[Rich66]

J Biol Chem. 2009 May 29;284(22):15206-14. Epub 2009 Mar 18.
Inhibition of tumor cell motility by the interferon-inducible GTPase MxA.

Mushinski JF, Nguyen P, Stevens LM, Khanna C, Lee S, Chung EJ, Lee MJ, Kim YS, Linehan WM, Horisberger MA, Trepel JB.
Laboratory of Cancer Biology and Genetics, Medical Oncology Branch, Pediatric Oncology Branch, and Urologic Oncology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
To identify pathways controlling prostate cancer metastasis we performed differential display analysis of the human prostate carcinoma cell line PC-3 and its highly metastatic derivative PC-3M. This revealed that a 78-kDa interferon-inducible GTPase, MxA, was expressed in PC-3 but not in PC-3M cells. The gene encoding MxA, MX1, is located in the region of chromosome 21 deleted as a consequence of fusion of TMPRSS2 and ERG, which has been associated with aggressive, invasive prostate cancer. Stable exogenous MxA expression inhibited in vitro motility and invasiveness of PC-3M cells. In vivo exogenous MxA expression decreased the number of hepatic metastases following intrasplenic injection. Exogenous MxA also reduced motility and invasiveness of highly metastatic LOX melanoma cells. A mutation in MxA that inactivated its GTPase reversed inhibition of motility and invasion in both tumor cell lines. Co-immunoprecipitation studies demonstrated that MxA associated with tubulin, but the GTPase-inactivating mutation blocked this association. Because MxA is a highly inducible gene, an MxA-targeted drug discovery screen was initiated by placing the MxA promoter upstream of a luciferase reporter. Examination of the NCI diversity set of small molecules revealed three hits that activated the promoter. In PC-3M cells, these drugs induced MxA protein and inhibited motility. These data demonstrate that MxA inhibits tumor cell motility and invasion, and that MxA expression can be induced by small molecules, potentially offering a new approach to the prevention and treatment of metastasis.

PMID: 19297326 [PubMed - indexed for MEDLINE]




J Neurooncol. 2007 Mar;82(1):91-3. Epub 2006 Sep 26.

A lipoxygenase inhibitor in breast cancer brain metastases.(Boswellia serrata)

PDF(3pgs): http://www.springerlink.com/content/...2/fulltext.pdf

Flavin DF.
Foundation for Collaborative Medicine and Research, Greenwich, CT 06831, USA. Dana_FK@hotmail.com
The complication of multiple brain metastases in breast cancer patients is a life threatening condition with limited success following standard therapies. The arachidonate lipoxygenase pathway appears to play a role in brain tumor growth as well as inhibition of apoptosis in in-vitro studies. The down regulation of these arachidonate lipoxygenase growth stimulating products therefore appeared to be a worthwhile consideration for testing in brain metastases not responding to standard therapy.
Boswellia serrata, a lipoxygenase inhibitor was applied for this inhibition. Multiple brain metastases were successfully reversed using this method in a breast cancer patient who had not shown improvement after standard therapy. The results suggest a potential new area of therapy for breast cancer patients with brain metastases that may be useful as an adjuvant to our standard therapy.

PMID: 17001517 [PubMed - indexed for MEDLINE]

Quote:

The patient was started on capecitabine and given radiation therapy of 44 Gy with no improvement seen for the first 2 weeks. The severity and inoperability of
her condition made using an additional therapy a consideration. An oxidoreductase [plant lipoxygenases (LOX)] inhibitor was applied (Boswellia serrata) which has no known major side effects. The enzyme, LOX, arachidonate: oxygen oxidoreductase (form mammalian LOX) is thought to be responsible for edema in primary brain tumors and present ongoing studies on LOX inhibitors in Germany indicate an overall improvement in response to radiation therapy as well as a decrease in some primary brain tumors seen even without radiation. Although it was not known if LOX inhibitors would be helpful in breast cancer brain metastases it was worth considering in this case since she had not only several large tumors but also additional extremely small tumors scattered throughout the brain. She was immediately placed on a LOX inhibitor. Following 10 weeks of therapy, the patient was scheduled for a new CT since her CEA and Ca 15–3 tumor markers had increased. The CT results showed a complete disappearance of all signs of metastases in her brain (Fig. 2a, b).
The patient has been maintained on the LOX inhibitor,

Boswellia serrata, 3 · 800 mg/day

with no new signs of cerebral involvement of her breast cancer for over 4 years, however, there have recently been skeletal metastases which most likely indicates LOX has a limited skeletal tissue involvement in cancer.


J Immunol. 2006 Mar 1;176(5):3127-40.
Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression.

Takada Y, Ichikawa H, Badmaev V, Aggarwal BB.
Cytokine Research Section, Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Acetyl-11-keto-beta-boswellic acid (AKBA), a component of an Ayurvedic therapeutic plant Boswellia serrata, is a pentacyclic terpenoid active against a large number of inflammatory diseases, including cancer, arthritis, chronic colitis, ulcerative colitis, Crohn's disease, and bronchial asthma, but the mechanism is poorly understood. We found that AKBA potentiated the apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced invasion, and inhibited receptor activator of NF-kappaB ligand-induced osteoclastogenesis, all of which are known to require NF-kappaB activation. These observations corresponded with the down-regulation of the expression of NF-kappaB-regulated antiapoptotic, proliferative, and angiogenic gene products. As examined by DNA binding, AKBA suppressed both inducible and constitutive NF-kappaB activation in tumor cells. It also abrogated NF-kappaB activation induced by TNF, IL-1beta, okadaic acid, doxorubicin, LPS, H2O2, PMA, and cigarette smoke. AKBA did not directly affect the binding of NF-kappaB to the DNA but inhibited sequentially the TNF-induced activation of IkappaBalpha kinase (IKK), IkappaBalpha phosphorylation, IkappaBalpha ubiquitination, IkappaBalpha degradation, p65 phosphorylation, and p65 nuclear translocation. AKBA also did not directly modulate IKK activity but suppressed the activation of IKK through inhibition of Akt. Furthermore, AKBA inhibited the NF-kappaB-dependent reporter gene expression activated by TNFR type 1, TNFR-associated death domain protein, TNFR-associated factor 2, NF-kappaB-inducing kinase, and IKK, but not that activated by the p65 subunit of NF-kappaB. Overall, our results indicated that AKBA enhances apoptosis induced by cytokines and chemotherapeutic agents, inhibits invasion, and suppresses osteoclastogenesis through inhibition of NF-kappaB-regulated gene expression.

Bosellia serrata-induced apoptosis is related with ER stress and calcium release.

Cancer Res. 2009 Jul 15;69(14):5893-900. Epub 2009 Jun 30.
Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.

Pang X, Yi Z, Zhang X, Sung B, Qu W, Lian X, Aggarwal BB, Liu M.
Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
The role of angiogenesis in tumor growth and metastasis is well established. Identification of a small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we showed that acetyl-11-keto-beta-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg/kg AKBA) after solid tumors reached approximately 100 mm(3) (n = 5). The inhibitory effect of AKBA on tumor growth was well correlated with suppression of angiogenesis. When examined for the molecular mechanism, we found that AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively suppressed vascular endothelial growth factor (VEGF)-induced microvessel sprouting in rat aortic ring assay ex vivo. Furthermore, AKBA inhibited VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells in a dose-dependent manner. Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) kinase (KDR/Flk-1) with IC(50) of 1.68 micromol/L. Specifically, AKBA suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, extracellular signal-related kinase, AKT, mammalian target of rapamycin, and ribosomal protein S6 kinase. Our findings suggest that AKBA potently inhibits human prostate tumor growth through inhibition of angiogenesis induced by VEGFR2 signaling pathways.