Current Drug Discovery Technologies - Volume 7, Issue 1, 2010

Despite the tremendous effort on research and development by government and industry, effective treatment of cancer in most patients remains elusive at present. Even if a given chemotherapeutic regimen is very effective at onset, it eventually will fail, due to drug resistance and /or organ toxicity. Thus, there is a great need to incorporate new mode of therapeutic approach in prevention and treatment of cancer. Chinese medicines (CM) have been used in China for about 5000 years for symptomatic treatment of diseases including cancer. The traditional approach of CM is to use different herbal formulae to restore the balance of Yin-Yang of body energy so body function can be normalized. Can this traditional Chinese medicine (TCM) approach provide an alternative to the evidence based conventional cancer chemotherapy? It would be a fiction to expect TCM to substitute as an alternative approach to modern cancer chemotherapy, despite its thousands of years of use in China. However, there are distinct potentials, from theory to herbal compounds, which could be derived from CM. For example, the balance concept of TCM may be an intriguing therapeutic approach for future cancer therapy— aiming not to eradicate all cancer cells but to keep it in balance with normal cells to result in bodily function as close to normal as possible and maintain in such a state as long as possible. Another potential contribution of TCM is its rich source of active anticancer compounds and their combinations which could be developed and proved to be effective therapeutic regimens (or adjunctive regimens) in the future. In tracing the source of new drugs for cancer, more than half of current anticancer agents used clinically in USA are either natural occurring or derived from natural products. These include Vinca alkaloids, taxanes, podophyllotoxin, camptothecins and anthracyclines. Despite the interest in plant-based new drug discovery, only a small portion of more than 250,000 known plant species have been investigated for cancer drug discovery. It is likely that herbs used in TCM can be a useful source of new anticancer drugs. Furthermore, the TCM formulae themselves (which always composed of mixtures of components) may simultaneously target multiple cancer-causing genes/pathways and thus achieve superior effect as compared to single agents aiming for a single molecular target. Nevertheless, before any TCM product can be accepted by the Western world as complementary and alternative medicine for cancer treatment/prevention, it is crucial to identify bioactive components, understand their pharmacological mechanisms, and achieve quality control of a given product along with demonstrating its clinical efficacy. In this issue of Current Drug Discovery Technologies, eight review articles highlighting in more detail some of these important points relating to development of CM as anti-cancer drugs. These articles describe the potential use of the balance concept, examples of CM-derived drugs that have been approved by US FDA and new technology (chemoinformatics) and targets (drug transporters and other molecular targets) as well as TCM products and formulations used for lung cancer. We hope that this special issue will provide a glimpse of examples and new technologies that can be applied toward improving the development of CM, potentially leading to new and effective anti-cancer agents in the future.

Traditional Chinese Medicines (TCM) are rapidly gaining attention in the West as sources of new drugs, dietary supplements and functional foods. However, lack of consistent manufacturing practices and quality standards, fear of adulteration, and perceived deficiencies in scientific validation of efficacy and safety impede worldwide acceptance of TCM. In addition, Western pharmaceutical industries and regulatory agencies are partial toward single ingredient drugs based on synthetic molecules, and skeptical of natural product mixtures. This review concentrates on three examples of TCM-derived pharmaceuticals and functional foods that have, despite these usual obstacles, risen to wide acceptance in the West based on their remarkable performance in recent scientific investigations. They are: Sweet wormwood (Artemisia annua), the source of artemisinin, which is the currently preferred single compound anti-malarial drug widely used in combination therapies and recently approved by US FDA; Thunder god vine (Tripterygium wilfordii) which is being developed as a botanical drug for rheumatoid arthritis; and green tea (Camellia sinensis) which is used as a functional beverage and a component of dietary supplements.

During the course of our investigation of longevity promoting natural products and Chinese herbs in the last 15 years, we come to the conclusion that in order to have healthy, productive and graceful maturing, it is necessary to maintain a dynamic balance between proinflammatory and anti-inflammatory loads. This may also help to prevent cancer as well as premature degeneration of various organ systems. Modern life style and food intake tend to overload proinflammatory factors. To overcome this it is desirable to regularly consume fresh fruits, vegetables and multiple grains, various beans including soybeans and/or minimally processed, unbleached products. When this is not sufficient or possible, taking proper dietary supplements under the guidance of knowledgeable health professional can be helpful.

Traditional Chinese Medicine (TCM), which has been used for thousands of years to treat diseases, provides unique theoretical and practical methodologies for disease control. With the increasing accumulation of TCM data, it is imperative to study and analyze these resources with modern technologies and to elucidate the molecular mechanisms of TCM therapy. However, the philosophy, framework and technique of TCM are quite different from those of Western medicine, which causes complications when attempting to design modern drug treatments based on TCM. To meet this challenge, some basic chemoinformatics techniques, including molecular similarity searching, virtual screening and inverse docking, have been utilized in an attempt to gain a deeper understanding of TCM and to accelerate the TCM-based drug discovery. Recent progress on the use of chemoinformatics in TCM research will be discussed and an example of the preliminary application of chemoinformatics methods in anticancer drug design will be provided.

Traditional Chinese/herbal medicine (TCM) is now commonly used by cancer patients of Asian ethnicity to supplement or replace prescribed treatments. The overall survival rate for lung cancer has not improved significantly in the past several decades; it remains the leading cause of cancer death. Much more attention has been paid by clinicians and researchers to the possible use of compound Chinese medicine (CCM) as effective anti-lung cancer medicines. In this review, we briefly summarize the clinical and experimental status of numerous CCMs recently developed primarily in China for the treatment of lung cancer, including formulations, treatment effectiveness, and molecular mechanisms. By presenting this information, our goal is to possibly open up new future avenues for the practice of lung cancer treatment.

Scientific progress in genetics, cell and molecular biology has greatly ameliorated our comprehensive understanding of the molecular mechanisms of neoplastic transformation and progression. The rapidly advancing identification of molecular targets in human cancers during the last decade has provided an excellent starting point for the development of novel therapeutics. A huge variety of potential molecular targets have been identified, many of which are already in the market for therapeutic purposes. It is now becoming possible to target pathways and/or molecules that are crucial in maintaining the malignant phenotype. Traditional Chinese medicine (TCM) is often considered as alternative or complementary medicine. TCM represents a holistic approach and lacks high-quality scientific evidence on its effectiveness. Therefore, it is frequently regarded with some scepticism by western academic medicine. In this review, we report that application of modern technologies allowed identification of novel molecular targets modulating the anti-tumour activity of natural products derived from TCM. Moreover, we tried to cross the bridge between TCM and Western modern medicine to be able to implement them for the sake of cancer patients.

The proteasome is a multicatalytic protease complex whose activity is required for the growth of normal or tumor cells. It has been shown that human cancer cells are more sensitive to proteasome inhibition than normal cells, indicating that the proteasome could be a target of chemotherapy. Studies suggest that traditional Chinese medicine (TCM) is an effective approach for cancer treatment. Here we reviewed several TCMs for their potential in treatment of cancer. This short review focuses mainly on the TCMs that potentially target the tumor cellular proteasome and NF-κB pathway whose activation is dependent on the proteasome activity.

The main cause of failure in cancer drug therapy is the emergence of cellular resistance to drugs. Cancer cells, after exposure to one drug, can become simultaneously insensitive to mechanistically and chemically unrelated drugs, a phenotype known as multidrug resistance (MDR). Although a number of mechanisms have been proposed to mediate MDR, the classical cellular mechanism involves the overexpression of several members of the ATP-binding cassette (ABC) superfamily of transporters, leading to increased efflux and decreased intracellular drug accumulation. Among these, P-glycoprotein (P-gp, ABCB1), MRP1 (ABCC1) and BCRP (ABCG2) are the main transporters conferring MDR. These transporters are frequently detected in recurrent cancer cells or cancer stem cells. To overcome MDR, various studies have been conducted to investigate the potential to discover effective MDR modulators from Chinese medicines (CMs) and other herbal products because many of these have been used for centuries without harmful side effects. This review summarizes: i) The contribution of P-gp, MRP1 and BCRP in cancer drug resistance; ii) known mechanisms of action for MDR modulators; iii) commonly used methods for identification and evaluation of novel modulators of transporter- mediated MDR; and iv) the modulating effects of CMs and other natural products on ABC transporters and MDR. The CM and their active components with potent modulating effects on MDR can be considered as promising lead agents for the design of more effective and less toxic drugs to overcome MDR.

Cancer is the second leading cause of death, for which current therapeutic approaches are still very limited. Chemoprevention is an important approach to decreasing cancer morbidity and mortality by the use of non-toxic natural or synthetic substances to reverse the processes of initiation and subsequent progression of cancer. A substantial amount of evidence from human, animal and cell line studies has shown that many herbal products used for traditional Chinese medicine (TCM) can exert chemopreventive effects. The underlying theory for TCM to treat or prevent cancer is to bring the patient back to a healthy state by modifying multiple cancer-causing events. Since carcinogenesis involves multiple abnormal genes/pathways, using TCM in cancer chemoprevention may be superior to the agents targeting a single molecular target alone. However, before TCM can be accepted universally as complementary and alternative medicine for cancer treatment and prevention, it is crucial to understand the molecular basis for their effects. This review highlights several known molecular mechanisms of selected TCM in chemoprevention. Many TCM products or single active components have been reported to inhibit a variety of processes in cancer cell growth, invasion and metastasis by modulating a wide range of molecular targets, including cyclooxygenase-2 (COX-2), nuclear factor-Kappa B (NF-κB) and nuclear factor erythroid 2 -related factor 2 (Nrf2)-mediated antioxidant signaling pathways. The TCM and their active components with potent chemopreventive effects can be considered as promising lead agents for the design of more effective and less toxic agents for cancer chemoprevention.