylated derivatives. Acetylated forms of BAs (such as AKBA and acetyl-beta-boswellic acid) show resistance to metabolism, whereas non-acetylated BAs are more metabolically active. AKBA, due to its high lipophilicity and limited absorption, has lower bioavailability compared to other BAs. AKBA undergoes less deacetylation, resulting in lower conversion to KBA.

Therefore, the pharmacokinetics and metabolism of BAs indicate that while AKBA and KBA have promising anti-inflammatory properties, their lipophilicity and metabolic pathways pose challenges for bioavailability. Strategies like combining BAs with phosphatidylcholine and consuming them with high-fat meals can improve absorption and efficacy, offering the potential for enhanced therapeutic benefits. ^17,24

5. Pharmacological Activity:

Boswellic acids possess the capability to influence a diverse array of targets within the body, as depicted in Figure 3. The wide-ranging effects of BAs on these molecular targets highlight their potential as versatile therapeutic agents. By interacting with key enzymes and signaling pathways, BAs may exert anti-inflammatory, anti-angiogenic, and potentially anti-cancer effects, among others. Understanding the mechanisms by which BAs act on these targets is essential for elucidating their therapeutic potential and developing targeted treatments for various diseases ^25-27.

Figure 3. Schematic illustration demonstrating the processes and activity of BAs derived from the Boswellia serrata plant.

5.1. 5-LO inhibition:

5-Lipoxygenase (5-LO) is a crucial enzyme in neutrophils, responsible for converting endogenous arachidonic acid into 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotrienes. These products play significant roles in various physiological responses, including vasoconstriction, bronchospasm, increased permeability, and chemotaxis ^28,29. BAs, when administered in a dose-dependent manner, inhibit the 5-LO enzyme in rat peritoneal neutrophils. This inhibition is crucial because it directly reduces the production of leukotrienes, which are key inflammatory mediators. Notably, BAs achieve this without affecting the activity of cyclooxygenase (COX) and 12-lipoxygenase enzymes, nor do they prevent the peroxidation of arachidonic acid [29,30]. BAs are unique in their action as they selectively inhibit 5-LO without engaging in redox reactions. This makes them distinct from other inhibitors that may have broader and less targeted effects. By selectively inhibiting 5-LO, BAs can reduce inflammation and its associated symptoms without interfering with other important enzymatic pathways involved in arachidonic acid metabolism. Hence, the selective inhibition of 5-LO by BAs highlights their potential as effective anti-inflammatory agents. By targeting a key enzyme in the inflammatory pathway without affecting other related enzymes, BAs offer a promising approach for managing conditions characterized by excessive leukotriene production, such as asthma, allergies, and other inflammatory diseases ^25,31,32.

5.2. Leukocyte elastase inhibition:

Human leukocyte elastase (HLE) is an enzyme that plays a critical role in various pulmonary diseases by degrading elastin, a protein crucial for maintaining lung elasticity. The activity of HLE leads to several detrimental effects on lung function, including:

· Loss of Lung Elasticity: HLE breaks down elastin, resulting in decreased flexibility of the lung tissue.

· Airway Constriction: The enzymatic activity contributes to the narrowing of the airways, making breathing more difficult.

· Mucous Production and Clearance: HLE damages the mechanisms responsible for mucus production and reduces the efficiency of mucus clearance from the lungs ³³.

Boswellic acids have been shown to inhibit the activity of HLE. This inhibition has significant therapeutic implications, particularly for conditions such as emphysema, where excessive elastase activity is a key factor in disease progression. By reducing the activity of HLE, BAs help to prevent the degradation of elastin, preserving the flexibility and function of lung tissue. It reduces the constrictive effects on the airways, potentially easing breathing. Further, it safeguards the mechanisms for mucus production and clearance, improving respiratory health. Therefore, the ability of BAs to inhibit human leukocyte elastase underscores their potential as therapeutic agents in the treatment of pulmonary diseases such as emphysema. By protecting elastin and maintaining proper lung function, BAs can play a crucial role in managing and mitigating the symptoms associated with these conditions ^24,34.

5.3. Topoisomerase inhibition:

Boswellic acids have a dual catalytic inhibitory effect on human topoisomerase I and IIa enzymes. These enzymes play a vital role in DNA replication and cell division by controlling the structure of DNA. They do this by temporarily breaking the DNA strands to reduce the strain caused by twisting during activities such as transcription and replication^35,36.

Boswellic acids inhibit DNA synthesis in human leukemia promyelocytic cells in a way that depends on the dosage. Higher concentrations of BAs result in a more significant decrease in DNA synthesis, which plays a crucial role in regulating the growth of cancer cells. BAs hinder the activity of topoisomerase I and IIa by competing with DNA for the binding sites on these enzymes. Through the establishment of this competition, BAs effectively hinder the enzymes' capacity to attach to and control the DNA, therefore impeding their ability to carry out their usual tasks in DNA replication and transcription ³⁵. The simultaneous ability of BAs to inhibit both topoisomerases I and IIa underscores their potential as medicines for treating cancer. By specifically targeting these enzymes, BAs can effectively hinder the process of DNA synthesis, hence restricting the cancer cells' capacity to reproduce and disseminate. Inhibiting topoisomerases hinders the restoration of DNA breaks, resulting in the build-up of DNA damage in cancer cells and facilitating their apoptosis (programmed cell death). Therefore, BAs have the potential to be used in the treatment of malignancies, namely those that include rapidly dividing cells such as leukemia promyelocytic cells, due to their ability to block both topoisomerase I and IIa enzymes. By disrupting crucial enzymes responsible for DNA synthesis and repair, BAs can effectively restrict the development and survival of cancer cells, offering a possible therapeutic approach to battle different types of malignancies ^10,37.

5.4. Inhibition of C2 convertase:

Boswellic acids (BAs) have the capability to inhibit the C2 convertase enzyme, a critical component of the classical complement pathway. This pathway is a part of the immune system that enhances the ability to clear pathogens and damaged cells, promote inflammation, and attack the pathogen's cell membrane ⁹.

5.4.1. Role of C2 Convertase:

The classical complement pathway is initiated when antibodies, specifically from certain classes (IgG and IgM), bind to antigens. This binding activates the C1 complex, which then cleaves C2 and C4, forming the C3 convertase (C4b2a), also known as the C2 convertase. The C2 convertase enzyme is crucial because it catalyzes the cleavage of C3 into C3a and C3b, leading to a cascade of further immune responses that include opsonization, inflammation, and cell lysis ³⁸.

5.4.2. Inhibition by Boswellic Acids:

· Blocking C2 Convertase: By inhibiting the C2 convertase enzyme, BAs can disrupt the classical complement pathway. This inhibition prevents the formation of the C3 convertase complex, thereby halting the cascade that leads to the activation of the complement system.

· Impact on Specific Immunity: The classical complement pathway is essential for specific immunity because it enhances the ability of antibodies to target antigens effectively. By blocking C2 convertase, BAs interfere with the pathway's ability to amplify immune responses against specific antigens ³⁹.

5.4.3. Therapeutic Implications:

The ability of BAs to inhibit the classical complement pathway through C2 convertase blockage can have significant therapeutic implications, particularly in conditions where the complement system is overactive or contributing to pathology, such as:

· Autoimmune Diseases: Conditions where the immune system attacks the body's own cells could benefit from reduced complement activity.

· Chronic Inflammation: Diseases characterized by prolonged inflammation might see improvement as the complement system's pro-inflammatory effects are mitigated ⁴⁰.

Boswellic acids, by blocking the C2 convertase enzyme, effectively inhibit the classical complement pathway, which is crucial for specific immunity. This inhibition can help modulate immune responses, particularly in autoimmune diseases and chronic inflammatory conditions, offering potential therapeutic benefits by preventing excessive or inappropriate activation of the complement system. Table 1 presents the pharmacological action of BAs and their derivatives.

6. Fundamentals of Angiogenesis and Antiangiogenic Activity of Boswellia serrata:

6.1. Fundamentals of Angiogenesis and its role in disease pathogenesis:

Angiogenesis is the process by which new blood vessels form from pre-existing ones, a crucial mechanism for various bodily functions, including reproduction, development, and wound healing. This process involves a delicate balance of activation and inhibition, ensuring that blood vessels form only when necessary. The human body tightly regulates angiogenesis through a variety of chemicals that have either pro-angiogenic or anti-angiogenic properties. Pro-angiogenic factors promote the formation of new blood vessels, while anti-angiogenic factors inhibit this process.

This regulation ensures that angiogenesis occurs efficiently during critical periods such as foetal development and wound healing and is suppressed when not needed. Angiogenesis is especially important for foetal growth. Proper blood vessel formation is essential for supplying nutrients and oxygen to the developing foetus. Disruptions in this process can lead to serious outcomes, including teratogenic effects (birth defects) and even miscarriage ⁴¹.

Angiogenesis is driven by various chemical and mechanical stimuli, classified into two main

categories ⁴².

· Pro-Angiogenic Factors: These include growth factors like VEGF (vascular endothelial growth factor), which stimulate the growth of new blood vessels.

· Anti-Angiogenic Factors: These inhibit vessel formation and ensure that angiogenesis is limited to necessary circumstances.

More than twenty different factors contribute to the fine-tuned control of angiogenesis, ensuring the process occurs appropriately throughout the body.

6.1.1. Pathologic Angiogenesis:

When the balance between pro-angiogenic and anti-angiogenic factors is disrupted, it can lead to pathological angiogenesis. This uncontrolled vessel growth is associated with a range of diseases, including ⁴³:

· Arthritis and Ischaemias: Abnormal vessel growth contributes to joint inflammation and tissue ischemia.

· Tumor Growth: Tumors exploit angiogenesis to obtain the blood supply needed for their growth and metastasis ².

· Inflammatory and Infectious Diseases: Conditions like atherosclerosis, restenosis (re-narrowing of blood vessels), and transplant arteriopathy are driven by excessive angiogenesis.

· Metabolic and Hormonal Disorders: Excessive vessel growth can be seen in obesity, endometriosis, and ovarian cysts.

· Ocular Diseases: Conditions such as diabetic retinopathy and retinopathy of prematurity involve abnormal blood vessel formation in the eye.

6.1.2. Applications in Angiogenesis Research:

Research into angiogenesis provides valuable insights and applications across various medical fields. By diagnosing angiogenesis-dependent diseases early, promoting angiogenesis in cases where it is beneficial, and inhibiting it in conditions where it is harmful, significant advancements can be made in patient care and treatment outcomes. Research on angiogenesis has a wide range of applications that can be categorized into three main areas: diagnostic applications, acceleration of angiogenesis, and inhibition of angiogenesis ^42,44.

6.1.2.1. Diagnostic Applications:

Angiogenesis plays a crucial role in the progression of various diseases. By understanding and detecting angiogenic activity, healthcare professionals can diagnose angiogenesis-dependent diseases such as cancer, arthritis, and retinopathies at earlier stages. This can involve the use of biomarkers or imaging techniques to identify abnormal blood vessel growth ⁴⁵.

6.1.2.2. Acceleration of Angiogenesis:

Promoting angiogenesis can significantly enhance the healing of wounds by improving blood flow and nutrient supply to the affected area. This is particularly beneficial for chronic wounds, such as diabetic ulcers, which can be difficult to heal. In conditions where tissues are deprived of adequate blood supply, such as in ischemic heart disease or peripheral artery disease, accelerating angiogenesis can help restore blood flow and improve tissue survival. This can reduce the extent of damage and improve recovery outcomes ^46,47.

6.1.2.3. Inhibition of Angiogenesis:

Tumors require a blood supply to grow and metastasize. By inhibiting angiogenesis, the blood supply to tumors can be reduced, effectively starving the cancer cells and inhibiting their growth. Anti-angiogenic therapies are an important part of cancer treatment strategies. Inflammatory conditions like arthritis involve excessive blood vessel formation, contributing to pain and swelling. Inhibiting angiogenesis can help manage these symptoms and slow disease progression. Diseases like diabetic retinopathy involve abnormal blood vessel growth in the eye, leading to vision loss. Inhibiting angiogenesis in the eye can prevent further damage and preserve vision. Conditions such as corneal vascularization, which can lead to impaired vision and other diseases characterized by unwanted blood vessel growth can benefit from anti-angiogenic treatments ⁴⁸.

Despite their precision, these targeted antiangiogenic and anticancer drugs have significant limitations, primarily due to associated toxicities. These drugs can adversely affect the processes of hematopoiesis (formation of blood cells), myelopoiesis (formation of bone marrow cells), and the health of endothelial cells (which line blood vessels). Anti-angiogenic medications, while targeting specific pathways, can inadvertently impact other essential bodily functions, including immune responses, blood flow regulation, and the coagulation process. This suggests that angiogenesis plays a broader role in maintaining bodily homeostasis. Natural health products offer a promising alternative due to their diverse anticancer mechanisms and ability to inhibit angiogenesis. Unlike synthetic drugs, these natural compounds can influence multiple molecular pathways beyond angiogenesis, such as Epidermal Growth Factor Receptor (EGFR), HER2/neu Gene, COX-2 Enzymes, NF-κB Transcription Factor, and Protein Kinases ⁴⁹.

Traditional medicine has long utilized various plants for cancer treatment. Some herbs have been extensively studied, revealing potential anticancer properties, while others are yet to be fully explored. Identifying the specific components or combinations of components responsible for the anticancer effects of these herbs remains an ongoing area of research. B. serrata, a therapeutic herb, has demonstrated effectiveness in treating conditions that rely on angiogenesis, such as ischemic diseases, arthritis, and retinal angiopathies. This highlights the potential of natural compounds in complementing or even substituting conventional antiangiogenic therapies, offering a broader spectrum of biological activity with potentially fewer side effects.

6.2. Antiangiogenic activity of Boswellia serrata:

B. serrata has been studied for its potential antiangiogenic properties. This plant, traditionally used in Ayurvedic medicine, contains compounds that may inhibit the growth of new blood vessels, offering a promising approach to treating diseases where pathological angiogenesis is a factor.

6.2.1. Antiangiogenic Activity Against Cancer:

Boswellic acid, the main active compound in B. serrata, has demonstrated efficacy in both preventing and treating various types of cancer, such as breast, bladder, cervix, prostate, colon, head and neck, liver, lung, and pancreatic cancers. Additionally, BAs have shown promise in the treatment of malignancies ⁵⁰. To enhance the anti-cancer properties of BAs, several semi-synthetic derivatives have been synthesized, demonstrating potential chemotherapy effects against various malignant human cell lines. BAs function to inhibit cancer metastasis through several mechanisms, including inducing apoptosis (programmed cell death), reducing angiogenesis in malignant cells, impeding blood supply to tumor tissue, and suppressing AKT phosphorylation. These mechanisms may vary depending on the specific type of cancer cells targeted ^51,52.

In a study investigating the potential of B. serrata against cancer, researchers examined the effects of B. serrata gum resin alcoholic extract (BSE) on tumor growth, metastasis, and angiogenesis using a mouse model of 4T1 breast cancer. Since many cancer medications originate from natural sources, the team aimed to evaluate the efficacy of BSE in inhibiting cancer progression.

The study began by testing the viability of BSE on 4T1 cancer cells, a type of triple-negative breast cancer cell line, using the MTT test. Subsequently, 4T1 cells were implanted into the mammary fat pad of female BALB/c mice, which served as the experimental subjects for investigating breast cancer prevention. The mice were divided into four groups, each consisting of five individuals. Over a 21-day period, the groups were orally administered BSE at doses of 50, 150, and 250 mg/kg, dissolved in distilled water.

To assess the impact of B. serrata gum resin alcoholic extract (BSE) on tumor tissues, researchers conducted an immunohistochemistry (IHC) examination to measure the expression of Ki-67 and CD31, which indicate cell proliferation and angiogenesis, respectively. Additionally, histological analysis of liver and lung samples was performed to evaluate metastasis. The in vitro toxicity investigation revealed that the 4T1 cell line was sensitive to BSE treatment, resulting in decreased cell viability. The inhibition of 4T1 tumor development by BSE was associated with a reduction in cell proliferation, as evidenced by decreased Ki-67 expression observed in the immunohistochemical examination. Furthermore, analysis of blood vessels in the tumor tissues showed a decreased vessel area in the BSE250 group compared to control tumors, indicating reduced angiogenesis. This finding was supported by immunohistochemical analysis of the CD31 angiogenesis marker. Importantly, BSE notably reduced the rate of metastasis, particularly in lung tissue. The study concluded that BSE induced cytotoxicity specific to certain cells and inhibited cell proliferation, angiogenesis, and metastasis in breast cancer cells. These results suggest that BSE holds promise as a potential treatment for advanced breast cancer ⁵³.

Similarly, another research team investigated the inhibitory effects of B. serrata on tumor development, metastasis, and angiogenesis using a mouse model of 4T1 breast cancer. They conducted an experiment to evaluate the impact of B. serrata gum resin alcoholic extract (BSE) on the viability of triple-negative cancer cells (4T1) using the MTT test. This was significant given the prevalence of cancer treatments derived from natural sources. For their anti-breast cancer study, researchers implanted 4T1 cells (1×10^5 cells/0.1 ml) into the mammary fat pad of female BALB/c mice. The mice were divided into four groups, each comprising five individuals (n=5), and were administered BSE at doses of 50, 150, and 250 mg/kg, or given distilled water, for a period of 21 days. Tumor tissues were then evaluated for the anti-proliferative and anti-angiogenic properties of BSE using immunohistochemistry (IHC) analysis to measure Ki-67 and CD31 expression. Additionally, metastasis rates were assessed in liver and lung tissues using histological examination. The results of the in-vitro toxicity analysis revealed that the 4T1 cell line was highly susceptible to BSE treatment, leading to a significant decrease in cell viability. The inhibition of 4T1 tumor development by BSE was associated with reduced cell proliferation, as indicated by decreased Ki-67 expression observed in the immunohistochemical examination. Furthermore, examination of blood vessels in the tumor tissues showed a reduction in vessel size in the BSE250 group compared to control tumors, as determined by immunohistochemistry using the angiogenesis marker CD31. Notably, BSE significantly reduced the rate of metastasis, particularly in lung tissue. The research team concluded that BSE induced cytotoxicity specific to certain cells and inhibited cell proliferation, angiogenesis, and metastasis in breast cancer cells, suggesting its potential benefit in treating advanced breast cancer ⁵⁰.

Both traditional and modern medicine have utilized resin extracts from Boswellia species to treat various ailments, including cancer, with minimal side effects. Researchers led by Ranjbarnejad and the group investigated the potential of chemoprevention to reduce mortality rates associated with colorectal cancer (CRC), the most prevalent form of cancer. Their study focused on exploring naturally occurring compounds, particularly the methanolic extract from B. serrata, for their anti-cancer properties.

In their experiment, human colon cancer cells (HT-29 strain) were exposed to different concentrations of B. serrata, and cell survival was assessed using the MTT test. The researchers used quantitative real-time polymerase chain reaction (PCR) to measure the levels of various proteins involved in cancer progression, such as microsomal prostaglandin E synthase-1 (mPGES-1), vascular endothelial growth factor (VEGF), C-X-C chemokine receptor type 4 (CXCR4), matrix metalloproteinase-2 (MMP-2), MMP-9, and hypoxia-inducible factor-1 (HIF-1). Apoptosis was evaluated by quantifying the proportion of cells in the sub-G1 phase, and ELISA tests were used to measure prostaglandin E2 (PGE2) levels and caspase 3 activity. Additionally, scratch tests and three-dimensional vessel formation experiments were conducted to assess tube formation capability and HT-29 cell migration.

The results indicated that B. serrata extract significantly inhibited the synthesis of mPGES-1, VEGF, CXCR4, MMP-2, MMP-9, and HIF-1. Moreover, it enhanced caspase 3 activity, leading to an increase in the proportion of cells in the sub-G1 phase, indicative of apoptosis. Treatment with B. serrata extract resulted in reduced cell survival, decreased PGE2 synthesis, impaired in vitro tube formation, and inhibited cell migration compared to the control group. In summary, B. serrata extract demonstrated inhibitory effects on HT-29 cell proliferation, angiogenesis, and migration, while inducing apoptosis. This was attributed to its ability to inhibit mPGES-1, reduce PGE2 levels, and subsequent downstream effects ⁵⁴.

6.2.2. Antiangiogenic activity against diabetic retinopathy:

One of the severe complications of diabetes is diabetic retinopathy (DR), which can lead to vision loss. This condition involves pathological angiogenesis, or abnormal blood vessel growth, in the retina. Anti-VEGF injections are commonly used to inhibit angiogenesis in DR, but their frequent administration poses challenges for patients and healthcare systems. As a result, alternative treatments, including those using natural ingredients like B. serrata, have gained attention ⁵⁵. As stated earlier, B. serrata exhibits both anti-inflammatory and antiangiogenic properties, primarily attributed to its bioactive components such as BAs. Research suggests that B. serrata extract (BSE) can reduce retinal neovascularization in diabetic mice by inhibiting VEGF expression, potentially reducing the need for frequent injections ⁵⁶.

Clinical studies indicate that BSE can stabilize diabetic retinopathy progression, preserving central macular thickness and visual acuity. Its antiangiogenic effects make it a promising alternative to traditional therapies, offering potential improvements in patient outcomes and quality of life. For diabetic macular edema (DME), anti-VEGF medications are standard treatment. However, the global burden of injections, exacerbated during the COVID-19 pandemic, strains healthcare systems. To address this challenge, a research group investigated the effects of oral administration of a combination of Curcuma longa and B. serrata (Retimix®) in patients with non-proliferative DR and treatment-naïve DME. This study aimed to explore an alternative management approach, particularly relevant during the pandemic.

The study, conducted retrospectively, involved recruiting patients divided into two groups: Group A (n=12), which underwent observation, and Group B (n=49), which received daily doses of Retimix®. Using spectral-domain optical coherence tomography, researchers assessed best-corrected visual acuity (BCVA) and central macular thickness (CMT) at the study's outset, one month in, and at the six-month mark. Analysis of variance (ANOVA) with a mixed design was employed to determine whether changes in CMT and BCVA over time were influenced by Retimix® usage. Statistical analysis revealed a significant interaction between time and treatment, indicating that changes in CMT and BCVA varied significantly between the groups. Based on these findings, it can be concluded that oral administration of Curcuma longa and B. serrata effectively maintains baseline CMT and BCVA values in patients with non-proliferative diabetic macular edema and treatment-naïve diabetic macular edema. This suggests that Retimix® could serve as a beneficial alternative therapeutic approach, particularly when standard medications are less accessible, such as during the COVID-19 pandemic. This study underscores the potential utility of natural remedies like Retimix® in managing diabetic retinopathy, offering hope for patients and clinicians seeking effective treatment options ⁵⁷.

Further, a study investigated the antiangiogenic properties of acetyl-11-keto-β-boswellic acid (AKBA), a bioactive compound derived from B. serrata, in a mouse model of oxygen-induced retinopathy (OIR). This model mimics the neovascular response observed in human retinopathy of prematurity. AKBA administration via the subcutaneous route was found to affect proteins involved in the OIR model. It increased the expression and activity of Src homology region 2 domain-containing phosphatase 1 (SHP-1) in the retina. Additionally, AKBA decreased the phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3), as well as the expression and phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2), leading to reduced retinal neovascularization in OIR mice without affecting retinal cell survival or function.

Further research using retinal explants cultured under hypoxia and a STAT3 phosphorylation activator suggested that AKBA's suppression of VEGFR-2 phosphorylation is likely mediated via a SHP-1/STAT3/VEGF axis. Additionally, the study investigated AKBA's effect on the angiogenic response of human retinal microvascular endothelial cells (HRMECs). AKBA was found to inhibit proliferation, migration, and tube formation in HRMECs stimulated with exogenous VEGF. Moreover, it reduced migration and tube formation in HRMECs even without prior AKBA treatment. These findings suggest that AKBA exhibits antiangiogenic effects in a model of pathological neovascularization, making it a potential therapeutic agent for mitigating the impact of proliferative retinopathies ⁵⁸.

6.2.3. Antiangiogenic activity against inflammatory disorders:

Antiangiogenic activity holds promise as an effective therapeutic approach for treating inflammatory diseases. Angiogenesis plays a significant role in various inflammatory disorders such as rheumatoid arthritis, psoriasis, and chronic inflammatory bowel diseases. By blocking angiogenesis, antiangiogenic drugs can reduce inflammation and tissue damage by limiting the delivery of oxygen and nutrients to inflamed tissues. Key pro-angiogenic factors like vascular endothelial growth factor (VEGF) and angiopoietins are targeted by these drugs.

Antiangiogenic therapy can effectively disrupt abnormal blood vessel formation associated with chronic inflammation by inhibiting these factors or their receptors. Additionally, they may help modulate the immune response, reducing the infiltration of inflammatory cells into affected tissues. Ongoing research aims to explore the efficacy and safety of various antiangiogenic substances, including plant extracts, to develop tailored therapies for patients with severe inflammatory diseases.

Boswellia species have been used in folk medicine for treating inflammatory conditions since ancient times. Scientific research has provided compelling evidence that B. serrata possesses potent anti-inflammatory effects by suppressing angiogenesis⁹.

The research team aimed to investigate the impact of boswellic acid (BA) on various aspects of inflammatory angiogenesis using a mouse-cannulated sponge implant angiogenesis model. Polyester and polyurethane sponges were implanted into Swiss albino mice to facilitate the development of fibrovascular tissue, serving as a framework for tissue production. Cannulas were surgically implanted to administer benzylamine (BA) at doses of 12.5 or 25 mg/kg/day for nine days. On the ninth day, the implants were removed and tested for hemoglobin (Hb) levels to assess vascularization. Additionally, levels of cytokines associated with inflammation, angiogenesis, and fibrosis were evaluated.

The study revealed that BA treatment significantly reduced sponge vascularization, evidenced by decreased Hb levels. Furthermore, levels of vascular endothelial growth factor (VEGF) and transforming growth factor (TGF-β1) were reduced with BA treatment at both doses. BA administration also led to decreased expression of VEGF and CD31, as well as a reduction in microvessel density (MVD) in the sponge implants. These findings suggest that BA regulates various elements of inflammatory angiogenesis, highlighting its potential therapeutic application ⁵⁹.

In a related context, research conducted by Siemoneit and colleagues explored the anti-inflammatory properties of BAs, primary active components found in Boswellia species. Initially recognized for their ability to inhibit leukotriene formation and 5-lipoxygenase, their impact on prostaglandin production and cyclooxygenases (COX) was later investigated. The study demonstrated that BAs, particularly 3-O-acetyl-11-keto-β-BA (AKBA), effectively inhibit COX-1 products in human platelets and isolated COX-1 enzyme assays. This inhibition is concentration-dependent, with AKBA exhibiting an IC50 value of 6 μM and 32 μM, respectively. The inhibitory effect of AKBA can be reversed, but its efficacy is reduced when used as a substrate for COX-1 due to increased arachidonic acid (AA) levels. Molecular docking analysis indicated favorable binding of BAs to the active site of COX-1, suggesting their role in suppressing COX-1 and contributing to their anti-inflammatory effects. However, BAs were found to be less efficient in inhibiting COX-2 compared to COX-1, suggesting a preference for COX-1 inhibition ¹⁹.

6.2.4. Antiangiogenic activity against cardiovascular disorders:

In conditions such as ischemic heart disease and peripheral arterial disease, inadequate angiogenesis can exacerbate tissue damage due to insufficient blood supply, while therapeutic angiogenesis aims to promote new vessel formation to restore perfusion. Conversely, in atherosclerosis and heart failure, dysregulated or excessive angiogenesis can lead to adverse outcomes, such as plaque instability and pathological remodeling of the heart. Understanding the delicate balance of angiogenic signals is essential for developing targeted therapies that either stimulate or inhibit vessel growth as needed, offering hope for improved treatment strategies in cardiovascular diseases ⁶⁰.

The study conducted by a group of researchers aimed to investigate the cytotoxicity, anti-inflammatory, and angiogenic properties of two B. serrata extracts on primary cultures of porcine aortic endothelial cells (pAECs). Using high-performance liquid chromatography (HPLC), they analyzed a dry extract (extract A) and a hydroenzymatic extract (extract G) of B. serrata, using pure BAs as standards.

The researchers found that extract G increased cell survival in a dose-dependent manner when cultured pAECs were challenged with LPS, without exhibiting any harmful effects. Conversely, extract A showed cytotoxic effects at higher doses but restored the viability of pAECs at lower doses after LPS challenge. Interestingly, pure BAs did not reduce LPS-induced cytotoxicity at the same concentrations as those found in the phytoextracts.

Furthermore, extract A exhibited proangiogenic properties at lower doses, similar to pure AKBA at equivalent concentrations, while extract G had no effect on endothelial cell migration. Overall, the study indicated that B. serrata extracts possess anti-inflammatory effects on endothelial cells, although their effects can vary depending on the dose and formulation used, potentially leading to cytotoxicity or proliferative stimulation ⁵⁶.

In a parallel study, Chen and colleagues investigated the cardioprotective effects of hydroxysafflor yellow A (HSYA) and acetyl-11-keto-β-boswellic acid (AKBA), focusing on their mechanisms of action. They targeted the PGC-1α/Nrf2 pathway due to its role in oxidative stress-related myocardial damage (MI). Using isoproterenol-induced myocardial infarction (MI) in Sprague-Dawley rats and H9C2 cells to mimic ischemia damage, they assessed various parameters including CK-MB, LDH, MDA, SOD activity, apoptotic cell death, mitochondrial ROS, and MMP levels. The results showed that HSYA and AKBA effectively prevented myocardial alterations, reducing levels of CK-MB and LDH, decreasing apoptosis, increasing the expression of PGC-1α and Nrf2, enhancing SOD activity, and reducing MDA and ROS levels. These findings suggest that HSYA and AKBA may work synergistically to protect against MI-induced damage ⁶¹.

7. Conclusion and Future Prospects:

The extensive research on Boswellia serrata extract, particularly its antiangiogenic properties, highlights its promising role as a therapeutic agent for treating angiogenesis-dependent disorders. Boswellia serrata extract has been shown to effectively inhibit the formation of abnormal blood vessels, which is a key factor in the progression of various conditions, including cancer, chronic inflammatory diseases, diabetic retinopathy, and cardiovascular disorders. Preclinical studies have demonstrated that Boswellia serrata extract can significantly suppress tumor growth, reduce inflammatory responses, and mitigate vascular complications by targeting the molecular pathways involved in angiogenesis. These findings are further supported by clinical evidence, which indicates that the extract not only curbs the progression of these diseases but also enhances patient outcomes by reducing disease severity and improving quality of life.

Despite these promising results, further research is essential to fully elucidate the mechanisms through which Boswellia serrata exerts its antiangiogenic effects. Additionally, optimizing dosing strategies and exploring the potential for combining Boswellia serrata with existing therapies could maximize its therapeutic benefits. Rigorous clinical trials are also necessary to confirm the safety and efficacy of Boswellia serrata extract in diverse patient populations and to establish standardized treatment protocols.

Continued research in this area could pave the way for new therapeutic strategies, ultimately leading to better patient care and improved outcomes across a range of angiogenesis-related diseases.

Declaration of Interest:

None.

ACKNOWLEDGMENTS:

None.

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Received on 23.06.2024 Revised on 09.10.2024

Accepted on 16.12.2024 Published on 12.06.2025

Available online from June 14, 2025

Research J. Pharmacy and Technology. 2025;18(6):2890-2902.

DOI: 10.52711/0974-360X.2025.00416

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Base Compound	Derived Compound	Pharmacological Effects	Study Type and Model	Citation
AKBA	2,3-Dehydro-11-keto-β-boswellic acid	Cytotoxic effects	In vitro, human tumor cell lines	62
	2α-Hydroxy-11-keto-β-boswellic acid	Cytotoxic effects	In vitro, mouse RAW 264.7 cells	63
	1α-Hydroxy-2,3-dehydro-11-keto-β-boswellic acid	Cytotoxic effects	In vitro, mouse RAW 264.7 cells
	11-Keto-β-boswellic acid methyl ester	Cytotoxic effects	In vitro, mouse RAW 264.7 cells
	2,3-Dehydro-11-keto-β-boswellic acid methyl ester	Cytotoxic effects	In vitro, mouse RAW 264.7 cells
KBA	3-O-naproxen-β-boswellic acid	Demonstrates anti-inflammatory and anti-arthritic properties	In vivo, carrageenan-induced mouse and rat models	64
	3-O-naproxen-11-keto-β-boswellic acid	Exhibits anti-inflammatory and anti-arthritic activities	In vivo, carrageenan-induced mouse and rat models
	3-O-ibuprofen-β-boswellic acid	Shows anti-inflammatory properties	In vivo, carrageenan-induced mouse and rat models
	3-O-aspirin-β-boswellic acid	Displays anti-inflammatory effects	In vivo, carrageenan-induced mouse and rat models
	3-O-aspirin-11-keto-β-boswellic acid	Exhibits anti-inflammatory potential	In vivo, carrageenan-induced mouse and rat models
	3-O-cinnamyl-11-keto-β-boswellic acid	Shows anti-inflammatory activity	In vivo, carrageenan-induced mouse and rat models
	3-O-succinoyl-11-keto-β-boswellic acid	Mild 5-LO inhibition	In vitro, human neutrophils	65
	3-O-glutaroyl-11-keto-β-boswellic acid	Mild 5-LO inhibition	In vitro, human neutrophils
	3-O-carboxymethyl-11-keto-β-boswellic acid	Mild 5-LO inhibition	In vitro, human neutrophils
	3-Cinnamoyl-11-keto-β-boswellic acid	Proapoptotic and anti-proliferative effects	In vitro, cancer cell lines and in vivo, PC-3 prostate cancer	66
	7β-Hydroxy-11-keto-β-boswellic acid	Inhibits NO production by LPS mechanism without affecting cell viability in macrophages (RAW 264.7)	In vitro, mouse RAW 264.7 cells	63
	7β,22β-Dihydroxy-11-keto-β-boswellic acid	Inhibits NO production by LPS mechanism without affecting cell viability in macrophages (RAW 264.7)	In vitro, mouse RAW 264.7 cells	63
β-BA	11α-Hydroxy-β-boswellic acid	Inhibits 5-lipoxygenase and cathepsin G; promotes apoptosis	In vitro, human neutrophils and cathepsin G	65
	11β-Hydroxy-β-boswellic acid	Mild 5-LO inhibition	In vitro, human neutrophils
	3-O-oxaloyl-β-boswellic acid	Inhibits cathepsin G and promotes apoptosis	In vitro, cathepsin G
	3-O-succinoyl-β-boswellic acid	Weak 5-LO inhibition	In vitro, human neutrophils
	3-O-glutaroyl-β-boswellic acid	Inhibits cathepsin G and promotes apoptosis	In vitro, cathepsin G
	3-O-carboxymethyl-β-boswellic acid	Inhibits cathepsin G and promotes apoptosis	In vitro, cathepsin G
	2β-Cyano-3-en-X-one of the methyl boswellates	Inhibits growth of cancer cells, cytotoxic, anti-inflammatory, and pro-differentiating activities	In vitro, mouse RAW 264.7 cells	63
	3α-Propionyloxy-β-boswellic acid	Cytotoxic to human cancer cells by inhibiting the PI3K pathway	In vitro, human cancer cells and in vivo, murine tumour models	11
	3α-Butyryloxy-β-boswellic acid	PI3K-mediated apoptosis	In vitro, mouse RAW 264.7 cells	63
α-BA	2α-Cyano-3-en-X-one of methyl boswellates	Inhibits growth of cancer cells, cytotoxic, anti-inflammatory, and pro-differentiating activities	In vitro, cancer cell lines	67