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Traditional Chinese Medicine (TCM) is a type of holistic, natural health care system with its origin deeply rooted in the ancient philosophy of Taoism. The practice of TCM dates back more than 2500 years and it is regarded as one of the oldest forms of medicines. Chinese herbal medicines are a very important component of TCM, which also includes other mind and body practices like acupuncture, moxibustion (burning an herb above the skin to apply heat to acupuncture points), tui na (Chinese therapeutic massage), dietary therapy, tai chi and qi gong (practices that combine specific movements or postures, coordinated breathing, and mental focus). The benefits and use of TCM have been passed on anecdotally from generations. TCM practitioners use herbal medicines alone or in combination with various mind and body practices to treat or prevent health problems.
Ben Cao Gang Mu (????) or the Compendium of Materia Medica (CMM), compiled and written by LI Shi-zhen, is the most comprehensive TCM literature available to date. The CMM contains information of more than 12,800 medicinal substances – primarily plants, but also some minerals and animal products and is extensively used by TCM practitioners worldwide (1). In TCM, different parts of the same or different plants are usually combined in different ratios and given as teas, capsules, liquid extracts, granules, or powders for disease alleviation (2).
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Integration of TCM with conventional cancer care is currently the norm in China, and there are numerous evidances to support the benefits. A host of recent studies have highlighted the importance of TCM in imparting long term survival benefits of improving the quality of life in cancer patients through psycho-behavioral intervention (3-5). A compilation of the reports and articles present in four major Chinese electronic databases including China National Knowledge Infrastructure (CNKI) (1911 – November 2011), Chinese Scientific Journal Database (VIP) (1989 – November 2011), Chinese Biomedical Literature Database (CBM) (1978 – November 2011), and Wanfang Database (1994 – November 2011) indicate a paradigm shift towards the growing importance of TCM as anticancer agents in China and the substantial amount of research being performed in developing TCM as mainstream cancer medicine (6). With a further push by President Xi Jinping and the CPC China, TCM is touted to become an alternative conventional medical practice in the years to come. Although the importance of TCM is increasing in the Western countries and several promising developments are afoot, they still lag far behind. In Western countries, TCM is practiced primarily as a complementary healthcare approach rather than being used as conventional medicines.
Triterpenoids represent the largest group of phytochemicals present in nature. Although these isopentenyl pyrophosphate oligomers were considered to be biologically inactive for a long period of time, accumulating evidence of their pharmacological activities coupled with a low toxicity profile has sparked renewed interest in these multifunctional compounds with regard to human health and disease (7). A large number of these triterpenoids have been reported to exhibit inhibitory effects on several cancer types in vitro and also in preclinical models of cancer (8). Out of nearly 200 different skeletons identified, pentacyclic triterpenes are the most common (9).
Natural pentacyclic triterpenoids (PTs) and their semisynthetic derivatives have often been reported to exhibit a wide range of biological activities. Anticancer and anti-inflammatory activities are the most rigorously studied aspects of these compounds (10). PTs are potential candidates for the development of more efficient anticancer or cancer preventive drugs. These biologically active compounds, mainly act by intervening with a diverse range of molecular targets and signaling pathways involved in cancer cell proliferation and survival, including the PI3K/Akt/mTOR and IKK/NF-kB signaling axis, STAT3 pathway, and MAPK cascades (11, 12). In this short review, we have shed light on the basic research being carried out on an important bioactive component of Chinese herbal medicine, “Jiu Bi Ying”, to develop it as a contemporary medication for the treatment of cancers.
The genus Ilex (Aquifoliaceae), comprising of approximately 500–600 species of dioecious trees and shrubs, is widely distributed in tropical and subtropical regions of the world. Out of these, 204 Ilex species (149 endemic) have been reported to be growing in South and East China (13), and more than 30 species of Ilex have been extensively used as traditional Chinese medicine (TCM) over the years (14). The barks of I. rotunda, commonly known as “Jiu Bi Ying” in China, has been used by traditional healers for the treatment of common cold and fever, urinary tract infection, bone pain, and cardiovascular diseases. The crude extract of this plant has been reported to possess diverse bioactivities including protecting the cardiovascular system, anti-inflammation, anti-bacterial, anti-oxidation and it has been officially recorded in the Chinese Pharmacopoeia since 2010 (15, 16).
It is widely accepted that the therapeutic effects of herbal medicines (TCM) are based on the integrative contributions and synergism of multiple bioactive constituents. Triterpenoids are the major bioactive compounds obtained from the bark and leaves of I. rotunda along with diterpenoids, lignins, phenolic acids and steroids (17). Rotundic acid is a naturally occurring pentacyclic tri-terpenoid and has been reported to inhibit cell growth and proliferation in several cancer types. A recent report by Li and Chen et al. showed that RA attenuated lipopolysaccharide (LPS) stimulated colitis-associated cancer progression by preventing NF-KB translocation into the nucleus of Caco2 (human colorectal adenocarcinoma) cells. Additionally, RA also inhibited LPS-induced nitric oxide (NO) release from intestinal cells thereby decreasing intestinal inflammation (18). A research group headed by He YF from the Jilin Academy of Chinese Medicine Sciences, China showed that RA induced apoptosis in Cas3-MCF 7 (human breast adenocarcinoma) cells by activating the tumor suppressor p53 gene. The results indicated that caspase 3 served as a crucial effector molecule in RA-induced apoptosis in MCF 7 cells (19). Li HJ et al. showed that RA successfully attenuated MCF 7 cell viability in a concentration-dependent manner. Additionally, the group also demonstrated that RA in combination with a lower dose of radiation produced a greater inhibitory effect as compared to the higher dose of radiation alone. The increased efficiency resulted from RA enhancing the expressions of radiation-induced ataxia-telangiectasia mutated (ATM) and p53proteins. The results revealed that radiation combined with RA induced Bcl2-associated X protein expression and cell apoptosis in MCF 7 cells by meddling with the ATM/p53 pathway (20). Kong LY et al. reported that rotundic acid obtained from the barks of Mitragyna diversifolia exhibited a potent inhibitory effect on the viability of MCF 7 and HT 29 (colorectal adenocarcinoma) cells (21).
Many groups have also tried and succeeded in enhancing the cytotoxicity of rotundic acid by creating their semisynthetic derivatives via structural modifications. Zhang et al. observed that modifying RA by trans-esterification at C3 and C23 enhanced its inhibitory potential in HeLa (human cervical cancer), A375 (human melanoma), HepG2 (human hepatoma), SPC-A1 (human lung adenocarcinoma), and NCI-H446 (human small cell lung cancer) cell lines. The modified RA derivative induced cell death by caspase 3 activation in HeLa cells (22). Similarly, Wang et al. synthesized six novel RA derivatives by modifications at 28-COOH group and evaluated their cytotoxicity on HeLa, HepG2, and SGC-7901 (human gastric carcinoma) cells. The group reported that one of the modified compounds showed enhanced effects as compared to RA and induced apoptosis and G0/G1 cell cycle arrest of HepG2 cells (23).
Reactive oxygen species (ROS) are critical mediators of cancer. Increased ROS accumulation during malignancy may lead to DNA damage and mutagenesis (24). Numerous studies have highlighted the important role played by these free radicals in tumor cell survival, proliferation, invasion, angiogenesis, metastasis, and drug resistance (25, 26). Therefore, redox regulation has emerged as an important target for anticancer therapy. Increasing evidences show the importance of ROS scavengers in cancer prevention (27, 28). Tian-Shung Wu et al. reported that rotundic acid exhibited mild inhibitory effects on the LPS-induced iNOS-dependent NO production and NOX-dependent ROS production in murine microglial cells (29). More recently, Mei-chin Yin et al. reported reduced levels of ROS in the heart and kidney of 0.1% w/w RA fed diabetic mouse. The group also stated that RA at the above concentration reduced cardiac and renal levels of inflammatory cytokines IL-1?, IL-6, TNF-?, and MCP-1 (30). Cancer cell cytotoxicity along with mild free radical scavenging activity makes RA a suitable candidate for further development as an anticancer drug.
Currently, the research on RA is in its nascent stage. As safety control and efficacy evaluation has been a long standing Achilles heel in the development of Chinese herbal medicines (31), further in-depth studies are needed to properly decipher the pharmacology of RA on different cancers and to determine its mechanism of action.
Though RA has been anecdotally reported to possess anticancer activities, the real-life scientific and valid information about the biological activities of RA against cancer is few. Research on the bioactivity of RA is still at its infancy but the ability to selectively induce cell death in cancer cells by modulating major cell survival pathways have generated quite a bit of excitement about further development of this herbal compound. Though there are some health and safety concerns on the use of traditional Chinese medicine especially in the western world, their growing popularity is a positive sign. Proper scrutiny of drug safety, pharmacovigilance and pharmacoepidemiology may not only lead to the development of RA but also many other herbal medicines as chemopreventive agents against cancers and other diseases”
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