HERBAL MEDICINE FOR CANCER PATIENTS

Kirsten Dhar – The Clinic of the College of Chinese Medicine, 

26-28 Finchley Rd, St John’s Wood, London, NW8 6ES 

ABSTRACTS – TRIALS – RESEARCH ARTICLES 

· Introduction to plant synergy 

Abstracts from the journal ‘Molecular Cancer Therapeutics’ (American Association for Cancer Research) 

· Summaries of Abstracts and Trials 

· Herbs for Cancer 

Introduction to plant synergy 

In Traditional Chinese Medicine (TCM), herbal prescriptions are given to patients as complex formulations containing multiple herbs. Notably, this approach amounts to the administration of several chemical entities at once. 

The underlying theory is, that interaction among the chemicals present within a single plant, as an entity, and also the different herbs in a formula exert synergistic pharmaco-dynamic actions not present when administered in form of an isolated active ingredient. Synergy of many different chemical components within the plant is responsible for these effects and involves a number of different processes. Whilst the exact mechanisms behind plant synergy and the allelopathic properties of the plant are still not fully understood, a great deal of research has been done in this field. Today’s understanding of basic molecular cell biochemistry and the consequent possibility of elucidating the actual mechanism of action of chemical components at the cellular level, or even gene level, have resulted in a rational explanation of the action of medicinal plants. 

In therapeutic use, medicine administered in form of the entire plant often shows higher plasma availability of the active ingredient than when given in an isolated and concentrated form. Since active components within the plant are rather low in concentration, it has become evident that there is an involvement of substances which are inactive medicinally but enhance the activity of and protect the integrity of the so-called active principles of the plant. In the case of Artemisia annua, a plant which is used to treat malaria, the isolated active principle artemisinine (2), administered orally at 3000mg over 4 days produced the same result (anti-parasitic, anti-pyretic, recrudescence rate) as a four day course of the tea leaves containing a total dose of 50mg artemisinine. Plant synergy also offers protection of an active ingredient from degradation by enzymes and it facilitates transport across barriers such as cell and organelle membranes. Passage of active ingredients through membranes, which occurs in the gut from the intestine wall into the blood stream through to the penetration of an infected cell or into a parasite, is another important aspect of synergistic properties. There is evidence of protective action and active transport across, for example, intestinal walls and inhibition or reversal of the excretory process which naturally takes place in this location. One of the key componants to such improved transport of a substance through the cell membrane are flavonoids. Plant tissue contains phospholipids, which may be partially or entirely lost in the extraction process when isolating the active ingredient. These phospholipids, however, are crucial in transport as they interact between polar heads of the phospholipids molecules of the membrane and the phenolic hydroxyl groups of flavonoids in the process of phospholipic bilayer diffusion. 

Moreover, plant synergy can neutralize the adverse effects and toxicities of specific individual chemicals and provide other signals to the host’s cells that result in higher efficacy of the crude drug when compared with isolated components. It can also overcome and, sometimes reverse, multi-drug resistance mechanisms in patients who are on medication over prolonged periods of time and in chemotherapy. MDR protein inhibitors are present in the plant and are biologically active when the whole extract is used rather than an isolated principle. 

There is no doubt that many other molecular mechanisms are involved in the behaviour often observed in chemical activity when the ingredient is retained in the original crude extract and not all of them are, as yet, fully understood. 

Abstracts from Molecular Cancer Therapeutics 

Reversal of cisplatin resistance with a BH3 mimetic, (–)-gossypol (Chinese Cotton Seed Plant), in head and neck cancer cells: role of wild-type p53 and Bcl-xL Mol Cancer Ther. 2005;4:1096-1104 

Joshua A. Bauer1, Douglas K. Trask2, Bhavna Kumar2, Gerrit Los6, Jason Castro2, Julia Shin-Jung Lee4,5, Jianyong Chen3, Shaomeng Wang3,5, Carol R. Bradford2,5 and Thomas E. Carey1,2,5 Departments of 1 Pharmacology, 2 Otolaryngology-Head and Neck Surgery, and 3 Internal Medicine and Medicinal Chemistry; 4 Biostatistics Unit; and 5 University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; and 6 Pfizer Global Research and Development, La Jolla, California Requests for reprints: Thomas E. Carey, Department of Otolaryngology, University of Michigan, 6020 KHRI, 1301 East Ann Street, Ann Arbor, MI 48109-0506. Phone: 734-764-4371; Fax: 734-764-0014. 

Background: Multi-drug resistance (MDR) is an important biological behaviour of tumour cells in chemotherapy and it is also one of the major causes of clinical chemotherapy failure. There is increasing interest into the exact mechanism of tumour cells' MDR and its reversion by Chinese herbs. Organ preservation protocols in head and neck squamous cell carcinoma (HNSCC) are limited by tumours that fail to respond. We observed that larynx preservation and response to chemotherapy is significantly associated with p53 over-expression, and that most HNSCC cell lines with mutant p53 are more sensitive to cisplatin than those with wild-type p53. To investigate cisplatin resistance, we studied two HNSCC cell lines, UM-SCC-5 and UM-SCC-10B, and two resistant sublines developed by cultivation in gradually increasing concentrations of cisplatin. The cisplatin-selected cell lines, UM-SCC-5PT and UM-SCC-10BPT, are 8 and 1.5 times more resistant to cisplatin than the respective parental cell lines, respectively. The parental lines over-express p53 and contain p53 mutations but the cisplatin-resistant cell lines do not, indicating that cells containing mutant p53 were eliminated during selection. Bcl-xL expression increased in the cisplatin-resistant lines relative to the parental lines, whereas Bcl-2 expression was high in the parental lines and decreased in the cisplatin-resistant lines. Thus, cisplatin selected for wild-type p53 and high Bcl-xL expression in these cells. We tested a small-molecule BH3 mimetic, (–)-gossypol, which binds to the BH3 domain of Bcl-2 and Bcl-xL, for activity against the parental and cisplatin-resistant cell lines. At physiologically attainable levels, (–)-gossypol induces apoptosis in 70% to 80% of the cisplatin-resistant cells but only in 25% to 40% of the parental cells. Thus, cisplatin-resistant cells seem to depend on wild-type p53 and Bcl-xL for survival and BH3 mimetic agents, such as (–)-gossypol, may be useful adjuncts to overcome cisplatin resistance in HNSCC. 

Triptolide Inhibits the Growth and Metastasis of Solid Tumours Vol. 2, 65-72, January 2003, Molecular Cancer Therapeutics

Shanmin Yang, Jinguo Chen, Zhen Guo, Xue-Ming Xu, Luping Wang, Xu-Fang Pei, Jing Yang, Charles B. Underhill and Lurong Zhang2 Department of Oncology, Georgetown University Medical Center, Washington, DC 20007 [S. Y., J. C., X-M. X., L. W., X-F. P., J. Y., C. B. U., L. Z.], and Key Laboratory of China Education Ministry on Cell Biology and Tumour Cell Engineering, Xiamen University, Fujian, People’s Republic of China 361003 [S. Y., Z. G., L. Z.] 

Triptolide (TPL), a diterpenoid triepoxide purified from the Chinese herb Tripterygium wilfordii (Lei Gong Teng) was tested for its anti-tumour properties in several model systems. In vitro, TPL inhibited the proliferation and colony formation of tumour cells at extremely low concentrations (2–10 ng/ml) and was more potent than Taxol. Likewise, in vivo, treatment of mice with TPL for 2–3 weeks inhibited the growth of xenografts formed by four different tumour cell lines (B16 melanoma, MDA-435 breast cancer, TSU bladder cancer, and MGC80-3 gastric carcinoma), indicating that TPL has a broad spectrum of activity against tumours that contain both wild-type and mutant forms of p53. In addition, TPL inhibited experimental metastasis of B16F10 cells to the lungs and spleens of mice. The anti-tumour effect of TPL was comparable or superior with that of conventional anti-tumour drugs, such as Adriamycin, mitomycin, and cisplatin. Importantly, tumour cells that were resistant to Taxol attributable to the over-expression of the multi-drug resistant gene 1 were still sensitive to the effects of TPL. Studies on cultured tumour cells revealed that TPL induced apoptosis and reduced the expression of several molecules that regulate the cell cycle. Taken together, these results suggest that TPL has several attractive features as a new anti-tumour agent. 

PG490-88, a derivative of triptolide (an active ingredient of some Chinese medicinal herbs), causes tumor regression and sensitizes tumors to chemotherapy Mol Cancer Ther. 2003;2:855-862

John M. Fidler1, Ke Li3, Cathie Chung2, Ke Wei2, Jessica A. Ross2, Mingxing Gao2 and Glenn D. Rosen2 Pharmagenesis, Inc., Palo Alto, CA; 2 Department of Medicine, Stanford University Medical School, Stanford, CA; and 3 Applied Biosystems, Foster City, CA 

Treatment of solid tumours with combinations of chemotherapeutic agents has not led to significant increases in long-term survival. Recent studies support a role for inhibitors of checkpoint arrest as a means to enhance the cytotoxicity of chemotherapy. We have shown previously that triptolide (PG490), an oxygenated diterpene derived from a Chinese medicinal plant, induces apoptosis in cultured tumour cells and sensitizes tumor cells to topoisomerase inhibitors by blocking p53-mediated induction of p21. Here we extend our studies to a tumour xenograft model and evaluate the efficacy and safety of PG490-88 (14-succinyl triptolide sodium salt), a water-soluble prodrug of PG490. We also look at the combination of PG490 or PG490-88 with CPT-11, a topoisomerase I inhibitor, in cultured cells and in the tumour xenograft model. We show that PG490-88 is a safe and potent anti-tumour agent when used alone, causing tumour regression of lung and colon tumour xenografts. We also show that PG490-88 acts in synergy with CPT-11 to cause tumour regression. A phase I trial of PG490-88 for solid tumours began recently and safety and optimal dosing data should accrue within the next 12 months. Our findings that PG490-88 causes tumour regression and that it acts in synergy with DNA-damaging chemotherapeutic agents suggest a role as an antineoplastic agent and chemosensitizer for the treatment of patients with solid tumours. 

Caspase-dependent and caspase-independent apoptosis induced by evodiamine in human leukemic U937 cells Mol Cancer Ther. 2006;5:2398-2407 

Tae-Jin Lee1, Eun Jung Kim1, Shin Kim1, Eun Mi Jung1, Jong-Wook Park1, Seung Hun Jeong2, Sang Eun Park2, Young Hyun Yoo2 and Taeg Kyu Kwon1 1 Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Taegu, South Korea and 2 Department of Anatomy and Cell Biology, Dong-A University College of Medicine (BK21 Program), and Medical Science Research Center, Busan, South Korea 

Evodiamine is one of the major bioactive compounds that have been isolated and purified from the fruit of Evodiae fructus (Wu Zhu Yu). Evodiamine exhibits anti-tumour activities against the human tumor cells, including multi-drug-resistant tumour cells. However, the molecular mechanism involved in cell death induced by evodiamine treatment remains poorly understood. In the present study, we showed that evodiamine activated the caspase-dependent apoptotic pathway. This apoptosis was only partially inhibited by a pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, which suggested that evodiamine-induced apoptosis in leukemic U937 cells is partially caspase independent. We observed the nuclear translocation of apoptosis-inducing factor in evodiamine-induced apoptosis of U937 cells, which may be responsible for the caspase-independent apoptotic execution. We next showed that evodiamine induced the substantial amount of apoptosis both in Bcl-2- and Akt-overexpressing U937 cells but not in human peripheral blood mononuclear cells. Although benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone inhibited caspase activity in Bcl-2-overexpressing U937 cells, it completely prevented neither the induction of apoptosis or the nuclear translocation of apoptosis-inducing factor, which suggests that evodiamine is, at least in part, able to bypass the resistance of leukemia cells via caspase-independent apoptotic pathways. Thus, therapeutic strategy using evodiamine may warrant further evaluation. 

Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukaemia cells Mol Cancer Ther. 2005;4:381-388 

Lijuan Xia1, Duo Chen1, Rui Han2, Qicheng Fang2, Samuel Waxman1 and Yongkui Jing1 1 Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York and 2 Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, China 

The Chinese herb Ru Xiang (Boswellia carterii) is investigated for its antineoplastic properties in this article. The mechanism of the cytotoxic effect of boswellic acid acetate, a 1:1 mixture of -boswellic acid acetate and ß-boswellic acid acetate, isolated from Boswellia carterri Birdw on myeloid leukaemia cells was investigated in six human myeloid leukaemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). Morphologic and DNA fragmentation assays indicated that the cytotoxic effect of boswellic acid acetate was mediated by induction of apoptosis. More than 50% of the cells underwent apoptosis after treatment with 20 µg/mL boswellic acid for 24 hours. This apoptotic process was p53 independent. The levels of apoptosis-related proteins Bcl-2, Bax, and Bcl-XL were not modulated by boswellic acid acetate. Boswellic acid acetate induced Bid cleavage and decreased mitochondrial membrane potential without production of hydrogen peroxide. A general caspase inhibitor (Z-VAD-FMK) and a specific caspase-8 inhibitor II (Z-IETD-FMK) blocked boswellic acid acetate–induced apoptosis. The mRNAs of death receptors 4 and 5 (DR4 and DR5) were induced in leukaemia cells undergoing apoptosis after boswellic acid acetate treatment. These data taken together suggest that boswellic acid acetate induces myeloid leukaemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5, and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid, which in turn decreases mitochondria membrane potential. 

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