Abstract
Scutellaria barbata (skullcap) has been used in traditional Chinese and Korean medicine for treating various inflammation illnesses and cancers. In vitro studies have demonstrated the anti-mutagenesis (chemo-preventive) effect of skullcap via modulating the metabolism of mutagenic compounds such as aflatoxin B1 and benzo[a]pyrene to reduce their DNA binding efficiency. In vitro and in vivo studies using flavonoid compound of skullcap in both human and animal models have shown promising anticancer effects. The aqueous extract of skullcap has shown to have the most effective anticancer chemical constituents. In vitro studies indicated that skullcap might be effective against all three stages of carcinogenesis (initiation, promotion, and progression). It has also been found to exert anticancer mechanisms such as anti-inflammation, anti-proliferation, induction of apoptosis against numerous cancer cell lines including digestive (liver and colorectal), respiratory (lung and nasopharyngeal), and lymphatic (leukemia) systems, and induction of sex hormone-specific glycolytic necrosis, especially those of the reproductive system (breast, uterine, and prostate) while inactive on normal human mammary epithelial cells. In vivo murine model showed aqueous extract of skullcap may enhance macrophage cell line activity leading to inhibition of tumor growth. It has also been shown to inhibit aberrant crypt formation in colon, delay prostate cancer development and progression in transgenic adenocarcinoma of mouse prostate mice, and reduced solid ascites tumor proliferation in the breast of mice. Aqueous extracts of skullcap have been found to have a favorable toxicity profile when used as an oral feeding in Phase 1 and 1B clinical studies in metastatic breast cancer patients. Based on the studies reported on skullcap, the best prospective therapeutic application of skullcap would be in breast, prostate, liver, colorectal, uterine, and lung cancer patients.
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8.1 Introduction
Scutellaria barbata D. Don (skullcap), Chinese name Ban-Zhi-Lian of the Lamiaceae family, is a 12–35 cm tall perennial herb, found along fields and ditches in southern China and Korea (Fig. 8.1). It is commonly known as skullcap, a mint with a mildly bitter taste commonly used in traditional Chinese and Korean medicine for the treatment of a variety of ailments such as appendicitis, hepatitis, snake bites, lung, liver and rectal cancer (Jiangsu New Medical College 1977; Chong and Lee 1988; Zhu 1998; Huang 1999). In China, skullcap has been used clinically in treating breast cancer, lung cancer, liver cancer, digestive tract cancers, and chorioepithelioma. Skullcap has been used in combination with Oldenlandia diffusa in patients with liver, rectal and lung cancer. However, it was stated that skullcap alone or in combination with other herbs has not been successful in complete cure of cancer (complete remission) but rather provides symptomatic relief (Chong and Lee 1988). Literature review also shows very limited in vitro and in vivo research on the inhibitory or anticancer properties and mechanisms of skullcap following the ethnopharmacological approach in the early 1900s. The purpose of this chapter is to describe the early chemopreventive studies of skullcap and follow its development into the isolation and understanding of the various chemical constituents as well as their in vitro and in vivo effect or mechanism based on research literature.
8.2 Early Studies
8.2.1 Anti-Mutagenesis and Anti-Carcinogenesis Chemo-prevention Properties
Our early studies found that aqueous extracts (whole) of skullcap possess anti-mutagenic and chemopreventive properties (Wong et al. 1992a, b, c, 1993a, b). These studies indicate that skullcap contains phytochemicals which inhibited mutagenesis, DNA binding, and metabolism of the pro-carcinogens aflatoxin B1 (AFB1) and benzo[a]pyrene bioactivated by Arcoclor 1254-induced rat S9. Inhibition effects of skullcap were also shown in the mutagenicity of AFB1 on mutant bacteria Salmonella typhimurium TA100 using dexamethansone (DXM)-induced rat hepatic S9, on cytochrome P450-linked aminopyrine N-demethylase (APND) activity in DXM-induced hepatic microsomes, and on the metabolism of AFB1 by DXM-induced S9. Aqeuous extract of skullcap consistently inhibited the mutagenicity of AFB1 bioactivated by either non-induced or DXM-induced hepatic S9. The effects correlated with the inhibition of cytochrome P450-linked APND activity in DXM-induced S9 mediated metabolism of [3H]AFB1. These findings suggest that skullcap contains antimutagenic and antitumorigenic property on AFB1 via inhibition of cytochrome p450 isozyme (CYP3)-mediated metabolism of the carcinogens. This data suggests that skullcap is effective against all three stages of carcinogenesis (initiation, promotion, and progression).
8.2.2 Immune Enhancing and Anti-Inflammation Effect of Skullcap
A later study showed that oral feeding with the aqueous herbal extract inhibited the growth of transplanted murine renal cell carcinoma (RenCa) in Balb/c mice significantly (Wong et al. 1996). In vitro data of the same study revealed that it enhanced the phagocytic oxidative burst in murine macrophage, J774 cells. This suggests its ability to inhibit tumor growth observed in vivo. An aqueous extract of skullcap was also shown to have greater antimutagenic effect in inhibiting DNA damage of peripheral lymphocytes when injected into cigarettes (Han et al. 1997). Our later study revealed skullcap treatment could elevate H2O2 and hydroxyl radical production in the macrophage-like RAW 264.7 mouse peritoneal cell line. It showed that skullcap modulated COX-2 (cyclooxygenase-2) and inducible NO (nitric oxide) synthase protein expression, as well as the activity of prostaglandin E2 and stable oxidation products of NO in vitro. This may be related to the formation of reactive oxygen species (Harris et al. 2003). Together these early studies aroused and led to continuous research interest in the chemical isolation and specific anticancer effect and mechanism of skullcap since the early 2000s.
8.3 Chemical Constitution
Skullcap has been reported to contain several bioactive flavonone compounds such as scutellarein, scutellarin, carthamidin, isocarthamidin, wogonin, apigenin, luteolon, pheophoride-a, and various clerodane diterpeonoids (Zhu 1998; Kim et al. 2005; Chan et al. 2006; Dai et al. 2006a, b; 2007a, b, 2008, 2009a, b, 2010). Tables 8.1 and 8.2 list more detail chemical compounds and extracts of skullcap with their respective in vitro and in vivo anticancer properties (effect and mechanism) classified according to organ system in animal and human respectively. These chemical constitutions of skullcap include various types of extracts (aqueous, chloroform, ethanol, ethyl acetate, methanol, methylene chloride, and n-hexane) and compounds. Among these, clerodane diterpeonoids are the most abundantly isolated compounds (>28) and are potential candidates for further studies of in vitro and in vivo mechanisms; while aqueous skullcap extract is the most dominant form of extraction with greater and more detailed effect and mechanism. One of such total aqueous extracts, BZL101 is suggested to have greater activity in in vitro assays compared to enriched chromatographically isolated pure compounds (Perez et al. 2010). For example, 9 flavonoid phytochemicals showed cytotoxic activity in vitro, but only at concentrations far higher than those found in the total aqueous extract. Also, the whole extract is more cytotoxic than any combination of the purified flavonoids. To learn more about the various chemical compounds of skullcap, readers may refer to Tables 8.1 and 8.2 for their specific chemical nature and specific anticancer effects or mechanisms respectively. The following sections will focus on the discussion of some of the anticancer properties and mechanisms of these chemical constituents on animal and human in vitro and in vivo, classified according to organ system.
8.4 Anticancer In Vitro and In Vivo Animal Studies
8.4.1 In Vitro Murine Cancer Cell Line Studies
Guided by ethnopharmacological approach, in vitro cell line data in Table 8.1 reveals studies done on the specific effect and mechanism of various chemical constituents of skullcap classified according to organ system. There are 6 murine cancer cell lines, 1 murine tissue (mammary glands in culture), and 4 organ systems studied. These include the lymphatic (macrophage—RAW 264.7 and J744 cancer cells), respiratory (lung—LLC), digestive (liver—H22), and reproductive [(breast—MCNeuA, and prostate—transgenic adenocarcinoma of mouse prostate (TRAMP)-C1]. Major anticancer mechanisms include anti-inflammation, induction of phagocytosis, induction of apoptosis, and anti-proliferation while inactive on normal human mammary epithelial huMEC cells relatively. Some of the molecular mechanisms include elevation of H2O2 and hydroxyl radical, modulation of COX-2, enhancement of macrophage oxidative burst, activation of caspase-3 and -9), activation of poly(ADP-ribose) polymerase (PARP) cleavage, reduction of mitochondrial membrane potential, and release of cytochrome c. See Table 8.1 for detail mechanism and references for each cell line respectively.
8.4.2 In Vivo Murine Models
On the other hand, in vivo studies show that five mouse organ systems were affected by various chemical constituents of skullcap, including the integumentary (inhibition of DMBA-induced skin cancer), digestive (inhibition of AOM-induced ACF colon cancer and inhibition of tumor volume in nude mouse transplanted liver Hep3B cancer cells), urinary (inhibition of tumor growth with transplanted kidney RenCa cancer cells), and reproductive (inhibition of solid Ehrlich ascites tumor and prolonging mice life span; delay of prostate cancer development and progression in TRAMP mice, and activation of caspase-3 in the prostate tissue of TRAMP mice). Again, the majority of the effects came from aqueous extract of skullcap (Table 8.1).
The TRAMP model is a spontaneous autochthonous transgenic mouse model. It mimics heterogenic tumor progression in human prostate cancer, providing a relevant pre-clinical model for identifying important pathways in tumorigenesis, androgen independence, and metastasis of prostate cancer (Gingrich et al. 1996, 1997; Gupta et al. 2000). Our in vivo data shows a delayed in tumor onset and development in the TRAMP mice. Palpable tumor development in 50% of the mice happened at 25 weeks in the placebo group, 29 weeks in the low-dose (8 mg skullcap daily) and mid-dose (16 mg) treatment groups, and 33 weeks in the high-dose (32 mg) group (log rank, P = 0.0211). Hematoxylin and eosin histopathological dorsal prostate tissue also reveals delay of prostate tumor progression and the activation of caspase-3 in the prostate tissue of the skullcap-treated mouse. These findings further suggest the potential efficacy of skullcap as a chemo-preventive and plausible treatment agent in prostate cancer (Wong et al. 2009).
8.5 Anticancer In Vitro Human Cell Lines and Clinical Studies
In this section, relevant in vitro human cell line and in vivo human data on the anticancer effect and mechanism of skullcap as classified by organ system, deserve more detailed description. For most of the systems, especially for reproductive system (breast, prostate, ovarian, and uterine), aqueous extract of skullcap is the most effective and dominant anticancer constituent in both in vitro and in vivo studies (Table 8.2).
8.5.1 In Vitro Cell Line Studies
Table 8.2 summarizes in vitro cell line data in showing the specific effects and mechanisms of the various chemical constituents of skullcap classified according to organ system. There are 34 human cancer cell lines (from 5 different organ systems) and 2 hematopoietic cell lines (red blood cell and peripheral lymphocytes). These include the lymphatic (leukemia—HL-60, KG-1, U937), respiratory (lung—A549, SPC-A-1; nasopharyngeal—HONE-1), digestive (oral—KB; stomach—AGS; pancreas—Panc-1; liver—Hep-G2, Hep3B, BEL-7402, QGY-7701); colon—LoVo; colorectal—HT29), urinary (kidney—ACHN), and reproductive (breast—MCF-7, MDA-MB-231, MDA-MB-361, MDA-MB-435S, MDA-MB-468, SK-BR-3, BT474; ovarian—HOC, SKOV-3, CAOV3; uterine—leiomyoma cells; cervix—HeLa; prostate—LNCaP, PC-3, DU-145). Major anticancer mechanisms include cytotoxic, anti-inflammation, induction of phagocytosis, induction of apoptosis, anti-proliferation while inactive on normal human mammary epithelial huMEC, and inhibition of glycolysis selectively in tumor cells but not in non-transformed MCF10A cells. Detailed mechanism of each cell line is listed in Table 8.2. BZL101 was reported to induce cell death via caspase activation in breast cancer cells but not in non-transformed (benign) mammary epithelial cells MCF10A and normal human fibroblasts IMR90. Hyperactivation of PARP and inhibition of glycolysis are likely the key mechanisms resulting in the energetic collapse and necrotic death that of breast cancer cells (Rugo et al. 2007; Fong et al. 2008).
Some of the molecular mechanisms include but not limited to induction of G1 and G2/M arrest; inhibition of Cyclins (A, D1, D2, D3, E) and CDKs (2, 4, 6); inhibition of COX-2; enhancement of macrophage oxidative burst; activation of caspase-3, -8, and -9; up-regulation of Bax (Bcl-2-associated X protein), p53 (tumor suppressor protein), Akt, JNK, Fas, MAPK (mitogen-activated protein kinase); activation of PARP cleavage; reduction of mitochondrial membrane potential; releasing of cytochrome c via the mitochondrial signaling pathways; down-regulation of Bcl-2 (B cell lymphoma 2), ERK; induction of c-fos gene expression; induction of expression of genes involved in oxidative response (GCLM, CBS, TRAF3, etc), DNA damage (TIPARP, CADD45a, etc), cell death (A20, TNF, etc), xenobiotic response (CYP1A1, CYP1B1, HSP70, etc), and NF-κB pathway (TNF, ICAM1, IL-8, etc). Detailed mechanism of each cell line is listed in Table 8.2. Recent in vitro study of breast cancer cells (early stage estrogen sensitive MCF-7 versus late estrogen insensitive MDA-MB-231) and prostate cancer cells (androgen sensitive LNCaP versus late androgen insensitive PC3) revealed phenotype specific anti-proliferative gene expression responses in these cancer cells (Marconett et al. 2010). Induction of G1 cell cycle arrest and ablated expression of regulators Cyclin D1, CDK2, CDK4, growth factor stimulatory pathways, and estrogen receptor-α expression in estrogen sensitive MCF-7 breast cancer cells (ablation of promoter activities) were observed. The skullcap extract also arrested early stage androgen sensitive LNCaP in G2/M phase with corresponding decreases in Cyclin B1, CDK1, and androgen receptor expression. It also induced S phase arrest with corresponding ablations in Cyclin A2 and CDK2 expression.
8.5.2 Clinical Studies
There were two clinical studies on patients with metastatic breast cancer (Rugo et al. 2007; Perez et al. 2010). An aqueous extract of skullcap BZL101 was found to have favorable toxicity profile and promising efficacy in a Phase I clinical trial in the treatment of advance breast cancer (Rugo et al. 2007). Oral feeding of BZL (40 g/day) was demonstrated to be safe and well-tolerated in Phase IB dose escalation trial of metastatic breast cancer (Perez et al. 2010). Preliminary success in the Phase I clinical trial on 21 metastatic breast cancer patients demonstrated that oral intake of BZL101, an aqueous extract of skullcap (up to 12 g in 350 ml solution per day) had a favorable toxicity profile and encouraging clinical activity in heavily chemotherapy pretreated patients (Rugo et al. 2007). In this study, the mean age of patients was 54 years and the mean number of prior treatments for metastatic disease was 3.9. There was no grade III or IV adverse events (AEs). The most frequently reported skullcap-related grade I and II AEs were: nausea (38%), diarrhea (24%), headache (19%), flatulence (14%), fatigue (10), constipation (10%), and vomiting (10%). At the conclusion of this Phase I clinical study, 16 patients were available for evaluation. Among them, 4 had stable disease (SD) for >90 days (25%), 3/16 had SD for >180 days (19%), 5 had objective tumor regression (1 of that was 1 mm short of a partial remission using the Response Evaluation Criteria in Solid Tumors criteria. A follow-up study using oral feeding on BZL (40 g/day) was demonstrated to be safe and well-tolerated in a Phase IB dose escalation trial of metastatic breast cancer (Perez et al. 2010). In this open-label, Phase IB, multicenter, dose escalation study, all 27 women had histologically confirmed breast cancer and measurable stage IV disease. These patients had a median of 2 prior chemotherapy treatments for metastatic disease, and were treated in four different dose cohorts. At the end, grade 3 and 4 AEs were uncommon. The following dose-limiting toxicities were observed: grade 3 diarrhea, fatigue, rib pain, and grade 4 AST elevation (aspartate aminotransferase liver enzyme and metastases). Among 14 evaluable patients according to the Response Evaluation Criteria in Solid Tumors criteria, 3 were classified with stable disease for >120 days (21%), 1 remains stable for 700 + days after 449 days BZL101 treatment. Three patients with objective tumor regression (>0% and <30%) were identified by independent radiology review. The maximum tolerated dose of BZL101 was not reached and it was defined as 40 g/day.
8.6 Discussion
8.6.1 Prospective Therapeutic Application and Direction for Cancer Patients
8.6.1.1 Breast Cancer
Breast cancer is the most common cancer among females in the United States (Jemal et al. 2010). The recent Phase I and Phase IB clinical studies involving the use of skullcap in advanced breast cancer patients indicate a promising therapeutic application of skullcap (Rugo et al. 2007; Perez et al. 2010). This data in collaboration with the known mechanisms of skullcap understood through in vitro studies (as described in Sect 8.5.1 and Table 8.2), along with the two positive preliminary clinical results suggest that skullcap aqueous extract may have a promising application in hormone related female cancers like ovarian, uterine, cervical and breast cancer, despite originally believed to be less effective in treatment of reproductive organ cancers (Chong and Lee 1988; Zhu 1998; Huang 1999).
8.6.1.2 Prostate Cancer
Prostate cancer is the most common form of cancer and the second leading cause of cancer death in American men (Jemal et al. 2010). Data from of our in vitro and in vivo animal studies suggested a few possible cancer prevention and inhibition mechanism of skullcap on prostate cancer (Wong et al. 2009). Phytochemicals in the whole aqueous extract of skullcap might work together to induce programmed cell death in prostate cancer cells through the expression of p53 and Bax, which activating the apoptosis pathway. Skullcap might also affect cancer progression through the regulation of Akt, phosphorylated Akt, and JNK to suppress the survival pathway in vitro.
Prostate cancer is an ideal subject for clinical trials of cancer prevention due to its prevalence, long natural history, relative ease of prostate gland biopsies, and the relative availability of surrogate tumor markers. Patients with early prostate-specific antigen elevation (‘prostate-specific antigen-only’ disease progression) and with early disease should be ideal candidates for novel investigational therapies such as skullcap (Smith and Kantoff 2001). The preliminary success of Phase I and IB clinical trials on the safety and efficacy of high dosage (40 g/day) aqueous extracts of skullcap (Rugo et al. 2007; Perez et al. 2010) suggest that a Phase I clinical study of the efficacy skullcap on prostate cancer would be rewarding. Prostate cancer like breast cancer is a hormonally-related tumor, and thus skullcap may also be effective. There is currently still no cure in Western medicine for advanced prostate cancer leading many patients to seek alternative medicines, such as traditional Chinese medicine (Tang and Eisenbrand 1992; The Pharmacopoeia Commission of PRC 2000). Further translational studies of skullcap and its selective cytotoxicity in prostate cancer cells and non-transformed prostate epithelial cells may reveal other plausible mechanisms for skullcap, such as induction of reactive oxygen species and inhibition of glycolysis in cancer cells would give more support for the clinical trial of skullcap in prostate cancer patients.
8.6.1.3 Liver, Colorectal, Uterine, and Lung Cancers
Scientific literature reviews yield another group of promising candidates for skullcap treatment including liver cancer (9 in vitro studies with 1 murine and 3 human cancer cell lines), colorectal cancer (9 in vitro studies with 2 human cell lines and 1 in vivo murine ACF model), uterine (6 in vitro studies with leiomyoma cells), and lung cancer (7 in vitro studies with 1 murine and 2 human cell lines) (Table 8.2). These studies have shown a favorable anticancer effect. Besides aqueous extract, phenorbide-a (C35H36N4O5), ethanol extract, and chloroform extract (phytol, wogonin, luteolin, and hispidulin) are especially effective (cytotoxic, anti-proliferation, induction of apoptosis and expression of Bcl-2) against liver cancer cells but with a low cytotoxic effect on normal liver L-O2 cell lines (Chan et al. 2006; Lin et al. 2006a, b; Tang et al. 2006, 2007; Yu et al. 2007). Following ethnopharmacological approach and with further positive translational studies plus animal studies, skullcap could be a promising therapeutic anticancer alternative for these types of patients.
8.6.2 Prospective and Challenges
According to Newman and Cragg (2007), about 30% of all new chemical compounds discovered in the last 20 years are derived from natural products and a further 20% are derivatives of these natural products. Additionally, over 60% of drugs approved for cancer treatment were derived from natural products (Newman et al. 2003). Since the approval of the first botanical drug in 2006, the Food and Drug Administration in USA has received over 350 botanical investigational new drug applications and the aqueous extract of skullcap, BZL101 was one of the earliest botanical investigational new drugs issued (Perez et al. 2010). With the present understanding of skullcap’s in vitro anticancer mechanisms (Tables 8.1 and 8.2) and the success of second Phase I clinical trial revealed that BZL101, a Phase II clinical trial for women with MBC is planned (Perez et al. 2010). Further positive clinical trial results would certainly facilitate the bringing of skullcap from bench to clinical use for breast cancer patients.
The Food and Drug Administration in USA defines dose by the total mass of the extract skullcap, BZL101, and not by the cumulative mass of the active compounds, and the aqueous extract of skullcap (BZL101 is the one of the well studied example) is the most effective type of extract. The challenge for future studies would be defining the relationship of response of pharmacokinetic profiles with the known active chemical components of skullcap. The drug development pathway of BZL101 is different from traditional pharmacognosy (identifying a single active chemical with significant enhanced activity per extract mass) in that the biological response appears to be dependent on simultaneous cytotoxic activity by a group of compounds rather than by just one (Perez et al. 2010). Since the mechanism for the biological response of skullcap has been studied and potential clinical response of BZL101 has been observed, studies on biomarkers for responses, or for patient selection, can be carried out to potentially replace traditional pharmacological analyses aiding clinicians to better understand the therapeutic index of BZL101. These would aid in the similar study and development of other aqueous extracts of skullcap.
References
Bui-Xuan, N. H., Tang, P. M., Wong, C. K., et al. (2010). Photo-activated pheophorbide-a, an active component of Scutellaria barbata, enhances apoptosis via the suppression of ERK-mediated autophagy in the estrogen receptor-negative human breast adenocarcinoma cells MDA-MB-231. Journal of Ethnopharmacology, 13, 95–103.
Campbell, M. J., Hamilton, B., Shoemaker, M., et al. (2002). Antiproliferative activity of Chinese medicinal herbs on breast cancer cells in vitro. Anticancer Research, 22, 3843–3852.
Cha, Y., Lee, E., Lee, H., et al. (2004). Methylene chloride fraction of Scutellaria barbata induces apoptosis in human U937 leukemia cells via the mitochondrial signaling pathways. Clinica Chimica Acta; International Journal of Clinical Chemistry, 348, 41–48.
Chan, J. Y., Tang, P. M., Hon, P. M., et al. (2006). Pheophorbide-a, a major anti-cancer component purified from Scutellaria barbata, induces apoptosis in human hepatocellular carcinoma. Planta Medica, 72, 28–33.
Chen, L. G., Hung, L. Y., Tsai, K. W., et al. (2008). Wogonin, a bioactive flavonoid in herbal teainhibits inflammatory cyclooxygenase-2 gene expression in human lung epithelial cancer cells. Molecular Nutrition & Food Research, 52, 1349–1357.
Chong, S. C., & Lee H. (1988). Chinese medicinal herbs of Hong Kong. Hong Kong: Commercial Press.
Chui, C. H., Lau, F. Y., Tang, J. C., et al. (2005). Activities of fresh juice of Scutellaria barbata and warmed water extract of Radix Sophorae Tonkinensis on anti-proliferation and apoptosis of human cancer cell lines. International Journal of Molecular Medicine, 16, 337–341.
Dai, S. J., Chen, M., Liu, K., et al. (2006a). Four new neo-clerodane diterpenoid alkaloids from Scutellaria barbata with cytotoxic activities. Chemical & Pharmaceutical Bulletin (Tokyo), 54, 869–872.
Dai, S. J., Tao, J. Y., Liu, K., et al. (2006b). Neo-clerodane diterpenoids from Scutellaria barbata with cytotoxic activities. Phytochemistry, 67, 1326–1330.
Dai, S. J., Sun, J. Y., Ren, Y., et al. (2007a). Bioactive ent-clerodane diterpenoids from Scutellaria barbata. Planta Medica, 73, 1217–1220.
Dai, S. J., Wang, G. F., Chen, M., et al. (2007b). Five new neo-clerodane diterpenoid alkaloids from Scutellaria barbata with cytotoxic activities. Chemical & Pharmaceutical Bulletin (Tokyo), 55, 1218–1221.
Dai, S. J., Shen, L., & Ren, Y. (2008). Two new neo-clerodane diterpenoids from Scutellaria barbata. Journal of Integrrative Plant Biology, 50, 699–702.
Dai, Z. J., Liu, X. X., Xue, Q., et al. (2008a). Anti-proliferative and apoptosis-inducing activity of Scutellaria barbata drug-containing serum on mouse’s hepatoma H22 cells. Zhong Yao Cai, 31, 550–553.
Dai, Z. J., Wang, X. J., Xue, Q., et al. (2008b). Effects of Scutellaria barbata drug-containing serum on apoptosis and mitochondrial transmembrane potential of hepatoma H22 cells. Zhong Xi Yi Jie He Xue Bao, 6, 821–826.
Dai, Z. J., Wang, Z. J., Li, Z. F., et al. (2008c). Scutellaria barbata extract induces apoptosis of hepatoma H22 cells via the mitochondrial pathway involving caspase-3. World Journal of Gastroenterology: WJG, 14, 7321–7328.
Dai, S. J., Pheng, W. B., Shen, L., et al. (2009a). Two new neo-clerodane diterpenoid alkaloids from Scutellaria barbata with cytotoxic activities. Journal of Asian Natural Products Research, 11, 451–456.
Dai, S. J., Pheng, W. B., Zhang, D. W., et al. (2009b). Cytotoxic neo-clerodane diterpenoids alkaloids from Scutellaria barbata. Journal of Natural Products, 72, 1793–1797.
Dai, S. J., Qu, G. W., Yu, Q. Y., et al. (2010). New neo-clerodane diterpenoids from Scutellaria barbata with cytotoxic activities. Fitoterapia, 81, 737–741.
Fong, S., Shoemaker, M., Cadaoas, J., et al. (2008). Molecular mechanisms underlying selective cytotoxic activity of BZL101, an extract of Scutellaria barbata, towards breast cancer cells. Cancer Biology & Therapy, 7, 577–586.
Gingrich, J. R., Barrios, J. R., Morton, R. A., et al. (1996). Metastatic prostate cancer in a transgenic mouse. Cancer Research, 56, 4096–4102.
Gingrich, J. R., Barrios, J. R., Kattan, M. W., et al. (1997). Androgen-independent prostate cancer progression in the TRAMP model. Cancer Research, 57, 4687–4691.
Goh, D., Lee, Y. H., & Ong, E. S. (2005). Inhibitory effects of a chemically standardized extract from Scutellaria barbata in human colon cancer cell lines, LoVo. Journal of Agricultural and Food Chemistry, 53, 8197–8204.
Gupta, S., Ahmad, N., Marengo, S. R., et al. (2000). Chemoprevention of prostate carcinogenesis by x-difluoromethylornithine in TRAMP mice. Cancer Research, 60, 5125–5133.
Han, F., Hu, J., & Xu, H. (1997). Effects of some Chinese herbal medicine and green tea antagonizing mutagenesis caused by cigarette tar. Zhonghua yu fang yi xue za zhi [Chinese Journal of Preventive Medicine], 31, 71–74.
Harris, G. K., Sharra, D. C., Leonard, S. S., et al. (2003). Effects of the Chinese medicinal herb Scutellaria barbata on cyclooxygenase-2 and inducible nitric oxide synthase expression on LPS-induced RAW 264.7 cells. In: Proceedings of the 94th Annual Meeting American Association of Cancer Research, 2003 April, Washington, DC. Philadelphia, PA: AACR, 44, 1419.
Huang, K. C. (1999). The pharmacology of Chinese herbs. Boca Raton: CRC Press.
Jemal, A., Siegel, R., Ward, E., et al. (2010). Cancer statistics, 2010. C CA: A Cancer Journal for Clinicians, 60, 277–300.
Jiangsu New Medical College. (1977). Dictionary of Chinese Materia Medica. Shanghai: Science and Technology Press of Shanghai.
Kim, D., Lee, T., Lim, I., et al. (2005). Regulation of IGF-I production and proliferation of human leiomyomal smooth muscle cells by Scutellaria barbata D. Don. in vitro: Isolation of flavonoids of apigenin and luteolon as acting compounds. Toxicology and Applied Pharmacology, 205, 213–224.
Kim, E. K., Kwon, K. B., Han, M. J., et al. (2007a). Induction of G1 arrest and apoptosis by Scutellaria barbata in the human promyeloctyic leukemia HL-60 cell line. International Journal of Molecular Medicine, 20, 123–128.
Kim, J. H., Lee, E. O., Lee, H. J., et al. (2007b). Caspase activation and extracellular signal-regulated kinase/Akt inhibition were involved in luteolin-induced apoptosis in Lewis lung carcinoma cells. Annals of the New York Academy of Sciences, 1095, 598–611.
Kim, K. W., Jin, U. H., Kim, D. I., et al. (2008). Antiproliferation effect of Scutellaria barbata D. Don. On cultured human uterine leiomyoma cells by down-regulation of the expression of Bcl-2 protein. Phytotherapy Research: PTR, 22, 583–590.
Lau, F. Y., Chui, G. H., Gambari, R., et al. (2005). Antiproliferative and apoptosis-inducing activity of Brucea javanica extract on human carcinoma cell. International Journal of Molecular Medicine, 16, 1157–1162.
Lee, T. K., Cho, H. L., Kim, D. I., et al. (2004a). Scutellaria barbata D. Don induces c-fos gene expression in human uterine leiomyomal cells by activating beta2-adrenergic receptors. International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society, 14, 526–531.
Lee, T. K., Kim, D. I., Han, J. Y., et al. (2004b). Inhibitory effects of Scutellaria barbata D. Don and Euonymus alatus Sieb aromatase activity of human leiomyomal cells. Cycle analysis. Immunopharmacology and Immunotoxicology, 26, 315–327.
Lee, T. K., Kim, D. I., Song, Y. L., et al. (2004c). Differential inhibition of Scutellaria barbata D. Don (Laminaceae) on HCG-promoted proliferation of cultured uterine leiomyomal and myometrial smooth muscle cells. Immunopharmacology and Immunotoxicology, 26, 329–342.
Lee, T. K., Lee, D. K., Kim, D. I., et al. (2004d). Inhibitory effects of Scutellaria barbata D. Don on human uterine leiomyomal proliferation through cell cycle analysis. International Immunonopharmacology, 4, 447–454.
Lee, H., Kim, Y., Choi, I., et al. (2010). Two novel neo-clerodane diterpenoids from Scutellaria barbata. Bioorganic & Medicinal Chemistry Letters, 20, 288–290.
Lin, J. M., Liu Y, & Luo R. C. (2006a). Effect of Scutellaria barbata extract against human hepatocellular Hep-G2 cell proliferation and its mechanism. Nan Fang Yi Ke Da Xue Xue Bao, 26, 975–977.
Lin, J. M., Liu, Y., & Luo, R. C. (2006b). Inhibitory effect of Scutellaria barbata extracts against human hepatocellular carcinoma cells. Nan Fang Yi Ke Da Xue Xue Bao, 26, 591–593.
Marconett, C. N., Morgenstern, T. J., San Roman, A. K., et al. (2010). BZL 101, a phytochemcial extract form the Scutellaria barbata plant, disrupts proliferation of human breast and prostate cancer cells through distinct mechanisms dependent on the cancer cell phenotype. Cancer Biology & Therapy, 10, 397–405.
Newman, D. J., & Cragg, G. M. (2007). Natural products as sources of new drugs over the last 25 years. Journal of Natural Products, 70, 461–477.
Newman, D. J., Cragg, G. M., & Snader, K. M. (2003). Natural products as sources of new drugs over the period 1981–2002. Journal of Natural Products, 66, 1022–1037.
Nguyen, D. L., Devadhason, R. R., & Wong, B. Y. (2008). Dosage-dependent regulation of caspase 8 activation in LNCaP and DU145 human prostate cancer cell lines by the Chinese medicinal herb Scutellaria barbata. 7th Annual AACR International Conference of Frontiers in Cancer Prevention Research, A39.
Perez, A. T., Arun, B., Tripathy, D., et al. (2010). A phase 1B dose escalation trial of Scutellaria barbata (BZL101) for patients with metastatic breast cancer. Breast Cancer Research and Treatment, 120, 111–118.
Powell, C. B., Fung, P., Jackson, J., et al. (2003). Aqueous extract of herba Scutellaria barbatae, a Chinese herb used for ovarian cancer, induces apoptosis of ovarian cancer cell lines. Gynecologic Oncology, 91, 332–340.
Rugo, H., Shtivelman, E., Perez, A., et al. (2007). Phase I trial and antitumor effects of BZL101 for patients with advance breast cancer. Breast Cancer Research: BCR, 105, 17–28.
Shoemaker, M., Hamilton, B., Dairkee, S. H., et al. (2005). In vitro anticancer activity of twelve Chinese medicinal herbs. Phytotherapy Research: PTR, 19, 649–651.
Smith, M. R., & Kantoff, P. W. (2001). Molecular biology of prostate cancer. In J. Mendelsohn, P. M. Howley, M. A. Israel, & L. A. Liotta (Eds.), The molecular basis of cancer (2nd ed., pp. 343–360). Philadelphia: WB Saunders Company.
Suh, S. J., Yoon, J. W., Lee, T. K., et al. (2007). Chemoprevention of Scutellaria barbata on human cancer cells and tumorigenesis in skin cancer. Phytotherapy Research: PTR, 21, 135–141.
Tang, P. M., Chan, J. Y., Au, S. W., et al. (2006). Pheophorbide a, an active component in Scutellaria barbata, possesses photodynamic activities by inducing apoptosis in human hepatocellular carcinoma. Cancer Biology & Therapy, 5, 1111–1116.
Tang, P. M., Chan, J. Y., Zhang, D. M., et al. (2007). Pheophorbide a, an active component in Scutellaria barbata, reverses P-glycoprotein-mediated multidrug resistance on a human hepatoma cell line R-HepG2. Cancer Biology & Therapy, 6, 504–509.
Tang, W., & Eisenbrand G. (1992). Chinese drugs of plant origin: Chemistry, pharmacology and use in traditional and modern medicine. Berlin: Springer.
The Pharmacopoeia Commission of PRC. (2000). Pharmacopoeia of the People’s Republic of China (English Edition). Beijing: People’s Republic of China.
Wei, P. Y., Pu, H. Q, Wei, X., et al. (2007). Apoptosis-induced effect of Scutellaria barbata extract on human lung cancer SPC-A-1 cells and the expression of apoptosis associated genes. Zhong Yao Cai, 30, 1270–1273.
Wong, B. Y., Lau, B. H., & Teel, R. W. (1992a). Chinese medicinal herbs modulate mutagenesis, DNA binding and metabolism of benzo[a]pyrene. Phytotherapy Research: PTR, 6, 10–14.
Wong, B. Y., Lau, B. H., & Teel, R. W. (1992b). Chinese medicinal herbs modulate mutagenesis, DNA binding and metabolism of benzo[a]pyrene 7,8-dihydrodiol and benzo[a]pyrene 7,8-dihydrodiol-9,10-epoxide. Cancer letters, 62, 123–131.
Wong B. Y., Lau, B. H., Tadi, P. P., et al. (1992c). Chinese medicinal herbs modulate mutagenesis, DNA binding and metabolism of aflatoxin B1. Mutation Research, 279, 209–216.
Wong, B. Y., Lau, B. H., Yamasaki, T., et al. (1993a). Inhibition of dexamethasone-induced cytochrome P450-mediated mutagenicity and metabolism of aflatoxin B1 by Chinese medicinal herbs. European Journal of Cancer Prevention, 2, 351–356.
Wong, B. Y., Lau, B. H., Yamasaki, T., et al. (1993b). Modulation of cytochrome P450IA1-mediated mutagenicity, DNA binding and metabolism of benzo[a]pyrene by Chinese medicinal herbs. Cancer Letters, 68, 75–82.
Wong, B. Y., Jia, T. Y., Wan, C. P., et al. (1996). Oldenlandia diffusa and Scutellaria barbata augment macrophage oxidative burst and inhibit tumor growth. Cancer Biotherapy & Radiopharmaceuticals, 11, 51–56.
Wong, B. Y., Nguyen, D. L., Cabrera, I. B., et al. (2007). Modulation of apoptosis via the induction of caspase 3, 8, and 9 in LNCaP cells by two Chinese medicinal herbs Scutellaria barbata and Oldenlandia diffusa. 6th Annual AACR International Conference of Frontiers in Cancer Prevention Research, 112, A135.
Wong, B. Y., Nguyen, D. L., Lin, T., et al. (2009). Chinese medicinal herb Scutellaria barbata modulates apoptosis and cell survival in murine and human prostate cancer cells and tumor development in TRAMP mice. European journal of cancer prevention: The Official Journal of the European Cancer Prevention Organisation (ECP), 18, 331–341.
Wong, B. Y., Kim, L. Y., Kim, B. Y., et al. (2010). Inhibition of azoxymethane-induced aberrant crypt foci in C57BL/6 mice by the Chinese medicinal herbs Scutellaria barbata. 101st Annual Meeting American Association of Cancer Research 2010, A5677.
Wu, Y, & Chen, D. F. (2009). Anti-complementary effect of polysaccharide B3-PS1 in Herba Scutellariae barbatae (Scutelllaria barbata). Immunopharmacology and Immunotoxicology, 30, 696–701.
Yin, X., Zhou, X., Jie, C., et al. (2004). Anti-cancer activity and mechanism of Scutellaria barbata extract on human cancer cell lines A549. Life Sciences, 75, 2233–2244.
Yu, J., Liu, H., Lei, J., et al. (2007). Antitumor activity of chloroform fraction of Scutellaria barbata and its active constituent. Phytotherapy Research: PTR, 21, 817–822.
Zhu, F., Di, Y. T., Liu, L. L., et al. (2010). Cytotoxic neoclerodane diterpenoids from Scutellaria barbata. Journal of Natural Products, 73, 233–236.
Zhu, Y. P. (1998). Chinese materia medica: Chemistry, pharmacology and applications. Amsterdam, Netherlands: Harwood Academic, 1998.
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Wong, B.Y., Wong, H.H. (2011). An Evidence-based Perspective of Scutellaria Barbata (Skullcap) for Cancer Patients. In: Cho, W. (eds) Evidence-based Anticancer Materia Medica. Evidence-based Anticancer Complementary and Alternative Medicine. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0526-5_8
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