Scutellaria Barbata - Assignment Example

Scutellaria Barbata Name xxxxxxxxxxxxxxxxxxxxx Course xxxxxxxxxxxxxxxxxxxxx Lecturer xxxxxxxxxxxxxxxxxxxxx Date xxxxxxxxxxxxxxxxxxxxx Introduction Medical practice needs a shift from radiation and chemotherapy which aim at reducing replication by causing DNA damage if the tumors, but end up causing harsh and fatal side effects on patients (Marconnet et al 2010).There is a critical need for alternative therapies, both for hormone- and non-hormone sensitive reproductive cancers, therapies with minimal side-effects. This need for alternative has led to research and development of bio-therapy. Cancer tumors growth has been described in two models or theories. The somatic model explains that they may develop due to the transformation of normal stem cells. This is through a series of events of events in which body cells acquire mutational changes. These events make up the tumor progression process which begins with cellular dysplasia, then physiologically to invasive cancer before finally coming into metastatic spread in which the cancerous cells increase. A restricted progenitor cell can also lead to cancer. Whatever the pathway a cancer takes in developing, it is important that treatment be offered. The therapy selected should be considerate of the pathway and induce anti-metastatic activity. Diagram: tumor progression (www2.unil.ch) There has been increased activity research in bioactivity of natural plants as a growing trend in medical research. Natural plants are now considered an important resource for developing new drugs. This is so in the prevention and management of cancer. There has been an intense search for biological anti-cancer drugs. Natural plants have proved to have anti-cancer value. Literature indicates that about 30 plant derived compounds have been isolated so far and are currently under trials (Nirmana, Samundeeswari, & Samkar 2011). There are four major structural classifications of plant-derived anticancerous compounds each with a distinct mechanism: vinca alkaloids which inhibit cell proliferation by causing a characteristic block during mitosis hence leading to apoptosis. This is by microtubular dynamics. Epipodophyllotoxin lignans are potential for treating testicular cancers, bronchial and lymphomas cancers (Shoeb 2006). Taxanes are used as first- and second-line treatments in ovarian, metastatic and breast cancer patients as well as conditions such as lymphoid malignancies. Camptothecin analogues work by inhibiting DNA Topoisomerase, a major player in replication and transcription of the DNA. Plants of the genus Scutellaria are a common part of Eastern and American traditional medicine (Joshee et al 2010). It is known to contain alkaloids and flavones. Flavanoids are compounds of low molecular weight. Research has described the biosynthesis of flavonoids leading to cloning and characterization of its biosynthetic enzymes (Joshee et al 2010). Scutellaria barbata (skullcap) has been used in traditional Chinese and Korean medicine for inflammation illnesses and cancers. This paper will discuss literature and research studies in a bid to describe the use of S. barbata extracts in cancer treatment. It shall discuss the effectiveness of the plant in the treatment of hormone sensitve cancers. It shall first detail on the anti-cancer chemical components discussing their mechanisms and then disuss application in treatment of a cancer, a case study. This is so given that it is an alternative innovation for cancer treatment. What are hormone sensitive cancers? Hormone sensitive cancers also known as reproductive cancers are among the most common cancers and leading cause of cancer deaths in the world. Basically, there are two kinds of hormone sensitive cancers; breast cancer and prostate cancer. These cancers thrive in response to certain steroid hormones and particularly androgen for prostate cancer and estrogen for breast cancer. This occurs as a result of the active conformational change of the steroid receptor induced by the binding of the steroid and cognate receptors (Welcsh 2009). Steroid receptors are therefore, allowed to interact freely with transcription factors or DNA found within target gene promoters and to modulate transcription of downstream target genes through their association with nuclear cofactors. Research has proven that out of all the cases of diagnosed breast cancers two thirds are estrogen sensitive while 80% of prostate cancers are androgen sensitive. However, reproductive hormones can develop from hormone sensitive state to hormone insensitive state which more advanced and complex (Wang et al 2004). What therapies are currently available for hormone sensitive cancers? Currently, there are several therapies that focus on hormone –dependent growth of reproductive hormones. The preferred clinical treatment option for breast cancer is aromatase inhibitor which acts by inhibiting synthesis of estrogen hence reducing the number of ligands available for binding to estrogen receptors. Other alternatives to aromatase inhibitors are selective estrogen receptor downregulator (SERDs) and selective estrogen receptor modulators (SERMs. SERDs antagonize the activity of estrogen receptors while SERDs ablate expression of estrogen receptors. Chemical castration is the principle behind treatment of prostate cancer and it majors on reducing circulation of androgen into the body tissues. On the other hand, hormone insensitive reproductive cancers can be treated using therapies that are aimed at DNA damage of actively replicating cells and this technique include radiotherapy and chemotherapy. What are the chemical components in S. barbata and how do they work? The aqueous extract of skullcap has been proven to contain chemopreventive and anti-mutagenic properties. Studies have shown that it possesses phytochemicals that act by inhibiting DNA binding, metabolism and mutagenesis of pro-carcinogens aflotoxin B1 (AFB1) and benzo[a]pyrene. Mutagenicity property of Afb1 was specifically demonstrated in the mutant bacteria Salmonella typhimurium. In addition, skullcap contains a number of bioactive flavonones such as scutellarin, scutellarein, carthamidin, wogonin, isocarthamidin, apigenin among others. Other chemical constituents of skullcap include chloroform, ethylacetate, methanol, ethanol, n-hexane and methylene chloride (Ying et al 2005). What is BZL 101 and how does treat reproductive cancers? BZL 101 is a form of an aqueous skullcap extract that has been proven to have anticancer properties. Phase 1 preclinical trials have indicated that BZL 101 has promising efficacy and favorable toxicity profile. It has high selective cytotoxicity since it only induces the death of cancer cells and does not damage non-transformed cells. This high selectivity is based on BZL 101 strong induction on reactive oxygen species (ROS) found in tumor cells where it causes excessive oxidative DNA damage leading to necrotic death. Besides causing significant oxidative death, BZL 101 also causes hyperactivation of poly (ADP-ribose) polymerase (PARP). Normally, PARP activated by mild DNA damage is used to facilitate cell survival and DNA repair but excessive damage leads to hyperactivation of PARP where it instead activates the necrotic death pathway. Hyperactivation of PARP caused by BZL 101 has also been shown to inhibit the process or repairing damaged DNA. Moreover, it leads to inhibition of glycolysis, depletion of NAD and NADH, loss of ATP which denies the cells nourishment leading to programmed cell death. Its efficacy has been proven using two lines of human breast cancer cells; estrogen sensitive MCF7 and estrogen insensitive MDA-MB-231. It was also analyzed using androgen insensitive PC3 and androgen sensitive LNCaP which are found during the early and final stages of reproductive cancers. The study revealed that BZL inhibited the growth of cancer cells by regulating cell cycle expression levels which vary depending on the cancer cell phenotype (Cho 2010). In the early stages of theMCF7, estrogen sensitive cells, BZL induced arrest of G1 cell cycle and stopped expression of G1 cell cycle regulators such as Cyclin D1, CDK4, and CDK2. Figure 1 show how multiple concentrations of BZL 101 react in downregulation of CDK2 and ERα transcript expression over a given period of time. Figure1: Downregulation of CD2 and CD4 at varying concentrations of BZL 101 and different instances. (Marconett et al 2010) In addition, it halted the growth factor stimulatory pathways and expression of estrogen receptor-α. These activities led to the loss of promoter activities in cancer cells which subsequently led to cell death. Figure 2 indicates the variation in response to BLZ 101 48 hours after treatment of each cancerous cell. There is significant increase in G1 peaks of MDA-MB-231 and MCF7 at BZL 101 concentrations of 3.0mg/ml and 2.0 mg/ml respectively. Early stages of androgen sensitive LNCaP can be arrested using BZL 101 during the G2/M phase where it decreases activity of Cyclin B1 and CDK4 as well as expression of androgen receptor. Figure 2: G1 peaks for both hormone sensitive and hormone insensitive cancer cell lines at varying concentrations of BZL 101. (Marconett et al 2010) Besides increasing the content of sub-G1 DNA in the cell, BZL 101 has been shown to induce cell cycle arrest in treatment of reproductive cancers. Figure 3 shows how the S-phase is arrested for both hormone insensitive cell lines: MDA-MB-231 and PC3 cancer cells. Treatment using BZL resulted to over 15% increase of cells in the S-phase. On the other hand, hormone sensitive cell lines, LNCaP and MCF7 displayed a BZL 101 induced arrest in G2 /M phase (9% increase) and G1 phase (15% increase). Figure 3: Arrest of G and S phases of the cancer cells by BZL 101 (Marconett et al 2010) Indeed, BZL 101 exerts specific phenotype anti-proliferative gene expression responses in human reproductive cancer cells. These findings are valuable in development of potential therapeutic strategies in treatment of breast and prostate cancers using BZL 101. How is S. barbata used in treatment of hormone sensitive cancers? Vitro and vivo studies of S. barbata extracts have shown promising anti-cancerous results in both human and animals. Vitro studies have indicated of skullcap as having anti-mutagenesis properties by changing the metabolism of mutagenic compounds which reduces their DNA binding efficiency (Cho 2011). In vitro studies have indicated skullcap as having effective response in all the three stages of carcinogenesis: initiation, promotion and progression. This is by exerting anicancer mechanisms such as anti-ploriferation, anti-inflammation and apoptosis induction. It has been found to induce sex hormone-specific glycolytic necrosis (Cho 2011). This is more in the prevention and treament of breast, prostate and uterine cancer. An In vivo model displayed the potential of the aqueous extract in inhibiting tumor growth by enhancing macrophage cell-line activity. A notable aqueous extract of S. barbata is BZL101which has has extensivly effective anti-cancer chemical components (Cho 2011). A study conducted by Joshee et al, 2010 compared the anti-tumor potential of Scutellaria flavonoids in action against breast cancer, prostate cancer and glioma cells. The results showed that the flavonoids: apigenin, baicalin, baicalein, scutellarein, chrysin and wogonin, inhibited ploriferation in addition to significantly enahncing apoptosis and inducing G1/G2 arrest. This corroborated results involving BZL101 which is known to inhibit breast cancer cell-lines through apoptosis. In treating breast cancer, research shows that apart from aromatase inhibitors inhibiting the peripheral production of oestrogen and the external oestrogen supply to the cancerous cell, it should inhibit intratumoral aromatase hindering internal production of oestrogen. This is because a large portion of breast cancerous cells express their own aromatase (Lee, Han, Han, & Kim 2004). With this background, the potential in S. barbata D. Don and Euonymus alatus Sieb was tested in aromatase-containing leiomymomal and myometrial cells. Leiomyoma is a common tumor in the female genitalia whose development has been largely linked to ovarian hormones. In its treatment, estrogen deprivation is an effective therapy. This is also the case for the other hormone sensitive cancer whose therapy is effective once the related hormones are deprived. The study demonstrated the potential of S. barbata in inhibiting aromatase. This was along time- and dose-related variations (Lee, Han, Han, & Kim 2004). Fong et al, 2008 and Marconnet et al,2010 in their studies have linked BZL101 as having great potential. BZL101 has anti-ploriferative effects in the initiation and progression stages of hormone-sensitive and insensitive prostate and breast cancers. This is by inducing arrests at the G1 and G2 /M phases. The G2 phase is the hallmark of DNA damage due to oxidative stress. BZL101 leads to accumulation of reactive oxygen species and accumulation of the breast cell-lines in the G2 phase (Fong et al, 2008). Increased reactive species induces DNA damage. BZL101 has effects on expression of oestrogen and androgen receptors. The receptors are central agonists in regulating the progression stage. BZL101 treatment has demonstrated ability to reduce MCF7 breast tumors levels of ERα protein and trascript (Marconnet et al,2010). This is because BZL contains has inherent selective estrogen receptor down regulator activity (SERD). This is in addition to altering growth factor receptor mechanisms and intracellularsignaling in breast cancer. In addition the above mentioned, this S. barbata extract has been related with inducing DNA damage which is further related to cytotoxic activity. There is a correlation between DNA damage and cell death induction with BZL101 (Fong et al 2008). Multiple other plannts have been discovered as having medicinal value. Their extracts continue to find use in the medical world. Such an extract is imatinib now licensed as Gleevec TM. It is used to treat chronic myelogenous leukemia (CML). References Cho, W. 2011. Evidence-based anticancer materia medica. New York: Springer. Fong, S., et al. 2008. Molecular mechanisms underlying selective cytotoxic activity of BZL101, an extract of Scutellaria barbata, towards breast cancer cells. Cancer Biology & Therapy 7(4) , 577-586. Joshee, N., et al. 2010. Scutellaria Biotechnology: Achievements and Future Prospects. Bulletin UASVM Horticulture, 67(1) , 24-33. Lee, T., Han, D., Han, J., & Kim, C. 2004. Inhibitory Effects of Scutellaria Barbata D. Don. and Euonymus Alatus Sieb. on Aromatase Activity of Human Leiomyomal Cells. Immunopharmacology and Immunotoxicology 26 (3) , 315-327. Marconnet, C., et al. 2010. 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