# Taxonomical Investigation, Chemical Composition, Traditional Use in Medicine, and Pharmacological Activities ofBoswellia sacra Flueck

Authors: Mansour Miran; Keyvan Amirshahrokhi; Yousef Ajanii; Reza Zadali; Maxwell W. Rutter; Ayesheh Enayati; Farahnaz Movahedzadeh
Journal: Evidence-Based Complementary and Alternative Medicine
 (2022)

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## Abstract

Aromatic oleo-gum-resin secreted fromB. sacra, reputed as frankincense, is widely used in traditional medicine to treat Alzheimer’s disease, gastric disorders, hepatic disorders, etc. Frankincense is also used in the cosmetic, perfume, and beverage and food industries. Frankincense is a rich resource for bioactive compounds, especially boswellic acids and derivatives. Although several reports have described frankincense’s constituents and pharmacological activities, there is no comprehensive study that covers the valuable information on this species. Therefore, the current review will focus on the phytochemistry, traditional uses, and pharmacological activities of B. sacra.


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## Body

## 1. Introduction

Boswellia sacra Flueck is a perennial plant belonging to the family Burseraceae. Aromatic oleo-gum-resin extracted from B. sacra, known as frankincense or olibanum (Figure 1), is used as a home remedy, especially in Middle East countries [1]. Frankincense is harvested by making shallow incisions into the tree trunk [2]. Frankincense is used in many industries such as cosmetic, pharmaceutical, beverage, food, detergents, and perfume industries [3, 4]. The oleo-gum resin of B. sacra has many uses for the human body, including analgesic, hepatoprotective, anticoagulant, antioxidant, tumor-suppressive, anti-inflammatory, cardioprotective, Alzheimer’s disease, gastric, hepatic, and skin disorders [5, 6]. B. sacra is an important source of bioactive compounds, including terpenoids which have a wide range of biological activities [6]. The most important compounds found in resin from Boswellia sacra are boswellic acids and their derivatives, which are responsible for a number of medicinal properties belonging to the plant.Figure 1
A photograph of frankincense gum resin taken fromhttps://nagaadgums.com.Accordingly, this review introducesB. sacra as a valuable herbal source in different industries such as pharmacy and food.


## 2. GenusBoswellia Roxb. Ex. Colebr

The genusBoswellia belongs to the family Burseraceae. It comprises 20–25 species of trees and shrubs widely distributed in dry areas of northeast Africa, Arabia, and India [7, 8]. Species of the genus, known as frankincense trees (olibanum), produce a resin gum traditionally harvested by making incisions on the trunks of the trees; as the resin is exposed, it darkens and hardens before being removed from the incision [9]. Among the species of the genus, only B. serrata Roxb. and B. sacra Flueck have economic importance.The taxonomy ofBoswellia (five species) except B. papyrifera (Del.) Hochst. in northern Somalia and southern Arabia has been revised. Therefore, the two extreme populations of Boswellia spp. vary in habitat, indumentum and shape of leaflets, number of inflorescence branches, and shape of fruits. There are also populations showing the intermediate characteristics of the extremes in Somalia and the Arabian Peninsula. Based on flower and fruit features, B. sacra is closely related to B. papyrifera. The genus has been reduced to two species, including B. sacra Flueck and B. frereana Birdwood. Based on morphological data, B. carterii Birdwood has been synonymized with B. sacra [10]. However, recent chemical analysis has shown that these are distinct species [11]. To confirm this data, further taxonomical research is required. B. sacra is typified as follows:Boswellia sacra Flueckiger, Lehrbuch der Pharmakognosie des Pflanzenreiches [12].Syn.:B. carteri Birdwood var. subintegra Engel., B. bhau-dajiana Birdwood var. serrulata, B. carteri Birdwood var. undulate-crenata Engel. B. undulato-crenata (Engl.) Engel. [10].


### 2.1. Botanical Description, Habitat, and Distribution

B. sacra is a tree with a distinct trunk that grows to a height of 1.5–8 m. The stems branch from the base, having pale yellowish-brown bark. The young stems can be either hairy or smooth. Resin is copious on the bark. It is milky when first exposed, then pale yellowish when dried. Leaves are densely crowded, arranged as alternates and imparipinnate with 13–19 leaflets. The inflorescence is either raceme or panicle. The flowers emerge synchronously with leaves. Pedicel length is 2–8 mm, covered with sparse hairs or smooth. Calyx is cup-shaped; the color is reddish-brown and reaches between 2 and 2.5 mm in length. Petals are white and elliptic, and the dimension is 4-5 × 2–2.5 mm. Stamens are numerous, approximately 10. The filament texture is smooth; the length is 2.5–3 mm. The anthers are oblong and white. The texture can be hairy or smooth. The length is 0.8–1.4 mm. The flowers are yellowish to orange. The pistil is furrowed, smooth, and 2.5–3 mm in length. The fruit is pyriform, reddish-brown, and has 3–4 locules. The dimension is 8–12 × 3.5–9 mm. Pyrenes are trigonous and often surrounded by a persistent wing. The dimension is 3.5–5.5 × 2-4.5 mm.Carter first collected this species from Arabia [13]. He incorrectly named the species as B. thulifera and B. serrate. Flueckiger [14] identified it as B. papyrifera and later correctly identified it as a new species “B. sacra” in 1867 [10].B. sacra is mainly a saxicolous species. The cushion or disklike swelling base of the trunk adheres the plant to the rock faces. This plays an important role in stabilizing the plant, especially in very steep terrain. This species is distributed in Somalia, most parts of the Horn of Africa, and up to the Arabian Peninsula [15]. The plant growing in control and wild habitats is shown in Figure 2.Figure 2
Photographs of (a) tree growing in control habitat; (b) tree growing in wild habitats given by Khan et al. [5].
(a)(b)


## 2.1. Botanical Description, Habitat, and Distribution

B. sacra is a tree with a distinct trunk that grows to a height of 1.5–8 m. The stems branch from the base, having pale yellowish-brown bark. The young stems can be either hairy or smooth. Resin is copious on the bark. It is milky when first exposed, then pale yellowish when dried. Leaves are densely crowded, arranged as alternates and imparipinnate with 13–19 leaflets. The inflorescence is either raceme or panicle. The flowers emerge synchronously with leaves. Pedicel length is 2–8 mm, covered with sparse hairs or smooth. Calyx is cup-shaped; the color is reddish-brown and reaches between 2 and 2.5 mm in length. Petals are white and elliptic, and the dimension is 4-5 × 2–2.5 mm. Stamens are numerous, approximately 10. The filament texture is smooth; the length is 2.5–3 mm. The anthers are oblong and white. The texture can be hairy or smooth. The length is 0.8–1.4 mm. The flowers are yellowish to orange. The pistil is furrowed, smooth, and 2.5–3 mm in length. The fruit is pyriform, reddish-brown, and has 3–4 locules. The dimension is 8–12 × 3.5–9 mm. Pyrenes are trigonous and often surrounded by a persistent wing. The dimension is 3.5–5.5 × 2-4.5 mm.Carter first collected this species from Arabia [13]. He incorrectly named the species as B. thulifera and B. serrate. Flueckiger [14] identified it as B. papyrifera and later correctly identified it as a new species “B. sacra” in 1867 [10].B. sacra is mainly a saxicolous species. The cushion or disklike swelling base of the trunk adheres the plant to the rock faces. This plays an important role in stabilizing the plant, especially in very steep terrain. This species is distributed in Somalia, most parts of the Horn of Africa, and up to the Arabian Peninsula [15]. The plant growing in control and wild habitats is shown in Figure 2.Figure 2
Photographs of (a) tree growing in control habitat; (b) tree growing in wild habitats given by Khan et al. [5].
(a)(b)


## 3. Traditional Medicine

The resin of frankincense is commonly used to treat bronchial and urinary infections. It is used as a rejuvenating medicine and treats menstrual pain, mouth problems, wounds, sores, ulcers, carbuncles, hemorrhoids, inflammation, and throat problems in some Asian countries. It is also known that frankincense oil has carminative, digestive, and diuretic properties. This gum resin’s water extract, known as “Moh-Lubban,” is traditionally used to treat coughs and stomach problems [1].In Oman,B. sacra gum extracts have long been used in various folk medicines for strengthening and stimulating the digestion process, dental infections, and for the treatment of colds, cough, muscle pain, fever, and asthma, as well as different types of cancer [16, 17]. In Arabian folk medicine, the gum resin is reputed to improve memory [18].


## 4. Chemical Composition

Frankincense gum resin contains 5–9% oil, a 60–70% alcohol-soluble fraction, and a 25–30% water fraction. The lipophilic part is a rich source of terpenoids, especially the medicinally important group of boswellic acids (BAs) [6, 19]. Plant resins are lipid-soluble mixtures of volatile and nonvolatile terpenoids [5].


### 4.1. Volatile Terpenoids

The chemical composition of the volatile oil ofB. sacra resin has been investigated by GC-FID, GC/MS, and headspace SPME methods that revealed α-pinene (38%) (1), β-ocimene (32.3%; 2), camphene (29.4%; 3), 1-propanol, 2-(2-hydroxypropoxy) (14.4%; 4), limonene (13.36%; 5), and 2- propanol, 1, 1′-oxybis (11.2%; 6) as the main compounds. Also, other compounds such as trans-pinocarveol (3.98%) (7), caryophyllene (3.03%; 8), cis-piperitol (2.53%; 9), β-selinene (2.49%; 10), myrcene (2.38%; 11), α-phellandren-8-ol (2.37%; 12), and delta-cadinene (2.21%; 13) have been reported in significant amounts in the essential oil from B. sacra (21–23) (Figure 3).Figure 3
The chemical composition of the volatile oil ofB. sacra resin.
(a)(b)


### 4.2. Sesquiterpenoids

Investigation ofB. sacra led to the isolation and identification of two oxygenated sesquiterpenes, namely, rotundone (14) and mustakone (15) [24] (Figure 4). These compounds were isolated from the volatile oil of gum resin by sensory-guided fractionation [24].Figure 4
Sesquiterpenoids isolated fromB. sacra.


### 4.3. Diterpenoids

Four new cembrane-type diterpenoids, including boscartins (16–19), together with five known compounds (1S, 3 R, 11S, 12 R, 7E)-1,12-epoxy-4-methylenecembr-7-ene-3,11-diol (20), isoincensole oxide (21), incensole oxide (22), incensole acetate (23), and incensole oxide acetate (24) were isolated fromB. sacra gum resin by Wang et al. In addition, hepatoprotective properties of isolated compounds were studied against HepG2 cells that had been damaged by paracetamol compared to bicyclol (as a positive control). Incensole acetate had a potent hepatoprotective effect at 10 μM. In contrast, boscartin M, isoincensole oxide, incensole oxide, and incensole oxide acetate had a mild hepatoprotective effect at 10 μM [25]. In the other report by Wang et al., the investigation of B. sacra led to the isolation of ten new cembrane-type diterpenes, including boscartins AL-AU (25–34) and five known analogs (35–39). Moreover, biological evaluations revealed that compounds 27, 29, 36, and 37 displayed hepatoprotective activities against paracetamol-induced HepG2 cell damage at 10 μM. Some compounds exhibited moderate neuroprotective activities in two different models [26]. Zhang et al. isolated eight diterpenoids (40–48), namely, sacraoxides A–G from the gum resin of B. sacra and found that sacraoxides E and F had inhibitory activities on nitric oxide (NO) production induced by lipopolysaccharide in RAW264.7 cells with IC50 values of 24.9 ± 1.7 and 36.4 ± 2.9 μM [27]. In another study, five diterpenoids (49–53) including two new prenylaromadendrane-type diterpenoids, and three known analogues, were isolated from the ethanol extract of the gum resin of B. sacra Flueck by Wang et al.. All compounds exhibited notable cytotoxicity against human malignant glioma (U87-MG) cell line against 5-fluorouracil as a positive control [28]. Figure 5 shows the structures of isolated diterpenoids from B. sacra.Figure 5
Structure of isolated diterpenoids fromB. sacra.
(a)(b)(c)(d)


### 4.4. Triterpenoids

B. sacra could be chemically characterized by the occurrence of triterpenoid compounds such as lupeolic acid, α- and β-boswellic acids (54, 55, and 56), and their respective O-acetyl derivatives (57, 58, and 59) [28]. Ali et al. isolated two new O-acetyl derivatives of pentacyclic triterpenic acids, 3α-acetoxyurs-5:12-dien-24-oic acid (60) and 3-acetoxylup-12 : 20-dien-24-oic acid (61) [29] from Omani frankincense of B. sacra along with four known compounds: commic acid-D (62), 9,11-dehydro-boswellic acid (63), 3- hydroxy-11-oxours-12-ene (64), and 11-hydroxy-3-oxours-12-ene (65) [30]. One ursane-type (66), one oleanane-type (67), namely, olean-11,13(18)-dien-3β,24-diol and 3-oxo-11a-hydroxy-urs-12-ene, respectively, as well as two lupane-type triterpenoids, lupeolic acid (68) and lupeol (69), have been reported by Al-Harrasi et al. from the resin of B. sacra [17]. The frankincense resin of B. sacra was pyrolyzed, and the smoke was trapped into water using a self-developed assembly. Two compounds, namely, 1,2,4a,9-tetramethyl-1,2,3,4,4a,5,6,14b-octahydropicene (70) and 2,9-dimethylpicene (71) were isolated from an n-hexane extract of the smoke-saturated water. Compounds 70 and 71 were evaluated for their antiproliferative activity against MDA-MB-231 breast cancer cells, and it was observed that these pyrolysate products were able to inhibit cancer cell growth [31]. A new ursane-type triterpene, namely, nizwanone (72) was reported from Omani frankincense B. sacra Flueck along with two known compounds papyriogenin B (73) and rigidenol (74) by Al-Harrasi et al. [32]. 11-keto-ursolic acid (75), 3α-hydroxy-8, 24-dien-tirucallic acid (76), 3-O-acetyl-oleanolic acid (77), and 3-O-acetyl-ursulic acid (78) were reported as triterpenoid compounds from a methanolic extract [33]. Similarly, ten more known compounds were isolated from the resin of B. sacra including one triterpene (79) [34]. Structures of isolated triterpenoids from B. sacra are shown in Figure 6.Figure 6
Structure of isolated triterpenoids fromB. sacra.
(a)(b)(c)(d)


### 4.5. Boswellic Acids and Derivatives

The primary active components from the extract ofB. sacra are boswellic acids (BAs). As shown in Figure 7, BAs are a group of oleanane or ursane pentacyclic triterpenoids with carboxylic acid at C- 4 and are divided into two groups, β-BAs (ursane-type) and α-BAs (oleanane-type). Their potency against inflammation, arthritis, ulcerative colitis, chronic colitis, asthma, and hepatitis is well documented. They also have exhibited antimicrobial, antidiabetic, antiviral, and antipruritic activity. One of the important uses of BAs in medicine is as an anti-inflammatory. Boswellic acids suppress leukotriene biosynthesis in neutrophilic granulocytes by nonredox, noncompetitive inhibition of 5-lipoxygenase [32, 35–37]. The pharmacological effects of B. sacra extract are commonly explained by the presence of boswellic acids [36]. Also, the anticancer activity of BAs is remarkable. In this regard, they have activity against cancers including bladder, brain, cervical, colon, colorectal, liver, leukemia, lung, melanoma, meningioma, multiple myeloma, neuroblastoma, ovarian, pancreatic, and prostate [38].Figure 7
Basic structure of triterpenoids in BAs.A new boswellic acid derivative, 11α-ethoxy-β-boswellic acid (EBA; 80), was isolated from Omani frankincense B. sacra Flueck by Al-Harrasi et al. [32]. They also reported the isolation of five boswellic acid derivatives (81–85) from the resin of B. sacra [17]. Similarly, ten more known compounds were isolated from the resin of B. sacra such as nine boswellic acids (86–91 and 92–94). Compounds 87 and 89–91 were found to be significantly active against α-glucosidase with an IC50 value ranging from 15.0 ± 0.84 to 80.3 ± 2.33 μM, while 92 exhibited moderate activity with an IC50 of 799.9 ± 4.98 μM [34]. 11-keto-β-boswellic acid (95), 3-O-acetyl-11-keto-β-boswellic acid (96), α-boswellic acid (97), β-boswellic acid (98), 3-O-acetyl- α-boswellic acid (99), and 3-O-acetyl-β-boswellic acid (100) were isolated as boswellic acid derivatives from a methanolic extract [33]. Structures of the isolated boswellic acids and their derivatives from B. sacra are shown in Figure 8.Figure 8
Structure of isolated boswellic acids and derivatives fromB. sacra.
(a)(b)(c)


## 4.1. Volatile Terpenoids

The chemical composition of the volatile oil ofB. sacra resin has been investigated by GC-FID, GC/MS, and headspace SPME methods that revealed α-pinene (38%) (1), β-ocimene (32.3%; 2), camphene (29.4%; 3), 1-propanol, 2-(2-hydroxypropoxy) (14.4%; 4), limonene (13.36%; 5), and 2- propanol, 1, 1′-oxybis (11.2%; 6) as the main compounds. Also, other compounds such as trans-pinocarveol (3.98%) (7), caryophyllene (3.03%; 8), cis-piperitol (2.53%; 9), β-selinene (2.49%; 10), myrcene (2.38%; 11), α-phellandren-8-ol (2.37%; 12), and delta-cadinene (2.21%; 13) have been reported in significant amounts in the essential oil from B. sacra (21–23) (Figure 3).Figure 3
The chemical composition of the volatile oil ofB. sacra resin.
(a)(b)


## 4.2. Sesquiterpenoids

Investigation ofB. sacra led to the isolation and identification of two oxygenated sesquiterpenes, namely, rotundone (14) and mustakone (15) [24] (Figure 4). These compounds were isolated from the volatile oil of gum resin by sensory-guided fractionation [24].Figure 4
Sesquiterpenoids isolated fromB. sacra.


## 4.3. Diterpenoids

Four new cembrane-type diterpenoids, including boscartins (16–19), together with five known compounds (1S, 3 R, 11S, 12 R, 7E)-1,12-epoxy-4-methylenecembr-7-ene-3,11-diol (20), isoincensole oxide (21), incensole oxide (22), incensole acetate (23), and incensole oxide acetate (24) were isolated fromB. sacra gum resin by Wang et al. In addition, hepatoprotective properties of isolated compounds were studied against HepG2 cells that had been damaged by paracetamol compared to bicyclol (as a positive control). Incensole acetate had a potent hepatoprotective effect at 10 μM. In contrast, boscartin M, isoincensole oxide, incensole oxide, and incensole oxide acetate had a mild hepatoprotective effect at 10 μM [25]. In the other report by Wang et al., the investigation of B. sacra led to the isolation of ten new cembrane-type diterpenes, including boscartins AL-AU (25–34) and five known analogs (35–39). Moreover, biological evaluations revealed that compounds 27, 29, 36, and 37 displayed hepatoprotective activities against paracetamol-induced HepG2 cell damage at 10 μM. Some compounds exhibited moderate neuroprotective activities in two different models [26]. Zhang et al. isolated eight diterpenoids (40–48), namely, sacraoxides A–G from the gum resin of B. sacra and found that sacraoxides E and F had inhibitory activities on nitric oxide (NO) production induced by lipopolysaccharide in RAW264.7 cells with IC50 values of 24.9 ± 1.7 and 36.4 ± 2.9 μM [27]. In another study, five diterpenoids (49–53) including two new prenylaromadendrane-type diterpenoids, and three known analogues, were isolated from the ethanol extract of the gum resin of B. sacra Flueck by Wang et al.. All compounds exhibited notable cytotoxicity against human malignant glioma (U87-MG) cell line against 5-fluorouracil as a positive control [28]. Figure 5 shows the structures of isolated diterpenoids from B. sacra.Figure 5
Structure of isolated diterpenoids fromB. sacra.
(a)(b)(c)(d)


## 4.4. Triterpenoids

B. sacra could be chemically characterized by the occurrence of triterpenoid compounds such as lupeolic acid, α- and β-boswellic acids (54, 55, and 56), and their respective O-acetyl derivatives (57, 58, and 59) [28]. Ali et al. isolated two new O-acetyl derivatives of pentacyclic triterpenic acids, 3α-acetoxyurs-5:12-dien-24-oic acid (60) and 3-acetoxylup-12 : 20-dien-24-oic acid (61) [29] from Omani frankincense of B. sacra along with four known compounds: commic acid-D (62), 9,11-dehydro-boswellic acid (63), 3- hydroxy-11-oxours-12-ene (64), and 11-hydroxy-3-oxours-12-ene (65) [30]. One ursane-type (66), one oleanane-type (67), namely, olean-11,13(18)-dien-3β,24-diol and 3-oxo-11a-hydroxy-urs-12-ene, respectively, as well as two lupane-type triterpenoids, lupeolic acid (68) and lupeol (69), have been reported by Al-Harrasi et al. from the resin of B. sacra [17]. The frankincense resin of B. sacra was pyrolyzed, and the smoke was trapped into water using a self-developed assembly. Two compounds, namely, 1,2,4a,9-tetramethyl-1,2,3,4,4a,5,6,14b-octahydropicene (70) and 2,9-dimethylpicene (71) were isolated from an n-hexane extract of the smoke-saturated water. Compounds 70 and 71 were evaluated for their antiproliferative activity against MDA-MB-231 breast cancer cells, and it was observed that these pyrolysate products were able to inhibit cancer cell growth [31]. A new ursane-type triterpene, namely, nizwanone (72) was reported from Omani frankincense B. sacra Flueck along with two known compounds papyriogenin B (73) and rigidenol (74) by Al-Harrasi et al. [32]. 11-keto-ursolic acid (75), 3α-hydroxy-8, 24-dien-tirucallic acid (76), 3-O-acetyl-oleanolic acid (77), and 3-O-acetyl-ursulic acid (78) were reported as triterpenoid compounds from a methanolic extract [33]. Similarly, ten more known compounds were isolated from the resin of B. sacra including one triterpene (79) [34]. Structures of isolated triterpenoids from B. sacra are shown in Figure 6.Figure 6
Structure of isolated triterpenoids fromB. sacra.
(a)(b)(c)(d)


## 4.5. Boswellic Acids and Derivatives

The primary active components from the extract ofB. sacra are boswellic acids (BAs). As shown in Figure 7, BAs are a group of oleanane or ursane pentacyclic triterpenoids with carboxylic acid at C- 4 and are divided into two groups, β-BAs (ursane-type) and α-BAs (oleanane-type). Their potency against inflammation, arthritis, ulcerative colitis, chronic colitis, asthma, and hepatitis is well documented. They also have exhibited antimicrobial, antidiabetic, antiviral, and antipruritic activity. One of the important uses of BAs in medicine is as an anti-inflammatory. Boswellic acids suppress leukotriene biosynthesis in neutrophilic granulocytes by nonredox, noncompetitive inhibition of 5-lipoxygenase [32, 35–37]. The pharmacological effects of B. sacra extract are commonly explained by the presence of boswellic acids [36]. Also, the anticancer activity of BAs is remarkable. In this regard, they have activity against cancers including bladder, brain, cervical, colon, colorectal, liver, leukemia, lung, melanoma, meningioma, multiple myeloma, neuroblastoma, ovarian, pancreatic, and prostate [38].Figure 7
Basic structure of triterpenoids in BAs.A new boswellic acid derivative, 11α-ethoxy-β-boswellic acid (EBA; 80), was isolated from Omani frankincense B. sacra Flueck by Al-Harrasi et al. [32]. They also reported the isolation of five boswellic acid derivatives (81–85) from the resin of B. sacra [17]. Similarly, ten more known compounds were isolated from the resin of B. sacra such as nine boswellic acids (86–91 and 92–94). Compounds 87 and 89–91 were found to be significantly active against α-glucosidase with an IC50 value ranging from 15.0 ± 0.84 to 80.3 ± 2.33 μM, while 92 exhibited moderate activity with an IC50 of 799.9 ± 4.98 μM [34]. 11-keto-β-boswellic acid (95), 3-O-acetyl-11-keto-β-boswellic acid (96), α-boswellic acid (97), β-boswellic acid (98), 3-O-acetyl- α-boswellic acid (99), and 3-O-acetyl-β-boswellic acid (100) were isolated as boswellic acid derivatives from a methanolic extract [33]. Structures of the isolated boswellic acids and their derivatives from B. sacra are shown in Figure 8.Figure 8
Structure of isolated boswellic acids and derivatives fromB. sacra.
(a)(b)(c)


## 5. Standardization

The used part of the plant is an oleo gum resin that is easily found in herbal stores. For standardization of the oleo gum resin, boswellic acids and their derivatives have been accounted as standard markers [1].


## 6.B. sacra Products

There areB. sacra essential oils as liquid form, for example in 10 ml bottles (Figure 9).Figure 9
FrankincenseB. sacra essential oil (https://www.amazon.com).


## 7. Bioactivities and Professional Pharmaceutical Applications

### 7.1. Anticancer Activity

The essential oil ofB. sacra has been found to induce breast cancer cell-specific cytotoxicity. B. sacra essential oil can suppress tumor aggressiveness in drug-resistant and cultured metastasized human breast cancer cells. B. sacra showed proapoptotic, antiproliferative, and anti-invasive properties in human breast cancer cell lines [39]. Essential oil from B. sacra suppresses viability and induces apoptosis in human pancreatic cancer cell lines. Frankincense essential oil activates the caspase-dependent apoptotic pathway, Akt and Erk1/2 signaling molecules and suppresses the levels of cyclin D1 (an important cell cycle regulator) expression in human pancreatic cancer cells. Essential oil of B. sacra gum resin has been suggested as a useful alternative therapeutic agent for patients with pancreatic adenocarcinoma, the major type of aggressive pancreatic cancer [40]. Besides, another study proposed that the essential oil was potent against colon cancer cells such as CD133+ and CD133-Colo-320 cells, and it was also considered that essential oil obtained from B. sacra led to a reduction of β-catenin signaling molecules which have a vital role in cancer cell proliferation [41]. In a case report study, oral administration of B. sacra gum resin was reported to be effective in urothelial cell carcinoma [42].


### 7.2. Analgesic Effects

The analgesic effects of crude extracts and fractions of Omani frankincense obtained fromB. sacra were studied in two mouse models of pain. Administration of the extract, essential oils, and subfractions from the resin of B. sacra in acetic acid-induced writhing and formalin tests demonstrated the antinociceptive properties of B. sacra as a traditional medicinal plant [16].


### 7.3. Hepatoprotective Effects

Biological evaluations of cembrane-type diterpenes isolated fromB. sacra showed that some of these compounds exhibited obvious hepatoprotective effects against paracetamol-induced HepG2 cell damage [26]. Administration of the water extract of oleo-gum-resin of B. sacra in rats demonstrated that this plant possesses hepatoprotective activity against carbon tetrachloride-induced acute and chronic hepatic damage [43].


### 7.4. Antimicrobial Effects

Essential oils fromB. sacra have been traditionally used to treat microbial and fungal infections. In vitro study of monoterpenoids of B. sacra essential oil showed antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Propionibacterium acnes. Frankincense essential oils also exhibited a significant antifungal effect against Candida albicans and Malassezia furfur [2].The inhibitory effect of different concentrations ofB. sacra resin, leaf extract, and essential oil has been evaluated on the growth and production of aflatoxins by Aspergillus flavus and Aspergillus parasiticus. This study revealed that the resin powder and essential oil of B. sacra markedly reduce aflatoxin production. Therefore, the resin powder and essential oil of B. sacra can be recommended as safe natural food preservatives to increase the shelf life of food and feed products with reference to their antimicrobial and aflatoxin inhibitory activities [44]. In another study, it was found that B. sacra oleoresin extract has a promising antibacterial and antibiofilm activity against Porphyromonas gingivalis [45]. Moreover, the potential of B. sacra extract was evaluated against a number of human gastrointestinal bacterial pathogens and autoimmune disease-stimulating bacteria in combination with conventional antibiotics. In this regard, the obtained results confirmed that the combination of conventional antibiotics with B. sacra extracts exhibited extremely higher activity than that of the individual components alone [46]. Recently, a research study revealed that B. sacra essential oil exhibited promising antifungal activity against some fungi species which lead to strawberry rot such as Botrytis cinerea, Aspergillus niger, and Rhizopus stolonifera [47].


### 7.5. Antioxidant Effects

It has been shown that the essential oil ofB. sacra gum resin has a strong antioxidant effect in the DPPH radical scavenging method. However, its antioxidant activity is lower as compared to the antioxidant property of ascorbic acid [48]. The effect of B. sacra oleo gum resin extract has been studied against testicular toxicity in rats. The extract of this plant decreased the gene expression of HSP70 (heat shock protein-70), GSTPi (glutathione-s-transferase-Pi), and IGFBP3 (insulin-like growth factor binding protein-3) in the testes. The result of this study suggests that the antioxidant effect of B. sacra may protect the testes against several toxicants through the inhibition of free radicals [1]. Moreover, recent evidence indicated that incorporation of B. sacra essential oil into nanoparticles enhanced the efficacy of some pharmacological properties such as antioxidant activity [49].


### 7.6. Anti-Alzheimer Effect

The genusBoswellia has been suggested to cure or prevent neurodegenerative disorders through anti-inflammatory, antioxidative, antiamyloidogenic, and antiapoptotic effects [50]. Evaluating the effect of essential oil obtained from resins of B. sacra showed that frankincense essential oil can significantly inhibit the acetylcholinesterase enzyme (AChE). Inhibition of AChE leads to increased acetylcholine levels in the brain and improves memory in Alzheimer’s disease patients. Therefore, B. sacra as a medicinal plant may protect against memory loss from Alzheimer’s disease [51].


### 7.7. Anti-Inflammatory Effect

The anti-inflammatory effects of essential oil fromB. sacra have been studied on an ovalbumin-induced allergic asthma mouse model. The results of this evaluation showed that inhalation of B. sacra essential oil has a potential therapeutic effect in allergic airway inflammation through increasing Th1 cytokine (IFN-γ) and decreasing Th2 cytokines (IL-4, IL-5, and IL-13) levels [52].


### 7.8. Antiseizure Effect

More recently, Wolfender and coworkers reported a comprehensive study on the antiseizure activity of resin ofB. sacra. Results of this study demonstrated that among all isolated terpenoids, β-boswellic acid which belongs to triterpenoid derivatives was the most active and resulted in a 90% reduction of pentylenetetrazole (PTZ)-induced seizures at 100 μg/mL [53]. The pharmacological activity of B. sacra gum resin and its phytochemicals is summarized in Table 1.Table 1
The pharmacological profiles ofB. sacra gum resin and its phytochemicals.
ActivityExtract/compoundsDose and treatment periodModelResultsMechanismReferenceAnticancerEssential oil, 11-keto-b-boswellic acid100μl, treat, 24 hT47D, MCF7, MDA-MB-231, MCF10-2AReduced cell viability, elevated cell death, suppressed cellular network formation, disrupted spheroid development of breast cancer cells, caused the breakdown of multicellular tumor spheroids (T47D), no cytotoxity on MCF10-2A, inhibited caspases in the MDA-MB-231, anti-invasive(+) cleaved caspase-3(−) caspase-8 p43/p41, caspase-9 p37/p35, pro-caspase-3, Akt, PARP, ERK1/2(Thr202/Tyr204), cdk4, cyclin D1[32, 35, 39]Essential oil, 11-keto-b-boswellic acid100μl, treat, 24 hMIA PaCa-2, Panc-28, BxPC-3, DANG[35, 40]Essential oil30μl, SQI, 3 daysHeterotopic xenograft mouseSuppressed viability, reduced cell growth, antiproliferative, antiapoptotic, induced cytotoxicity, reduced tumor volume, anti-tumor(+) Caspase-3 activation, apoptosis(−) cyclin D1, cdk4, caspase-8 p43/p41, caspase-9p37/p35, procaspase-3, PARP, Akt ser (473), ERK1/2(Thr202/Tyr204), proliferating[42]3 mL daily, oral, 25 monthsA 52-year-old male with urothelial cell carcinoma(+) No(−) AST, ALT, bilirubin, creatinine, BUNMethanolic extract, Boswellic acids6.25–100μg/ml, incubated, 24 and 48 hHuman pancreatic (PANC1), colon (HCT116), lung adenocarcinoma (MOR), breast cancer MCF7 and MDA-MB-231, the human prostate cancer LNCaP, and SerBob cell linesInhibited tumor growth, anticancer, improved kidney and liver function, decreased tumor volume(+)-(−)-[55]Anti-tumor cytotoxicity, inhibited cell viabilityAnti-inflammatoryEssential oil0.3%, inhalation, 8 weeksOvalbumin-induced BALB/c mice allergic asthmaReduced eosinophils, decreased goblet cell hyperplasia, inhibited hyperresponsiveness, anti-inflammatory, immunity(+) Th1, IFN-γ, (−) Th2, IL-4, IL-5, IL-13, CD4+, CD3+/CCR3+, B220+/CD23+[51]AnalgesicMethanolic extract, essential oils, subfractions300 mg/kg, orallyAcetic acid-induced writhes and formalin-induced pain in miceAnalgesic, inhibited writhes, inhibited licking, and biting response(+) No(−) No[32]AntimicrobialEssential oil0.1 ml, treat, 24 hStaphylococcus aureus (ATCC 25923; ATCC 6538), Pseudomonas aeruginosa (ATCC 15442; ATCC 9027), Candida albicans (ATCC 10231), Malassezia furfur (ATCC 14521)Antifungal, antimicrobial(+) No(−) No[2]Resin essential oil2.5, 5, 7.5, 10 g/100 ml1, 2, 3, 4 ml/100 ml, incubated, 15 daysAspergillus flavus (SQU21), Aspergillus parasiticus (CBS921.7)Inhibited microbial and aflatoxins, enhanced fungal growth, inhibited aflatoxin biosynthesis and secretion pathway(+) Mycelial dry weights(−) Inhibited fungal growth and aflatoxins production[4]Anti-AlzheimerEssential oil, (+) pinene0.5 mg/ml, incubated, 15 minAChE, Jack bean ureaseAnti-Alzheimer’s disease, protected stomach ulcers(+) No(−) AChE, urease enzyme[50]Diterpenoids of ethanolic extract10μM, incubated,1 hGlutamate-induced toxicity rat cortical neurons, human neuroblastoma SK-N-SH cellsAChE modelNeuroprotection(+) No(−) No[26]Boswellic acids, ethyl acetate fraction0.75 mM, 0.23, 0.46,0.93 mg/ml, incubated, 20 minAnti-Alzheimer’s disease(+) No(−) AChE[18]HepatoprotectiveDiterpenoids of ethanolic extract10μM, incubated,1 hParacetamol-induced HepG2 cellsHepatoprotective, inhibited damage(+) No(−) No[25, 26]Methanolic extract250, 500 and 1000 mg/kg, oraly, 28-daySafety and toxicological studies on ratReduced mean cellular hemoglobin (MCH), induced hypochromic normocytic anemia, may not be safe to use(+)-(−)-[55]Wound healingMethanolic extracts10–20μg/ml, incubated, 24 hH2O2- induced injury on adult human dermal fibroblastsImproved proliferation, migration, and wound healing process(+) pERK/ERK(−) ROS[56]Note. (+): increased or activated; (−): decreased or inhibited.


## 7.1. Anticancer Activity

The essential oil ofB. sacra has been found to induce breast cancer cell-specific cytotoxicity. B. sacra essential oil can suppress tumor aggressiveness in drug-resistant and cultured metastasized human breast cancer cells. B. sacra showed proapoptotic, antiproliferative, and anti-invasive properties in human breast cancer cell lines [39]. Essential oil from B. sacra suppresses viability and induces apoptosis in human pancreatic cancer cell lines. Frankincense essential oil activates the caspase-dependent apoptotic pathway, Akt and Erk1/2 signaling molecules and suppresses the levels of cyclin D1 (an important cell cycle regulator) expression in human pancreatic cancer cells. Essential oil of B. sacra gum resin has been suggested as a useful alternative therapeutic agent for patients with pancreatic adenocarcinoma, the major type of aggressive pancreatic cancer [40]. Besides, another study proposed that the essential oil was potent against colon cancer cells such as CD133+ and CD133-Colo-320 cells, and it was also considered that essential oil obtained from B. sacra led to a reduction of β-catenin signaling molecules which have a vital role in cancer cell proliferation [41]. In a case report study, oral administration of B. sacra gum resin was reported to be effective in urothelial cell carcinoma [42].


## 7.2. Analgesic Effects

The analgesic effects of crude extracts and fractions of Omani frankincense obtained fromB. sacra were studied in two mouse models of pain. Administration of the extract, essential oils, and subfractions from the resin of B. sacra in acetic acid-induced writhing and formalin tests demonstrated the antinociceptive properties of B. sacra as a traditional medicinal plant [16].


## 7.3. Hepatoprotective Effects

Biological evaluations of cembrane-type diterpenes isolated fromB. sacra showed that some of these compounds exhibited obvious hepatoprotective effects against paracetamol-induced HepG2 cell damage [26]. Administration of the water extract of oleo-gum-resin of B. sacra in rats demonstrated that this plant possesses hepatoprotective activity against carbon tetrachloride-induced acute and chronic hepatic damage [43].


## 7.4. Antimicrobial Effects

Essential oils fromB. sacra have been traditionally used to treat microbial and fungal infections. In vitro study of monoterpenoids of B. sacra essential oil showed antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Propionibacterium acnes. Frankincense essential oils also exhibited a significant antifungal effect against Candida albicans and Malassezia furfur [2].The inhibitory effect of different concentrations ofB. sacra resin, leaf extract, and essential oil has been evaluated on the growth and production of aflatoxins by Aspergillus flavus and Aspergillus parasiticus. This study revealed that the resin powder and essential oil of B. sacra markedly reduce aflatoxin production. Therefore, the resin powder and essential oil of B. sacra can be recommended as safe natural food preservatives to increase the shelf life of food and feed products with reference to their antimicrobial and aflatoxin inhibitory activities [44]. In another study, it was found that B. sacra oleoresin extract has a promising antibacterial and antibiofilm activity against Porphyromonas gingivalis [45]. Moreover, the potential of B. sacra extract was evaluated against a number of human gastrointestinal bacterial pathogens and autoimmune disease-stimulating bacteria in combination with conventional antibiotics. In this regard, the obtained results confirmed that the combination of conventional antibiotics with B. sacra extracts exhibited extremely higher activity than that of the individual components alone [46]. Recently, a research study revealed that B. sacra essential oil exhibited promising antifungal activity against some fungi species which lead to strawberry rot such as Botrytis cinerea, Aspergillus niger, and Rhizopus stolonifera [47].


## 7.5. Antioxidant Effects

It has been shown that the essential oil ofB. sacra gum resin has a strong antioxidant effect in the DPPH radical scavenging method. However, its antioxidant activity is lower as compared to the antioxidant property of ascorbic acid [48]. The effect of B. sacra oleo gum resin extract has been studied against testicular toxicity in rats. The extract of this plant decreased the gene expression of HSP70 (heat shock protein-70), GSTPi (glutathione-s-transferase-Pi), and IGFBP3 (insulin-like growth factor binding protein-3) in the testes. The result of this study suggests that the antioxidant effect of B. sacra may protect the testes against several toxicants through the inhibition of free radicals [1]. Moreover, recent evidence indicated that incorporation of B. sacra essential oil into nanoparticles enhanced the efficacy of some pharmacological properties such as antioxidant activity [49].


## 7.6. Anti-Alzheimer Effect

The genusBoswellia has been suggested to cure or prevent neurodegenerative disorders through anti-inflammatory, antioxidative, antiamyloidogenic, and antiapoptotic effects [50]. Evaluating the effect of essential oil obtained from resins of B. sacra showed that frankincense essential oil can significantly inhibit the acetylcholinesterase enzyme (AChE). Inhibition of AChE leads to increased acetylcholine levels in the brain and improves memory in Alzheimer’s disease patients. Therefore, B. sacra as a medicinal plant may protect against memory loss from Alzheimer’s disease [51].


## 7.7. Anti-Inflammatory Effect

The anti-inflammatory effects of essential oil fromB. sacra have been studied on an ovalbumin-induced allergic asthma mouse model. The results of this evaluation showed that inhalation of B. sacra essential oil has a potential therapeutic effect in allergic airway inflammation through increasing Th1 cytokine (IFN-γ) and decreasing Th2 cytokines (IL-4, IL-5, and IL-13) levels [52].


## 7.8. Antiseizure Effect

More recently, Wolfender and coworkers reported a comprehensive study on the antiseizure activity of resin ofB. sacra. Results of this study demonstrated that among all isolated terpenoids, β-boswellic acid which belongs to triterpenoid derivatives was the most active and resulted in a 90% reduction of pentylenetetrazole (PTZ)-induced seizures at 100 μg/mL [53]. The pharmacological activity of B. sacra gum resin and its phytochemicals is summarized in Table 1.Table 1
The pharmacological profiles ofB. sacra gum resin and its phytochemicals.
ActivityExtract/compoundsDose and treatment periodModelResultsMechanismReferenceAnticancerEssential oil, 11-keto-b-boswellic acid100μl, treat, 24 hT47D, MCF7, MDA-MB-231, MCF10-2AReduced cell viability, elevated cell death, suppressed cellular network formation, disrupted spheroid development of breast cancer cells, caused the breakdown of multicellular tumor spheroids (T47D), no cytotoxity on MCF10-2A, inhibited caspases in the MDA-MB-231, anti-invasive(+) cleaved caspase-3(−) caspase-8 p43/p41, caspase-9 p37/p35, pro-caspase-3, Akt, PARP, ERK1/2(Thr202/Tyr204), cdk4, cyclin D1[32, 35, 39]Essential oil, 11-keto-b-boswellic acid100μl, treat, 24 hMIA PaCa-2, Panc-28, BxPC-3, DANG[35, 40]Essential oil30μl, SQI, 3 daysHeterotopic xenograft mouseSuppressed viability, reduced cell growth, antiproliferative, antiapoptotic, induced cytotoxicity, reduced tumor volume, anti-tumor(+) Caspase-3 activation, apoptosis(−) cyclin D1, cdk4, caspase-8 p43/p41, caspase-9p37/p35, procaspase-3, PARP, Akt ser (473), ERK1/2(Thr202/Tyr204), proliferating[42]3 mL daily, oral, 25 monthsA 52-year-old male with urothelial cell carcinoma(+) No(−) AST, ALT, bilirubin, creatinine, BUNMethanolic extract, Boswellic acids6.25–100μg/ml, incubated, 24 and 48 hHuman pancreatic (PANC1), colon (HCT116), lung adenocarcinoma (MOR), breast cancer MCF7 and MDA-MB-231, the human prostate cancer LNCaP, and SerBob cell linesInhibited tumor growth, anticancer, improved kidney and liver function, decreased tumor volume(+)-(−)-[55]Anti-tumor cytotoxicity, inhibited cell viabilityAnti-inflammatoryEssential oil0.3%, inhalation, 8 weeksOvalbumin-induced BALB/c mice allergic asthmaReduced eosinophils, decreased goblet cell hyperplasia, inhibited hyperresponsiveness, anti-inflammatory, immunity(+) Th1, IFN-γ, (−) Th2, IL-4, IL-5, IL-13, CD4+, CD3+/CCR3+, B220+/CD23+[51]AnalgesicMethanolic extract, essential oils, subfractions300 mg/kg, orallyAcetic acid-induced writhes and formalin-induced pain in miceAnalgesic, inhibited writhes, inhibited licking, and biting response(+) No(−) No[32]AntimicrobialEssential oil0.1 ml, treat, 24 hStaphylococcus aureus (ATCC 25923; ATCC 6538), Pseudomonas aeruginosa (ATCC 15442; ATCC 9027), Candida albicans (ATCC 10231), Malassezia furfur (ATCC 14521)Antifungal, antimicrobial(+) No(−) No[2]Resin essential oil2.5, 5, 7.5, 10 g/100 ml1, 2, 3, 4 ml/100 ml, incubated, 15 daysAspergillus flavus (SQU21), Aspergillus parasiticus (CBS921.7)Inhibited microbial and aflatoxins, enhanced fungal growth, inhibited aflatoxin biosynthesis and secretion pathway(+) Mycelial dry weights(−) Inhibited fungal growth and aflatoxins production[4]Anti-AlzheimerEssential oil, (+) pinene0.5 mg/ml, incubated, 15 minAChE, Jack bean ureaseAnti-Alzheimer’s disease, protected stomach ulcers(+) No(−) AChE, urease enzyme[50]Diterpenoids of ethanolic extract10μM, incubated,1 hGlutamate-induced toxicity rat cortical neurons, human neuroblastoma SK-N-SH cellsAChE modelNeuroprotection(+) No(−) No[26]Boswellic acids, ethyl acetate fraction0.75 mM, 0.23, 0.46,0.93 mg/ml, incubated, 20 minAnti-Alzheimer’s disease(+) No(−) AChE[18]HepatoprotectiveDiterpenoids of ethanolic extract10μM, incubated,1 hParacetamol-induced HepG2 cellsHepatoprotective, inhibited damage(+) No(−) No[25, 26]Methanolic extract250, 500 and 1000 mg/kg, oraly, 28-daySafety and toxicological studies on ratReduced mean cellular hemoglobin (MCH), induced hypochromic normocytic anemia, may not be safe to use(+)-(−)-[55]Wound healingMethanolic extracts10–20μg/ml, incubated, 24 hH2O2- induced injury on adult human dermal fibroblastsImproved proliferation, migration, and wound healing process(+) pERK/ERK(−) ROS[56]Note. (+): increased or activated; (−): decreased or inhibited.


## 8. Future Perspectives

It is strongly believed that detailed information on the phytochemical and biological activities ofB. sacra, as presented in this review, provides certain evidence for the use of this plant in different medicines and future pharmaceutical studies. It seems that the oleo gum resin of B. sacra is an important resource in the appearance of new drugs and herbal medicine formulations. However, more determining the pharmacological activity of B. sacra, especially in future clinical studies, is suggested. It is better that should have been a correlation between traditional uses of B. sacra and new studies. Further studies are needed to isolate the active compounds for the observed pharmacological activities. Also, the herbal medicine formulation should be prepared and standardized on the basis of the active compounds. Further studies should be focused on the mechanisms behind the anti-inflammatory and memory improvement activities and those biological activities that have been reported traditionally.


## 9. Conclusion

This present work was designed to show thatB. sacra is a valuable medicinal plant and an interesting subject to researchers. Many studies have indicated that B. sacra is a rich source of terpenoid compounds, especially triterpenoids, responsible for a wide range of biological activities. Although different studies have investigated these, there is no data on the clinical effectiveness of B. sacra. The findings of this review study on B. sacra suggested that clinical trial studies should be undertaken to explore the anti-inflammatory activity and memory improvement effects. B. sacra has a long and brilliant history in traditional medicine, and that is why clinical trial studies are strongly recommended for its drug development.



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*Source: 8779676-2022-02-18.xml*