Phase I trial and antitumor effects of BZL101 for patients with advanced breast cancer. Breast Cancer Res Treat

University of California, San Francisco Carol Franc Buck Breast Care Center, San Francisco, USA.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 09/2007; 105(1):17-28. DOI: 10.1007/s10549-006-9430-6
Source: PubMed

ABSTRACT Botanical therapies are often used by breast cancer patients yet few clinical trials have evaluated their safety and efficacy. We studied mechanisms of activity and performed a phase I clinical trial in patients with advanced breast cancer to evaluate BZL101, an aqueous extract from Scutellaria barbata.
Preclinical studies were conducted in vitro to characterize cell death induced by BZL101. In a phase I trial, eligible patients had histologically confirmed, measurable metastatic breast cancer. Treatment consisted of 350 ml per day of oral BZL101, administered as sole cancer therapy until disease progression, toxicity or personal preference to discontinue. Primary endpoints were safety, toxicity and tumor response.
BZL101 extract induced strong growth inhibition and apoptosis of breast cancer cell lines. In the phase I trial, 21 patients received BZL101. Mean age was 54 years (30-77) and mean number of prior treatments for metastatic disease was 3.9 (0-10). There were no grade III or IV adverse events (AEs). The most frequently reported BZL101-related grade I and II AEs included: nausea (38%), diarrhea (24%), headache (19%) flatulence (14%), vomiting (10%), constipation (10%), and fatigue (10%). Sixteen patients were evaluable for response. Four patients had stable disease (SD) for >90 days (25%) and 3/16 had SD for >180 days (19%). Five patients had objective tumor regression, one of which was 1 mm short of a PR based on RECIST criteria.
BZL 101 inhibits breast cancer cell lines by inducing apoptosis. In a phase I clinical trial, BZL101 was safe and had a favorable toxicity profile. BZL101 demonstrated encouraging clinical activity in this heavily pretreated population.

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Available from: Hope Rugo, Sep 27, 2015
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    • "Kral [4] reported the appearance of S. racemosa in the southeast U.S. Ethnobotanical information suggests that the Cauca people of Columbia and Ecuador used certain ecotypes of S. racemosa in ceremonial or sedative preparations [5]. S. barbata has been tested in two clinical trials for the treatment of advanced and metastatic breast cancer with positive results [6] [7]. Laboratory studies using Barbat skullcap extracts have shown to induce apoptosis in prostate cancer, and hepatoma H22 cells [8]-[10]. "
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    ABSTRACT: Micropropagation protocols to minimize hyperhydricity were optimized for medicinal Scutellaria barbata and Scutellaria racemosa. Six cytokinins and eight different carbon sources at two differ-ent incubation periods of 14 and 21 days were studied for adventitious shoot bud induction using nodal explants. In S. barbata, 5 µM meta-Topolin and 0.1 µM NAA supplemented shoot induction medium produced four shoots each after 14 and 21 day incubation. Observation of S. racemosa nodal explants recorded four and five shoots after 14 and 21 day incubation. In both species, con-trol explants (no plant growth regulators in the medium) consistently resulted in the bud break with two shoots in both 14 and 21 day incubation. The effect of carbon source on shoot regenera-tion was studied by supplementing eight different sugars at 0.1 M concentration to the optimized shoot induction medium (5 µM meta-Topolin and 0.1 µM NAA). S. barbata nodal explants cultured on shoot induction medium supplemented with fructose and glucose for 14 days produced 10 and nine adventitious shoots respectively; and after 21 day incubation adventitious shoot count reached 19 in glucose supplemented medium. S. racemosa explants in the same experiment pro-duced five shoots in maltose and four shoots in sorbitol supplemented medium after 14 day incu-bation; whereas after 21 day incubation, sucrose and maltose produced five shoots; fructose, glu-cose, and sorbitol produced four shoots. Regenerated plants were successfully acclimatized and Scanning Electron Microscopy of the leaf surface revealed differences in stomatal behavior and cuticle deposition between in vitro and acclimatized plants. The antioxidant assay conducted on both Scutellaria species showed considerable total polyphenol content, TEAC activity and flavo-noid content in fresh and dried leaf samples attributing to their medicinal potential.
    American Journal of Plant Sciences 11/2014; 5(5):3662-3672. DOI:10.4236/ajps.2014.524382
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    • "Thus, strategies targeting AIF-mediated caspase-independent cell death have been applied as a therapeutic treatment for cancers. For example, a plant drug from Scutellaria barbatae that stimulates AIF translocation from the mitochondria to the nucleus showed anti-tumor effects in breast cancer patients [24]. Since cathepsin release from lysosomes regulates the AIF-mediated cell death pathway and several members of the cathepsin family have been implicated in cancer progression and metastasis [25], [26], cathepsin is a potential target to modulate caspase-independent cell death for cancer treatment. "
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    ABSTRACT: Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE) cells carrying the Apc(min) mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC) cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth.
    PLoS ONE 05/2012; 7(5):e36418. DOI:10.1371/journal.pone.0036418 · 3.23 Impact Factor
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    • "S. barbata extract was shown to have cytotoxic activity against various tumor cell lines in vitro [1], [2], [3], [4], [5], [6], [7], [8], [9], [10] and antitumor activity in vivo [11], [12], [13] in models of renal, hepatocellular and prostate carcinoma. More importantly, two early stage clinical trials with Bezielle showed promising efficacy and excellent safety for treatment of advanced breast cancer [14], [15]. In the phase Ia clinical trial sixteen patients, all of which went through multiple treatment therapies prior to enrollment were evaluable for response. "
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    ABSTRACT: Bezielle (BZL101) is a candidate oral drug that has shown promising efficacy and excellent safety in the early phase clinical trials for advanced breast cancer. Bezielle is an aqueous extract from the herb Scutellaria barbata. We have reported previously that Bezielle was selectively cytotoxic to cancer cells while sparing non-transformed cells. In tumor, but not in non-transformed cells, Bezielle induced generation of ROS and severe DNA damage followed by hyperactivation of PARP, depletion of the cellular ATP and NAD, and inhibition of glycolysis. We show here that tumor cells' mitochondria are the primary source of reactive oxygen species induced by Bezielle. Treatment with Bezielle induces progressively higher levels of mitochondrial superoxide as well as peroxide-type ROS. Inhibition of mitochondrial respiration prevents generation of both types of ROS and protects cells from Bezielle-induced death. In addition to glycolysis, Bezielle inhibits oxidative phosphorylation in tumor cells and depletes mitochondrial reserve capacity depriving cells of the ability to produce ATP. Tumor cells lacking functional mitochondria maintain glycolytic activity in presence of Bezielle thus supporting the hypothesis that mitochondria are the primary target of Bezielle. The metabolic effects of Bezielle towards normal cells are not significant, in agreement with the low levels of oxidative damage that Bezielle inflicts on them. Bezielle is therefore a drug that selectively targets cancer cell mitochondria, and is distinguished from other such drugs by its ability to induce not only inhibition of OXPHOS but also of glycolysis. This study provides a better understanding of the mechanism of Bezielle's cytotoxicity, and the basis of its selectivity towards cancer cells.
    PLoS ONE 02/2012; 7(2):e30300. DOI:10.1371/journal.pone.0030300 · 3.23 Impact Factor
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