Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells

Division of Hematology/Oncology, Department of Medicine, Box 1178, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6547. .
Molecular Cancer Therapeutics (Impact Factor: 5.68). 04/2005; 4(3):381-8. DOI: 10.1158/1535-7163.MCT-03-0266
Source: PubMed


The mechanism of the cytotoxic effect of boswellic acid acetate, a 1:1 mixture of alpha-boswellic acid acetate and beta-boswellic acid acetate, isolated from Boswellia carterri Birdw on myeloid leukemia cells was investigated in six human myeloid leukemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). Morphologic and DNA fragmentation assays indicated that the cytotoxic effect of boswellic acid acetate was mediated by induction of apoptosis. More than 50% of the cells underwent apoptosis after treatment with 20 mug/mL boswellic acid for 24 hours. This apoptotic process was p53 independent. The levels of apoptosis-related proteins Bcl-2, Bax, and Bcl-XL were not modulated by boswellic acid acetate. Boswellic acid acetate induced Bid cleavage and decreased mitochondrial membrane potential without production of hydrogen peroxide. A general caspase inhibitor (Z-VAD-FMK) and a specific caspase-8 inhibitor II (Z-IETD-FMK) blocked boswellic acid acetate-induced apoptosis. The mRNAs of death receptors 4 and 5 (DR4 and DR5) were induced in leukemia cells undergoing apoptosis after boswellic acid acetate treatment. These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5, and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid, which in turn decreases mitochondria membrane potential.

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    • "To study the possible mechanism involved in the anticancer activity of B. serrata extract and combination, we evaluated induction of apoptosis of HepG2 cells by measuring caspase-3 activity. Induction of caspase-3 has been demonstrated following boswellic acid treatment in colon cancer [15], lukemic cells [31], and prostate cancer cells [32]. Induction of apoptosis and expression of cleaved caspase 3 was significantly (P < 0.001) induced in vitro by combination treatment compared to B. serrata or DOX alone (Figure 3). "
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    ABSTRACT: The study investigated the growth-inhibiting and apoptosis mediating effects of B. serrata extract as monotherapy and combination therapy with DOX against hepatocellular carcinoma cell lines. Boswellic acid rich fraction of B. serrata extract was prepared. MTT assay on HepG2 and Hep3B cells was carried out using B. serrata alone and in combination with DOX. Further, caspase-3 activity, TNF-α level, and IL-6 level were estimated. Isobolographic analysis was carried out to evaluate the effect of combination therapy. Additionally, protective effect of B. serrata extract on DOX induced hepatic toxicity was also evaluated in Wistar rats. B. serrata extract inhibited growth of HepG2 (IC50 value of 21.21 ± 0.92 μg/mL) as well as HepG2 (IC50 value of 18.65 ± 0.71 μg/mL). DOX inhibited growth in HepG2 and Hep3B cells with an IC50 of 1.06 ± 0.04 μg/mL and 1.92 ± 0.09 μg/mL. Isobolographic analysis showed combination index (CI) of DOX and B. serrata extract of 0.53 ± 0.03 to 0.79 ± 0.02 suggesting synergistic behavior against the two cell lines. B. serrata extract also caused dose dependent increase in caspase-3 activity, TNF-α level, and IL-6 level which was higher (P < 0.001) with DOX (1 μM) and B. serrata extract (20 μg/mL) combination. B. serrata extract also protected Wistar rats against DOX induced hepatic toxicity.
    Full-text · Article · Aug 2014 · BioMed Research International
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    • "The studies have shown that boswellic acids are potent apoptotic agents to cancer cells. The boswellic acid acetate seems to induce apoptosis in six human myeloid leukemia cell lines through a caspase-mediated pathway which is activated by the induction of the death receptors 4 and 5 (DR4, DR5).[27] The anticancer activity of AKBA is attributed to the inhibitory effect on the lipoxygenases, leading to the inhibition of cell proliferation and induction of apoptosis in tumor cells.[15] "
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    ABSTRACT: Frankincense ( Rǔ Xiāng; Boswellia Species), the resinous extract from the trees of the genus Boswellia, has been used for centuries in cultural ceremonies, as a cosmetic agent, and as a traditional medicine to treat a variety of ailments, especially inflammatory diseases including asthma, arthritis, cerebral edema, chronic pain syndrome, chronic bowel diseases, cancer, and some other illnesses. Boswellic acids are the active compounds of frankincense and AKBA (3-O-acetyl-11-keto-β-boswellic acid) is the most important and effective acid among them. Some studies have shown that the use of frankincense can also improve the learning and enhance the memory in animals and human beings. It seems that frankincense might have a potential ability to be used as an alternative natural medicine not only for chronic and inflammatory diseases but also for brain and memory disorders.
    Full-text · Article · Mar 2013 · Journal of Traditional and Complementary Medicine
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    • "Purified boswellic acids exhibit potent cytotoxic activities against cultured human neuroblastoma cell lines (IMR-32, NB-39, and SK-N-SH) [26], and inhibit DNA, RNA, and protein synthesis in human leukemia HL-60 cells [27]. Furthermore, boswellic acids including acetyl-11-keto-β-boswellic acid (AKBA) have been shown to possess anti-tumor activity against a variety of human cancer cell lines including meningioma cells [28], leukemia cells [27,29], hepatoma cells [30], melanoma cells, fibrosarcoma cells [31], colon cancer cells [32,33], prostate cancer cells [34,35], and pancreatic cancer cells [36,37] in both in vitro and in vivo conditions. "
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    ABSTRACT: Background Regardless of the availability of therapeutic options, the overall 5-year survival for patients diagnosed with pancreatic cancer remains less than 5%. Gum resins from Boswellia species, also known as frankincense, have been used as a major ingredient in Ayurvedic and Chinese medicine to treat a variety of health-related conditions. Both frankincense chemical extracts and essential oil prepared from Boswellia species gum resins exhibit anti-neoplastic activity, and have been investigated as potential anti-cancer agents. The goals of this study are to identify optimal condition for preparing frankincense essential oil that possesses potent anti-tumor activity, and to evaluate the activity in both cultured human pancreatic cancer cells and a xenograft mouse cancer model. Methods Boswellia sacra gum resins were hydrodistilled at 78°C; and essential oil distillate fractions were collected at different durations (Fraction I at 0–2 h, Fraction II at 8–10 h, and Fraction III at 11–12 h). Hydrodistillation of the second half of gum resins was performed at 100°C; and distillate was collected at 11–12 h (Fraction IV). Chemical compositions were identified by gas chromatography–mass spectrometry (GC-MS); and total boswellic acids contents were quantified by high-performance liquid chromatography (HPLC). Frankincense essential oil-modulated pancreatic tumor cell viability and cytotoxicity were determined by colorimetric assays. Levels of apoptotic markers, signaling molecules, and cell cycle regulators expression were characterized by Western blot analysis. A heterotopic (subcutaneous) human pancreatic cancer xenograft nude mouse model was used to evaluate anti-tumor capability of Fraction IV frankincense essential oil in vivo. Frankincense essential oil-induced tumor cytostatic and cytotoxic activities in animals were assessed by immunohistochemistry. Results Longer duration and higher temperature hydrodistillation produced more abundant high molecular weight compounds, including boswellic acids, in frankincense essential oil fraactions. Human pancreatic cancer cells were sensitive to Fractions III and IV (containing higher molecular weight compounds) treatment with suppressed cell viability and increased cell death. Essential oil activated the caspase-dependent apoptotic pathway, induced a rapid and transient activation of Akt and Erk1/2, and suppressed levels of cyclin D1 cdk4 expression in cultured pancreatic cancer cells. In addition, Boswellia sacra essential oil Fraction IV exhibited anti-proliferative and pro-apoptotic activities against pancreatic tumors in the heterotopic xenograft mouse model. Conclusion All fractions of frankincense essential oil from Boswellia sacra are capable of suppressing viability and inducing apoptosis of a panel of human pancreatic cancer cell lines. Potency of essential oil-suppressed tumor cell viability may be associated with the greater abundance of high molecular weight compounds in Fractions III and IV. Although chemical component(s) responsible for tumor cell cytotoxicity remains undefined, crude essential oil prepared from hydrodistillation of Boswellia sacra gum resins might be a useful alternative therapeutic agent for treating patients with pancreatic adenocarcinoma, an aggressive cancer with poor prognosis.
    Full-text · Article · Dec 2012 · BMC Complementary and Alternative Medicine
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