| Introduction |
| Mechanism
of Anti-inflammatory Action |
| Pharmacological Effects
of Boswellic Acids |
| Summary
of Patents on Boswellic Acids |
| References |
| Glossary |
| Boswellin-Booklet |
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| H O M E |
Pharmacological Effects of
Boswellic Acids
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a) Apoptosis Induction by AKBA
Apoptosis or programmed cell death (PCD) is an essential process in normal animal development and in the renewal of cell populations in the human body.12,13 Thus, it may be important in limiting the growth of cancerous tumors.16 Since cytostatic drugs which influence the mechanisms of PCD have limited use due to the severe side effects they cause, compounds which induce PCD with low toxicity are being sought.14 A previous study15 showed that 5-lipoxygenase inhibitors induced apoptosis and inhibited cell proliferation in tumor cells. Thus, AKBA was investigated as a cytotoxic agent.16
The effects of AKBA were studied in two human cancer cell lines, HL-60 and CCRF-CEM. AKBA reduced the viability and proliferation of the leukemic cells from both lines in a dose-dependent manner (IC50 value = 30 µM), unlike its structural analog amyrin. Morphological changes of the cells detected by light microscopy and flow cytometry indicated that AKBA induces apoptotic cell death. Since the cancerous cells are not capable of producing 5-lipoxygenase metabolites unless they are differentiated with certain agents, another mechanism is responsible. Inhibition of DNA topoisomerase I, an enzyme that can mediate structural transitions in DNA and chromatin by its ability to break and rejoin double strands of DNA, may explain AKBA’s apoptotic effects.16,17
Wildfeurer and coworkers18 studied Boswellia serrata as a leukotriene synthesis inhibitor of intact human PMNLs and as an herbal medicine for guinea pigs suffering from experimental autoimmune encephalomyelitis (EAE). Mixed acetyl boswellic acids significantly inhibited the ionophore-stimulated release of leukotrienes LTB4 (IC50 = 8.48 m g/ml) and LTC4 (IC50 = 8.43 m g/ml) from the PMNLs. Purified 3-O-acetyl-11-keto-b-boswellic acid was approximately 3 times more potent an inhibitor LTB4 (IC50 = 2.53 m g/ml) and LTC4 (IC50 = 2.26 m g/ml) than the extracted acetyl boswellic acid mixture.
Experimental autoimmune encephalomyelitis (EAE) in guinea pigs is an accepted animal model for multiple sclerosis (MS) due to the similarities between both conditions concerning demyelination and perivascular mononuclear cell infiltration observed in the central nervous system (CNS). The control animals progressively deteriorated, while the clinical symptoms of the animals repeatedly treated with the acetyl boswellic acid extract (20 mg/kg i.p.) subsided between days 11 and 21. At the end of the experiment (day 21), 11 out of 20 animals survived in the treated group compared to 6 out of 20 in the control group.18
Shao and coworkers19 examined the antitumor activity of the four major pentacyclic triterpene acids of Boswellia serrata (the b-boswellic acids), b-boswellic acid (compound 1), 3-O-acetyl-b-boswellic acid (compound 2), 11-keto-b-boswellic acid (compound 3), and 3-O-acetyl-11-keto-b-boswellic acid (compound 4), in human leukemia HL-60 cells in culture. Cell growth was monitored by measuring the rates of [3H]-thymidine, [3H]-uridine, and [3H]-leucine incorporation in DNA, RNA, and protein synthesized in the HL-60 cells, respectively. All the compounds exhibited inhibitory activity in a dose-dependent manner as shown in Figure 5. Comparison of the IC50 values indicated that the order of inhibitory activity for the compounds was 3-O-acetyl-11-keto-b-boswellic acid > 11-keto-b-boswellic acid > 3-O-acetyl-b-boswellic acid > b-boswellic acid. The data showed that AKBA’s inhibitory action on DNA synthesis was irreversible. In addition, this compound significantly inhibited cellular growth by 54.5, 71.8, and 98.6% without affecting cell viability at concentrations of 1, 4, and 16 mM, respectively. In comparison to a cell viability of 97.0% for the control, cell viability was maintained at 96.8, 96.5, and 96.7%, for HL-60 cells treated with 1, 4, and 16 m M of AKBA, respectively. It is suspected that inhibition of cancerous cell growth may be associated with the interference of cell proliferation rather than direct cytotoxicity.19
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Figure 5. Inhibitory effects of compounds 1-4 on DNA (top), RNA (middle), and protein (bottom) synthesis in HL-60 cells. (ref. 19)
Boswellia carterii Birdw., another species of Boswellia, was found to induce differentiation in myeloid leukemia cells (HL-60, U937, and ML-1) and inhibit the growth of erythroid leukemia cells (DS-19 and K562). The authors have identified the compound responsible for the anticancer properties of Boswellia carterri as BC-4 or boswellic acid acetate. BC-4 consists of its a and b forms (Figure 6) and is a potential agent for cancer treatment due to its powerful growth inhibitory effects and cancer cell differentiation induction in human leukemia cells.20
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Figure 6. Chemical structure of BC-4
Based on cell morphology and NBT (nitroblue tetrazolium) reduction, BC-4 induced monocytic differentiation in myeloid leukemia cells in all three cell lines. The differentiation-inducing effect was dose and time-dependent. As shown in Figure 7, approximately 50% of the ML-1, U937, and HL-60 cells obtained NBT reduction without losing cell viability when dosed with 10 µg/ml of BC-4. At a higher dose (12.5 µg/ml), NBT reduction was observed in about 90% of ML-1 and U937 cells and 75% of HL-60 cells.20
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Figure 7. Cell viability and NBT reduction in human leukemia cells (myeloid) treated with BC-4.
Differentiation was also identified by monocytic morphologic maturation accompanied by increased cytoplasm and polygonal nuclei which were observed in more than 90% of the cells treated with 12.5 µg/ml BC-4. In addition, another indication of differentiation, significant increases in the specific and non-specific esterase activities, were observed.20
Subsequent tests revealed that BC-4 is a specific myeloid leukemia differentiation inducer, and that its effects are dose-dependent, showing growth inhibition without substantial loss of cell viability at BC-4 concentrations up to 15 µg/ml and cell death at concentrations of 20 µg/ml. In fact, morphological studies conducted on HL-60 cells indicated that BC-4 is a noteworthy apoptosis-inducer at concentrations greater than 15 µg/ml. In contrast to myeloid cells, BC-4 did not induce differentiation in the erythroid cells but produced an antiproliferative effect instead.20
Twenty-nine patients with malignant glioma (tumor of non-nervous cells in the central nervous system) were administered high doses of boswellic acids extract in tablet form (3 x 1200 mg/day) for a period of seven days. Although no effects on tumor proliferation were observed, peritumoral brain edema was reduced by 33%. In addition, neurological symptoms were markedly improved.24
Ulcerative colitis is a chronic inflammatory condition which affects the rectal mucosa, left colon, and in some cases the entire colon and is characterized by rectal bleeding and diarrhea. Thirty four patients suffering from grade II and grade III ulcerative colitis were treated with 350 mg of a Boswellia serrata gum resin preparation three times a day for 6 weeks. For comparison 8 patients with the same conditions were treated with the conventional medicine, sulfasalazine, in 3 g daily doses. The effectiveness of the treatment was determined by evaluating the stool properties, histopathology and scan microscopy of rectal biopsies, and blood parameters (Hb, serum iron, calcium, phosphorous, proteins, total leukocytes, and eosinophils) of the patients. All parameters tested improved after treatment with the gum resin. In comparison to the sulfasalazine-treated group, 82% of patients treated with Boswellia serrata went into remission. Of those given sulfasalazine, the remission rate was 75%.25
Boswellia serrata is useful in treating bronchial asthma. A double-blind, placebo-controlled study was conducted on 40 asthma sufferers (23 males and 17 females) ranging in age from 18 to 75 years old. The mean duration of illness for the patients was 9.58 ± 6.07 years. After treatment with 300 mg of the gum resin three times a day for 6 weeks, 70% of the patients showed improvement compared to 27% of the patients in the control group treated with 300 mg of lactose three times a day for 6 weeks. Disappearance of physical symptoms, dyspnea, number of attacks, increase in forced expiratory volume (FEV1) and peak expiratory flow rate (PEFR), and a decrease in the eosinophilic count and erythrocyte sedimentation rate (ESR) were reported for patients who received the Boswellia serrata extract.26
© Sabinsa Corporation 2001