Begell House Inc.
Onco Therapeutics
OT
2694-4642
2
4
2011
Preface: Approaches of Chinese Medicine to Oncology
v-vii
10.1615/ForumImmunDisTher.2012005120
Thomas
Efferth
Department of Pharmaceutical Biology, Institute of Biochemistry and Pharmacy, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, Germany
Preface
Natural Products as Inhibitors of Epidermal Growth Factor Receptor
281-301
10.1615/ForumImmunDisTher.2012004386
Thomas
Efferth
Department of Pharmaceutical Biology, Institute of Biochemistry and Pharmacy, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, Germany
cancer
pharmacognosy
phytochemicals
traditional Chinese medicine
small molecules
tyrosine kinase activity
The epidermal growth factor receptor (EGFR) and its ligand are signaling molecules involved in several crucial functions in cancer biology, including cell proliferation, differentiation, invasion and metastasis, and suppression of apoptosis. Overexpression and activation of EFGR in tumors is associated with poor prognosis of patients. Therefore, EGFR represents an important molecular target for treatment in clinical oncology. Several EGFR inhibitors have been developed and clinically approved during recent years. Unfortunately, tumors develop resistance against EGFR small-molecule inhibitors due to point mutations in the tyrosine kinase domain of the receptor. Therefore, the development of novel EGFR tyrosine kinase inhibitors with activity to otherwise resistant EGFR mutated tumors is urgently required. As the majority of anticancer drugs are of natural origin, natural products are a valuable source for the identification and development of novel treatment options for cancer. Here, we give an overview on natural products derived from medicinal herbs, food sources, marine organisms, or microorganisms that are able to inhibit EGFR signaling. Molecular modes of action in cell lines, tumor activities in animal experiments, as well as derivatives of EGFR-inhibiting natural products are discussed.
Anti-Inflammatory and Anti-Cancer Activity of Boswellic Acids from Frankincense (Boswellia serrata Roxb. et Colebr, B. carterii Birdw.)
303-313
10.1615/ForumImmunDisTher.2012004432
Thomas
Efferth
Department of Pharmaceutical Biology, Institute of Biochemistry and Pharmacy, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, Germany
Henry Johannes
Greten
Heidelberg School of Traditional Chinese Medicine, Heidelberg, Germany and Biomedical Sciences Institute Abel Salazar, University of Porto, Portugal
apoptosis
cancer
inflammation
frankincense
natural products
olibanum
in vitro
in vivo
clinical trial
The oleo-resinous gum of Boswellia trees has been used for religious rituals, but also for medical purposes in different civilizations for ages. The active principles of the gum resin are boswellic acids. The ethnopharmacology of frankincense indicate activity towards inflammatory diseases and cancer. There is compelling evidence from experimental investigations that boswellic acids reveal anti-inflammatory activity, and the results of clinical trials confirm that Boswellia extracts are also clinically effective. No serious side effects were recorded. Occasional side effects included fatigue, vomiting, diarrhea, unspecific skin rash, azoospermia, and neutropenia. Several investigations using Boswellia extracts or isolated boswellic acids demonstrated growth inhibition of tumors in mice and rats, and increased survival time of animals. The treatment effects were associated with inhibition of AKT, reduced NF-κB activation, and down-regulation of anti-apoptotic proteins. Clinical application in glioblastoma patients showed an improvement of clinical symptoms in terms of edema reduction, but no reduction of tumor size.
Microarray-Based Determination of Response of Tumor Cells to Cycloshikonin
315-322
10.1615/ForumImmunDisTher.2012004452
Thomas
Efferth
Department of Pharmaceutical Biology, Institute of Biochemistry and Pharmacy, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, Germany
Henry Johannes
Greten
Heidelberg School of Traditional Chinese Medicine, Heidelberg, Germany and Biomedical Sciences Institute Abel Salazar, University of Porto, Portugal
Chinese medicine
microarray
Lithospermum erythrorhizon
natural products
pharmacogenomics
Shikonin is a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with various biological activities. Cycloshikonin is a metabolite, which appears during biotransformation of shikonin in the gastrointestinal tract. We performed a COMPARE analysis with >1400 standard antitumor agents included in the NCI database to identify drugs whose IC50 values correlate with those of cycloshikonin. Drugs with the highest correlation coefficients were either antimetabolites (e.g., caracemide, rifamycin, diglycoaldehye, asalex) or DNA-damaging alkylating agents (e.g., pibenzimol dihydrochloride, pyrimidine-5-glycodialdehyde). Although the major target of antimetabolic compounds is the inhibition of nucleic acid biosynthesis, many antimetabolites are also known to induce DNA damage. It is, therefore, reasonable to speculate that cycloshikonin might also damage DNA. Next, we performed correlation-based COMPARE analysis of the IC50 values for cycloshikonin and the microarray-based transcriptome-wide mRNA expression of the cell line panel. Among the genes that were associated with cellular response to cycloshikonin were genes from diverse functional groups such as transcription factors and signal transduction (RXF5, ZNF142, POLR3C, NUDT3, CXCR5), structural components of ribosomes (RPS15A, RLP17, RPL30, RPS27, RPS10, RPL5, RPL6, RPL32, RPL41), oxidative stress response and oxidoreductases (RDH14, GCLM, TXNRD1, SRXN1, EPHX1), cytoskeletal elements (ASPH, KRT83, TXNRD1, CAPNS1) and others (PIGR, PPIP5K2, DNAH1, SNPRE, HPS1, SLC7A11, GPC1, CLPTM1, ADAM9, ATP1B1, ANXA1). This microarray-based investigation delivered novel candidate genes that were associated with the response of cancer cells to cycloshikonin. These results merit further investigation to prove the causative contribution of these genes to resistance and sensitivity toward cycloshikonin.
From Molecular Tumor Diagnostics to Individualized Treatment with Phytochemicals Derived from Chinese Herbs
323-340
10.1615/ForumImmunDisTher.2012004570
Thomas
Efferth
Department of Pharmaceutical Biology, Institute of Biochemistry and Pharmacy, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, Germany
Prognostic marker
predictive marker
chemotherapy
epidermal growth factor receptor
multidrug resistance
P-glycoprotein
natural products
Assays to predict the response of tumors towards chemotherapy are relevant for custom-tailored, individualized therapies. Clinically, chemotherapy is frequently hindered by drug resistance. Since most established cytostatic drugs lack sufficient tumor specificity, normal tissues are also affected by severe side effects. Novel strategies to broaden the narrow therapeutic range by separating the effective dose and toxic dose would be of great benefit for the patients. Whereas the statistical probability of therapeutic success is well-known for larger groups of patients from clinical therapy trials, it is, however, not possible to predict how an individual tumor will respond to therapy. Therefore, efforts have been undertaken to predict drug response in vitro. The idea is to determine sensitivity or resistance beforehand to subsequently choose the most effective clinical treatment for individual patients. This review provides an overview of our own experiences with predictive and prognostic markers for therapy response of tumors and survival time of patients from immunohistochemical detection to pharmacogenomic techniques. Markers identified in molecular biological approaches may not only serve for prediction of drug resistance of tumors and survival times of patients but may also as targets for novel treatment strategies. In the past, my co-investigators and I have studied chemical constituents of herbs used in traditional Chinese medicine. Our efforts have been focused on two target proteins, the multidrug resistance-conferring drug efflux transporter P-glycoprotein and the epidermal growth factor receptor (EGFR). Specific phytochemical inhibitors were identified for both target proteins. These small-molecule inhibitors may serve as adjuncts for future combination therapy regimens useful for managing individualized treatment for cancer patients.
Treating Colorectal Cancer with Western and Chinese Medicine
341-350
10.1615/ForumImmunDisTher.2012004745
Hans
Lampe
Clinic for Internal Medicine III, University of Rostock, Ernst Heydemann Str. 6, 18055 Rostock, Germany
M.
Leithauser
Clinic for Internal Medicine III, University of Rostock, Ernst Heydemann Str. 6, 18055 Rostock, Germany
C.
Junghanss
Clinic for Internal Medicine III, University of Rostock, Ernst Heydemann Str. 6, 18055 Rostock, Germany
M.
Freund
Clinic for Internal Medicine III, University of Rostock, Ernst Heydemann Str. 6, 18055 Rostock, Germany
oncology
integrative medicine
personalized medicine
complementary treatment
side effects
herb-drug interaction
Research into new treatment concepts has improved the clinical course of colorectal cancer (CRC) significantly over the last decades. For early stages, cure rates have reached 60% with standard treatments, and for advanced disease median survival times have been improved to more than 20 months today. Targeted therapies promise further improvements for the future. Chinese medicine (CM) has contributed some drugs to present treatment concepts and may add new strategies for the future, especially where identifiable targets are missing. Although Western medicine (WM) focused on a most precise diagnosis of tumor histology and the extent of dissemination, CM has developed functional diagnoses of disturbed body functions. And as WM aims at producing most specific targeted drugs, CM intends to stabilize disturbed body functions. A combined treatment that synergizes the specific tumor attack and the patient's stabilization seems promising. This approach only started a few decades ago. At present, the experiences and promising results from smaller studies stand against possible risks of unknown interactions. Therefore, in everyday life, Western and Chinese medicines should be used in sequence, whereas in studies and special situations the combined approach should be applied to offer possible benefits without causing unnecessary risks to the patients.
Quality Assurance as Basis for the Implementation of TCM into the Western Medicinal System−A Case Study of Prunella vulgaris
353-360
10.1615/ForumImmunDisTher.2012004353
Michael
Bauer
Phytochem Referenzsubstanzen GbRmbH; Krumbacher Strasse 9, Ichenhausen, D89335 Germany
Hans
Rausch
Phytochem Referenzsubstanzen GbRmbH; Krumbacher Strasse 9, Ichenhausen, D89335 Germany
Traditional Chinese medicine
quality control
fingerprint chromatography
Spica prunellae
Traditional Chinese medicine (TCM) has achieved an increasing degree of popularity in the European Union in recent years, but the issue of its safety and efficacy has also risen international concern. Therefore several official authorities (European Medicines Agency, European Directorate for the Quality of Medicines, International Organization for Standardization − Technical Committee 249) have been concerning themselves with the elaboration of guidelines and monographs for the authentication of TCMs. In this article we bring up some information on the legal status of TCMs in the EU and describe common problems which occur during the quality control of TCMs. The second part contains a case study on Spica prunellae, illustrating some of these problems as well as the development of TLC and HPLC methods for the quality control of said herbal drug.
Mitochondrial Quality Control in Aging and Parkinson's Disease
361-369
10.1615/ForumImmunDisTher.2012004377
Marina
Jendrach
Experimental Neurology, Department of Neurology, Goethe University Medical School, Heinrich-Hoffmann-Str. 7, 60528 Frankfurt/Main, Germany
Mitochondria
fission
fusion
mitophagy
apoptosis
Energy and energy equivalents are mainly produced in mitochondria. Thus, the continuous functionality and integrity of mitochondria are of high importance for cell health and survival, and this is especially the case in long-lived cells with a prolonged postmitotic phase, e.g., endothelial cells or neurons. Mitochondrial functionality and integrity is achieved by the quality control mechanisms of mitochondrial dynamics (i.e., fission and fusion) and autophagy (i.e., mitophagy). In senescent cells, a decline of both mitochondrial quality control mechanisms is observed, and in Parkinson's disease mitochondrial dysfunction is mediated by impaired quality control. These characteristics are discussed as causes for the development and/or progression of Parkinson's disease. Here we review the effect of oxidative stress on quality control in different in vitro aging cell models and Parkinson's disease cell models, underlining the importance of mitochondrial dynamics and autophagy for cell fitness.