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According to U.S. Breast Cancer Statistics, about 1 in 8 U.S. women will develop invasive breast cancer during their lifetime. Chemotherapeutics that are used on patients currently often lead to tumor resistance, bone marrow suppression and cachexia. This study evaluated a novel combination of three non-mutagenic compounds for their effectiveness against mammary tumor cells, toxicity towards immune cells, ability to provoke the expression of immunogenic cell death (ICD) markers, and killing in 3D tumor models. Methotrexate (MTX), 2-deoxyglucose (2DG), and wogonin (WGN) were combined at doses well below their EC50 values yet effectively killed human and mouse breast cancer cells. The combination inhibited cancer cell colony formation and induced a high degree of cell death in multiple malignant tumor cell lines. Importantly, the combination did not significantly inhibit the viability of peripheral-blood mononuclear cells (PBMCs), even when employed at 3X the concentration that killed cancer cells. In marked contrast, low-dose doxorubicin, a common therapeutic for breast cancers, significantly decreased PBMC viability and increased the percentage of cell death. Our novel combinatorial therapy (Trifecta) elicited the significant expression of three ICD hallmarks: calreticulin surface expression, ATP secretion, and HMGB-1 release. In all cases, Trifecta elicited an equal or greater degree of ICD-marker expression compared to doxorubicin, a known inducer of ICD. We show significant efficacy of Trifecta against human and mouse mammary 3D tumor models grown in Matrigel® ECM-complex containing culture medium, and reaffirm the marked resistance of tumorspheres towards the conventional chemotherapeutic doxorubicin. The effectiveness of Trifecta in an acceptable surrogate model for mouse studies bodes well for translation of our findings to the clinic. In conclusion, Trifecta has proven highly effective against tumor cells grown either as monolayers or tumorspheres, without si, 2020, Includes bibliography., Degree granted: Dissertation (Ph.D.)--Florida Atlantic University, 2020., Collection: FAU Electronic Theses and Dissertations Collection

Wogonoside,wogonin,baicalin and baicalein are major chemical constituents of S.baicalensis.Baicalin,baicalein and wogonin have been reported previously to exert anti-cancer effects.The present study compared the anti-cancer effects of the four flavonoids individually towards four human cancer cell lines after 24- and 48-hour treatment based on cell viability assay.As a result,wogonin inhibited the growth of the four cell lines.The IC50 values after 48 hours of incubation were 97.9μM for A549 lung adenocarcinoma cells,while 15.3μM for HeLa cervical carcinoma cells,147μM for HepG2 hepatocellular carcinoma cells and 104μM for MCF-7 breast adenocarcinoma cells.In contrast,wogonoside,the glycoside of wogonin,showed no inhibitory effect against any one of the four cell lines.Baicalein inhibited the growth of HeLa cells,while baicalin inhibited the growth of HepG2 cells,both with higher IC50 values and less potent than wogonin.These findings established wogonin as the most active anti-cancer agent among the four major flavonoids of S.baicalensis.Since baicalin,the most abundant flavonoid in the herb,was found to enhance the growth of MCF-7 cells.Clinical applications of ingredients from S.baicalensis to the treatment of cancer should be carried out with purified compounds. 汉黄芩苷、汉黄芩素、黄芩苷及黄芩素是黄芩的主要成分。对前三种黄酮的抗癌活性文献有不同的报导。方法：本研究比较了4种黄酮在相同浓度下对4个肿瘤细胞株24 h及48 h存活率的影响。结果：实验结果显示,汉黄芩素对4种细胞株都有明显的抑制作用,48 h半抑制浓度分别为97.9μM（肺腺癌A549）、15.3μM（子宫颈癌HeLa）、147μM（肝细胞癌HepG2）及104μM（乳腺癌MCF-7）。其相应的糖化物,汉黄芩苷对4种细胞均未显示抑制。黄芩素抑制HeLa细胞,而糖化的黄芩苷抑制HepG2,且对MCF-7显示刺激作用。结论：以上结果显示,汉黄芩素在4种主要黄芩黄酮中具有最强的抑制肿瘤细胞生长效能,而其他3种黄酮的抗肿瘤作用并不一致,黄芩苷甚至促进个别肿瘤细胞株的生长。因此,黄酮抗癌作用的研究及可能的临床应用更应在单体水平进行。

The search for flavonoids with novel therapeutic effects has been intense. Wogonin, as a naturally existing monoflavonoid, has been shown to have therapeutic potential in vitro and in vivo. Methods for its extraction from herbs and its chemical synthesis have been developed. Pharmacokinetic studies have shown a rapid tissue distribution and prolonged plasma elimination phase of wogonin. It has been shown experimentally that wogonin exerts anti-oxidant activity, which may, in part, underlie its anti inflammatory, anti-cancer, antiviral and neuroprotective actions. The recent discovery of its anxiolytic activity suggests a new mechanism of action, involving interaction with the benzodiazepine (BZD) binding site of the GABA(A) receptor and modulation of this receptor activity. Although the safety record of wogonin is remarkable and voluminous literature about its pharmacological effects is available, it has not been used in Western medicine in the form of a pure chemical. In this article we review its therapeutic effects, its sources and pharmacokinetic profile to highlight its therapeutic potential.

The search for flavonoids with novel therapeutic effects has been intense. Wogonin, as a naturally existing monoflavonoid, has been shown to have therapeutic potential in vitro and in vivo. Methods for its extraction from herbs and its chemical synthesis have been developed. Pharmacokinetic studies have shown a rapid tissue distribution and prolonged plasma elimination phase of wogonin. It has been shown experimentally that wogonin exerts anti-oxidant activity, which may, in part, underlie its anti inflammatory, anti-cancer, antiviral and neuroprotective actions. The recent discovery of its anxiolytic activity suggests a new mechanism of action, involving interaction with the benzodiazepine (BZD) binding site of the GABA(A) receptor and modulation of this receptor activity. Although the safety record of wogonin is remarkable and voluminous literature about its pharmacological effects is available, it has not been used in Western medicine in the form of a pure chemical. In this article we review its therapeutic effects, its sources and pharmacokinetic profile to highlight its therapeutic potential.

The search for flavonoids with novel therapeutic effects has been intense. Wogonin, as a naturally existing monoflavonoid, has been shown to have therapeutic potential in vitro and in vivo. Methods for its extraction from herbs and its chemical synthesis have been developed. Pharmacokinetic studies have shown a rapid tissue distribution and prolonged plasma elimination phase of wogonin. It has been shown experimentally that wogonin exerts anti-oxidant activity, which may, in part, underlie its anti inflammatory, anti-cancer, antiviral and neuroprotective actions. The recent discovery of its anxiolytic activity suggests a new mechanism of action, involving interaction with the benzodiazepine (BZD) binding site of the GABA(A) receptor and modulation of this receptor activity. Although the safety record of wogonin is remarkable and voluminous literature about its pharmacological effects is available, it has not been used in Western medicine in the form of a pure chemical. In this article we review its therapeutic effects, its sources and pharmacokinetic profile to highlight its therapeutic potential.

The search for novel anxiolytics devoid of undesirable side-effects typical of classical benzodiazepines (BDZs) has been intense, and flavonoids, as a relative new class of ligands, have been shown to possess anxiolytic effects in vivo. The present study evaluated the pharmacological properties of a naturally occurring monoflavonoid, 5,7-dihydroxy-8-methoxyflavone or wogonin. The affinity (K-i) of wogonin for the benzodiazepine site (BZD-S) on the gamma-aminobutyric acidA (GABA(A)) receptor complex was 0.92 muM. Using electrophysiological techniques, we showed that wogonin enhanced the GABA-activated current in rat dorsal root ganglion neurons, and in Xenopus laevis oocytes expressing recombinant rat GABA(A) receptors, the enhancement was partially reversed by the co-application of a I muM concentration of the BZD-S antagonist anexate (Ro15-1788). Acute toxicity and behavioral effects were examined in mice. Acute lethal activity was low, with an LD50 of 3.9 g/kg. Oral administration of wogonin (7.5 to 30 mg/kg) elicited an anxiolytic response that was similar to that elicited by diazepam in the elevated plus-maze; a dose-dependent increase in open arm entries and time spent in open arms was observed. More importantly, its anxiolytic effect was blocked by the co-administration of Ro15-4788. In the holeboard test, not only did wogonin-treated mice experience an increased number of head-dips but they also spent more time at it, showing no signs of sedation. Furthermore, wogonin did not cause myorelaxant effects in the horizontal wire test. Taken together, these data suggest that wogonin exerts its anxiolytic effect through positive allosteric modulation of the GABAA receptor complex via interaction at the BZD-S. Its anxiolytic effect was not accompanied by sedative and myorelaxant side-effects typical of BDZs. (C) 2002 Elsevier Science Inc. All rights reserved.

The search for novel anxiolytics devoid of undesirable side-effects typical of classical benzodiazepines (BDZs) has been intense, and flavonoids, as a relative new class of ligands, have been shown to possess anxiolytic effects in vivo. The present study evaluated the pharmacological properties of a naturally occurring monoflavonoid, 5,7-dihydroxy-8-methoxyflavone or wogonin. The affinity (K-i) of wogonin for the benzodiazepine site (BZD-S) on the gamma-aminobutyric acidA (GABA(A)) receptor complex was 0.92 muM. Using electrophysiological techniques, we showed that wogonin enhanced the GABA-activated current in rat dorsal root ganglion neurons, and in Xenopus laevis oocytes expressing recombinant rat GABA(A) receptors, the enhancement was partially reversed by the co-application of a I muM concentration of the BZD-S antagonist anexate (Ro15-1788). Acute toxicity and behavioral effects were examined in mice. Acute lethal activity was low, with an LD50 of 3.9 g/kg. Oral administration of wogonin (7.5 to 30 mg/kg) elicited an anxiolytic response that was similar to that elicited by diazepam in the elevated plus-maze; a dose-dependent increase in open arm entries and time spent in open arms was observed. More importantly, its anxiolytic effect was blocked by the co-administration of Ro15-4788. In the holeboard test, not only did wogonin-treated mice experience an increased number of head-dips but they also spent more time at it, showing no signs of sedation. Furthermore, wogonin did not cause myorelaxant effects in the horizontal wire test. Taken together, these data suggest that wogonin exerts its anxiolytic effect through positive allosteric modulation of the GABAA receptor complex via interaction at the BZD-S. Its anxiolytic effect was not accompanied by sedative and myorelaxant side-effects typical of BDZs. (C) 2002 Elsevier Science Inc. All rights reserved.

The search for novel anxiolytics devoid of undesirable side-effects typical of classical benzodiazepines (BDZs) has been intense, and flavonoids, as a relative new class of ligands, have been shown to possess anxiolytic effects in vivo. The present study evaluated the pharmacological properties of a naturally occurring monoflavonoid, 5,7-dihydroxy-8-methoxyflavone or wogonin. The affinity (K-i) of wogonin for the benzodiazepine site (BZD-S) on the gamma-aminobutyric acidA (GABA(A)) receptor complex was 0.92 muM. Using electrophysiological techniques, we showed that wogonin enhanced the GABA-activated current in rat dorsal root ganglion neurons, and in Xenopus laevis oocytes expressing recombinant rat GABA(A) receptors, the enhancement was partially reversed by the co-application of a I muM concentration of the BZD-S antagonist anexate (Ro15-1788). Acute toxicity and behavioral effects were examined in mice. Acute lethal activity was low, with an LD50 of 3.9 g/kg. Oral administration of wogonin (7.5 to 30 mg/kg) elicited an anxiolytic response that was similar to that elicited by diazepam in the elevated plus-maze; a dose-dependent increase in open arm entries and time spent in open arms was observed. More importantly, its anxiolytic effect was blocked by the co-administration of Ro15-4788. In the holeboard test, not only did wogonin-treated mice experience an increased number of head-dips but they also spent more time at it, showing no signs of sedation. Furthermore, wogonin did not cause myorelaxant effects in the horizontal wire test. Taken together, these data suggest that wogonin exerts its anxiolytic effect through positive allosteric modulation of the GABAA receptor complex via interaction at the BZD-S. Its anxiolytic effect was not accompanied by sedative and myorelaxant side-effects typical of BDZs. (C) 2002 Elsevier Science Inc. All rights reserved.