Anticancer effects of Chinese herbal medicine, science or myth?

Anticancer effects of Chinese herbal medicine, science or myth? 1 first-author 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:lmp@zju.edu.cn †E-mail:lmp@zju.edu.cn lmp@zju.edu.cn 2 Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310006, China Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310006, China Department of Dermatology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Department of Dermatology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Currently there is considerable interest among oncologists to find anticancer drugs in Chinese herbal medicine (CHM). In the past, clinical data showed that some herbs possessed anticancer properties, but western scientists have doubted the scientific validity of CHM due to the lack of scientific evidence from their perspective. Recently there have been encouraging results, from a western perspective, in the cancer research field regarding the anticancer effects of CHM. Experiments showed that CHM played its anticancer role by inducing apoptosis and differentiation, enhancing the immune system, inhibiting angiogenesis, reversing multidrug resistance (MDR), etc. Clinical trials demonstrated that CHM could improve survival, increase tumor response, improve quality of life, or reduce chemotherapy toxicity, although much remained to be determined regarding the objective effects of CHM in human in the context of clinical trials. Interestingly, both laboratory experiments and clinical trials have demonstrated that when combined with chemotherapy, CHM could raise the efficacy level and lower toxic reactions. These facts raised the feasibility of the combination of herbal medicines and chemotherapy, although much remained to be investigated in this area. Chinese herbal medicine Anticancer BACKGROUND OF CHINESE HERBAL MEDICINE (CHM) 1 CHM is one branch of traditional Chinese medicine (TCM). TCM and western medicine have different ethnic and social backgrounds. The main difference between TCM and western medicine rests how to deal with illness. TCM, focusing on holism and naturalism, combines Chinese medical experience with Chinese culture. In general, Chinese practitioners focus on the “yin” and “yang” balance in the body, which is in accordance with the law of nature. The body will be healthy if it keeps balance between “yin” and “yang”. Diseases will occur if the balance is disrupted. CHM is empirically based and has a history of over 4000 years. The biological ingredients of herbal remedies are extracted from natural substances: plants, animal parts, shells, insects and even stones and minerals. The drugs used in CHM often result from a combination of multiple ingredients, called formula, to ensure effective actions on different targets simultaneously (Attele et al., 1999 1999 ). The composite formulas usually have greater efficacy than single ingredients. This may be due to the synergistic interactions of the ingredients (Xue and Roy, 2003 2003 ). In Chinese herbalism, every herb has its own properties. Chinese herbalists believe that illness can be effectively treated by combining herbs based on their various characteristics and the patient’s overall status. The composition of the formula and the dosage of the individual ingredients depend on the signs and symptoms of the patient, which is the basic principle of CHM. These formulas can be modified to fit specific individuals more closely. This theory is in accordance with the idea of “individual therapy” in western medicine. CHM is very popular in China, and has been historically used in treating chronic diseases, such as constipation, dermatitis, insomnia, among other conditions. ANTICANCER ROLE OF CHM 1 Recently, modern biomolecular science has contributed to the interpretation of the anticancer effects of CHM. As more information becomes available, CHM is becoming recognized worldwide. The gap between East and West is narrowing. Although the anticancer role of CHM needs further investigation, the achievements in this field do give us some important information. Literature searches were conducted through PubMed until Feb. 2005. Additional manual searches were carried out on relevant medical journals. Search items were “herb”, “anticancer mechanism”, “traditional Chinese medicine”, and “cancer therapy”. No restrictions were placed on the language of publication. Only primary data or data that superseded earlier work were included. Case reports were not included. Anticancer clinical trials using CHM in patients and studies investigating anticancer mechanisms of CHM from a western perspective were included. The anticancer effects of CHM have been reported in many Chinese journals. Studies lacking controls were excluded. Two authors independently assessed the quality of the studies, and extracted data. Laboratory evidence emerging recently 2 Experiments in test tubes and animals explored the mechanisms for the anticancer role of CHM (Table 1 1 ). It was demonstrated that CHM plays its anticancer role by inducing apoptosis and differentiation, enhancing the immune system, inhibiting angiogenesis, reversing multidrug resistance (MDR), etc. Many herbal remedies played their anticancer roles through multiple mechanisms (Ikezoe et al., 2003a 2003a ; 2003b 2003b ; Cheng et al., 2003a 2003a ; Hong-Fen et al., 2001 2001 ; Hsieh et al., 2002 2002 ; Wartenberg et al., 2003 2003 ). Note: HNSCC, head and neck squamous cell carcinoma; PGE2, prostaglandin E2; COX-2, cyclooxygenase 2; EC: endotheliocytes; NK, natural killer; MDR, multidrug resistance; MMP, matrix metalloproteinase; CTLs, cytotoxic T lymphocytes; TDLN, tumor-draining lymph nodes. Anticancer-number-one, Panax ginseng , Poria cocos , Atractylodes macrocephala , Anglica sinensis , A. membranaceus , Curcuma zedoaria , Scutellaria baicalensis , Phellodenron chinense , Coptis chinensis , Glycyrrhiza uralensis , Crataegus pinnatifida , Hordeum õulgare , Salõia miltiorrhiza , Schisandra chinensis , Hedyotis diffusa , Ophiopogon japonicus , Lobelia chinesis lour , Scutellaria barbaba , Massa fermentata medicinalis ; PC-SPES, Reishi mushroom , Baikal skullcap , Rabdosia , Dyer ’ s woad , Chrysanthemum , Saw palmetto , Panax ginseng , and Licorice ; Dang-gui-bu-xai-tang, Radix Angelicae sinensis and Radix Astragali membranaceus Type of cancer Model Herb Mechanism Ref. 2 HNSCC SCC-25 and KB cell lines, four nude mice with s.c. inoculation of KB cells Scutellaria baicalensis Inhibition of cell growth in vitro and in vivo, inhibition of PGE2 synthesis via suppression of COX-2 expression Zhang et al., 2003 2003 KB, KBv200 cell lines Asiaticoside Induction of apoptosis and enhancement of the anti-tumor activity of vincristine Huang et al., 2004 2004 7 Leukemia U937 cell line Mylabris phalerlata , Scutellaria barbata Induction of apoptosis Huh et al., 2003 2003 ; Cha et al., 2004 2004 NB4, HL60 cell lines Red orpiment Induction of apoptosis Zhong et al., 2003 2003 AKR/J mice Echinacea purpurea Enhancement of nonspecific immune or cellular immune systems (or of both) Hayashi et al., 2001 2001 CCRF-CEM, CEM/E1000, CEM/VLB (100) cell lines Artesunate (ART), Bufalin ART significantly increased daunorubicin accumulation in CEM/E1000 cells, but not in CEM/VLB (100) or CCRF-CEM parental cells. Bufalin caused a small, but significant increase in daunorubicin accumulation in CEM/VLB (100) and CEM/E1000 cells Efferth et al., 2002 2002 NB4 cell line Arsenic trioxide Induction of apoptosis Chen et al., 1996 1996 HL-60 cell line Hydrolysable tannis from Eugenia jambos L. Induction of apoptosis Yang et al., 2000 2000 HL-60, NB4, U937 and THP-1 cell lines PC-SPES Inhibition of growth, induction of differentiation and apoptosis Ikezoe et al., 2003a 2003a 2 Colorectal carcinoma CoLo205 cell line Magnolol Induction of apoptosis Lin et al., 2002 2002 Mice bearing colon26/clone 20 carcinoma cells Coptidis rhizome and Berberine Reduction of IL-6 mRNA levels and protein levels in tumors and sera Iizuka et al., 2002 2002 3 Gastric cancer MGC-803 cell line Isoliquiritigenin Induction of apoptosis Ma et al., 2001 2001 AGS cell line Astragali (AR) Cytostatic Lin et al., 2003 2003 MNK45 and KATO-III cell lines Anemarrhena asphodeloides Induction of apoptosis Takeda et al., 2001 2001 2 Hepatic cancer Hep-G2 cell line Magnolol Induction of apoptosis Lin et al., 2002 2002 SMMC-7221 cell line Isoverbascoside Induction of differentiation Chen et al., 2002a 2002a 2 Lung cancer A549 cell line Bupleuri radix Inhibition of telomerase activity and activation of apoptosis Cheng et al., 2003a 2003a Lung cancer cells Triptolide Induction of apoptosis in combination with Apo2L/TRAIL Frese et al., 2003 2003 5 Breast cancer 95-D cell line Acutiaporberine Induction of apoptosis Chen et al., 2002b 2002b F344 rats Anticancer-number-one Increasement of NK cell activity and inhibition of tumor metastasis Hong-Fen et al., 2001 2001 MCF-7 cell line Rosemary Reversing MDR Plouzek et al., 1999 1999 MCF-7 cell line Tea and tea polyphenlos Suppression of fatty acid synthase (a key enzyme in lipogenesis) Yeh et al., 2003 2003 MCF-7 and MCF-7/ADM cell lines Asiaticoside Enhancement of the anti-tumor activity of vincristine Huang et al., 2004 2004 Ovarian cancer SKOV3, CAOV3 and OVCAR-3 cell lines Scutellaria barbatae Induction of apoptosis Powell et al., 2003 2003 3 Prostate cancer LNCaP cell lines PC-SPES Activation of the JNK/c-Jun/AP-1 signal pathway resulting in growth arrest and apoptosis of prostate cancer cells Ikezoe et al., 2003b 2003b Prostate carcinoma cells Equiguard Down-regulation of expression of androgen receptor and prostate-specific antigen, induction of apoptosis Hsieh et al., 2002 2002 Embryoid bodies and multicellular DU-145 prostate tumor spheroids Baicalein , Epicatechin , Berberine , Acteoside Down-regulation of MMP expression, inhibition of angiogenesis Wartenberg et al., 2003 2003 2 Glioma Rat C6 glioma cells Saikosaponin a , b Induction of differention Tsai et al., 2002 2002 Mice that injected with LZEJ-C3 cells subcutaneously Dang-gui-bu-xai-tang Increasement of the population of CTLs and NK cells, and down-regulation of activated T helper cells (CD4+/CD25+) in spleen and TDLN Hsieh et al., 2003 2003 1. Characters of anticancer effect of herbal remedies 3 The synergistic effects of various components in Scutellaria baicalensis extract [ baicalin (80%), wogonoside (16%), baicalein (2%), wogonin (1%) and other compounds in trace amounts] were demonstrated (Zhang et al., 2003 2003 ). Both the extract and its pure compound- baicalein inhibited cancer cell growth (in vitro). The extract could inhibit prostaglandin E2 (PGE2) production, whereas its pure compound, baicalein , could not. Another pure compound wogonin significantly inhibited cyclooxygenase 2 (COX-2) activity in lipopolysaccharide (LPS)-stimulated macrophages. The various components in the herb act on different anticancer pathways such as COX-dependent and COX-independent pathways. Some herbs were most effective on cancer of a certain type. It was demonstrated that artesunate (ART) was most active against leukemia and colon cancer cell lines [mean GI50 values: (1.11±0.56) μmol/L and (2.13±0.74) μmol/L, respectively]. Non-small cell lung cancer (NSCLC) cell lines showed the highest mean GI50 value [(25.62±14.95) μmol/L] indicating the lowest sensitivity towards ART (Efferth et al., 2002 2002 ). This may be due to the herb’s affinity for specific organs. There exists an interesting phenomenon that some herbs might be selective for cancer cells instead of normal cells. It was reported that Scutellaria baicalensis demonstrated a strong inhibition in two tested human head and neck squamous cell carcinoma (HNSCC) cell lines, while no growth inhibition of HaCaT cells (a non-tumorigenic cell line) was observed (Zhang et al., 2003 2003 ). The butanol fraction of Mylabris phalerlata was specifically cytotoxic on human monocytic leukemic U937 cells rather than on peripheral blood mononuclear lymphocytes (Huh et al., 2003 2003 ). The herb formula PC-SPES inhibited proliferation of HL-60, NB4, U937 and THP-1 human leukemia cells with ED 50 of 0.17, 0.09, 0.18, 0.32 μl/ml respectively. On the contrary, PC-SPES (0.1 μl/ml) stimulated growth of normal myeloid committed stem cells by 1.4 fold of control ( P =0.03) (Ikezoe et al., 2003a 2003a ). It was demonstrated that magnolol at concentrations of 3~10 μmol/L inhibited DNA synthesis and decreased cell number in cultured human cancer cells (COLO-205 and Hep-G2) in a dose-dependent manner but not in non-transformed human cells such as keratinocytes, fibroblasts, and human umbilical vein endothelial cells (HUVEC). When magnolol concentration was increased to 100 μmol/L, apoptosis was observed in COLO-205 and Hep-G2 cells, but not in cultured human fibroblasts and HUVEC (Lin et al., 2002 2002 ). Triptolide was also demonstrated to sensitize lung cancer but not normal human bronchial epithelial cells to Apo2L/TRAIL-induced apoptosis (Frese et al., 2003 2003 ), However, it is still unclear how this tumor-specific killing occurs. Further investigation is needed to clarify the mechanism behind this interesting phenomenon. 2. Enlarged efficacy of herbal remedies in combination with routine chemical reagents 3 Some studies have assessed the use of herbs in combination with routine chemical reagents. Asiaticoside could enhance the anti-tumor activity of vincristine in several cancer cell lines including KB, KBv200, MCF-7, and MCF-7/ADM. The apoptosis rates and the Bcl-2 phosphorylation levels were much higher in asiaticoside plus vincristine groups than in vincristine or asiaticoside groups. Asiaticoside plus vincristine enhanced S-G (2)/M arrest, up-regulated Cyclin B1 protein expression, and down-regulated P34 (cdc2) protein expression in KB cells (Huang et al., 2004 2004 ). PC-SPES enhanced the antiproliferative and prodifferentiative effects of ATRA (all-trans retinoic acid) on leukemia cells. PC-SPES (0.125 μl/ml) alone, ATRA (10 −8 mol/L) alone or the combination of the two inhibited growth of HL-60 cells after 4 d of culture, by approximately 40%, 30% and 80%, respectively. Measured by expression of CD11b antigen, the induced differentiation rate was also much higher in the combination group (60%) than in PC-SPES group (27%) or ATRA group (18%) alone (Ikezoe et al., 2003a 2003a ). An extract of the common dietary herb rosemary ( Rosemarinus officinalis Labiatae ) increased the intracellular accumulation of commonly used chemotherapeutic agents, including doxorubicin (DOX) and vinblastine (VIN), in drug-resistant MCF-7 human breast cancer cells (Plouzek et al., 1999 1999 ). Current status of clinical trials 2 Simultaneously, clinical trials of different phases have been conducted. The critical data from the seven clinical trials, searched from PubMed, are listed in Table 2 2 . These studies were carried out in the USA (Wheeler et al., 2003 2003 ; Oh et al., 2004 2004 ; Soignet et al., 1998 1998 ), Egypt (Mabed et al., 2004 2004 ), China (Shen et al., 2004 2004 ; Piao et al., 2004 2004 ), Russia, Bulgaria and Ukraine (Semiglasov et al., 2004 2004 ) from 1998 to 2004. Various kinds of herbs were used, including Semen coicis , Arsenic trioxide, Viscum fraxini -2, standardized mistletoe extracts, PC-SPES. Various types of cancer have been investigated, including acute promyelocytic leukemia, thyroid cancer, nasopharyngeal carcinoma, esophagus cancer, mesothelioma, NSCLC, hepatocellular carcinoma, pancreatic cancer, colon cancer, prostate cancer, breast cancer, ovarian cancer, carcinoid, and liposarcoma. Note: Kanglaite injection, produced by the Chinese company Zhejiang Kanglaite pharmaceutical (ZKP, Hangzhou). APL: Acute promyelocytic leukemia; HCC: Hepatocellular carcinoma; CR: Complete response; PR: Partial response; DES: Diethylstilbestrol; PSA: Prostate-specific antigen; ATRA: All-trans retinoic acid; IA: Idarubicin, Ara-C; sME: Standardized mistletoe extracts; CMF: Cyclophosphamide, methotrexate, fluorouracil; QoL: Quality of life; NSCLC: Non-small cell lung cancer; CAP: Cyclophosphamide, adriamycin, cisplatin; CAF: Cyclophosphamide, adriamycin, 5-fluorouracil; CP: Cyclophosphamide, cisplatin; IcP: Ifosfamide, carboplatin; VP: Vinorelbine, cisplatin; MViP: mitomycine, vindesine, cisplatin 2 Patients 2 Herb 2 Herb dosage 2 Treatments 2 Effect 2 Reference Type of cancer No. Lung 3 9 Kanglaite injection, an extract of the coix seed 9 10000 mg/d up to 50000 mg/d, for 21 consecutive days every 4 weeks (increased by 10000 mg/d in each of four subsequent levels) 9 Herb 9 No dose limiting toxicities were observed in the first cycle up to the maximum dose of 50000 mg/d. A maximum tolerated dose (MTD) could not be defined. 9 Wheeler et al., 2003 2003 Esophagus 3 Prostate 2 Mesothelioma 2 Colon 2 Carcinoid 1 Pancreas 1 Thyroid 1 Liposarcoma 1 HCC 23 Viscum fraxini-2 2 ampoules (10000 ng/ml), subcutaneously, once weekly Herb CR: 13.1%; PR: 8.1%; 39.1%: progressive; 39.1%: no evaluation of response due to early death Mabed et al., 2004 2004 Prostate cancer 90 PC-SPES 960 mg orally, t.i.d., (DES 3 mg orally q.d. as control) Herb PSA declines ≥50% were noted in 40% with PC-SPES and 24% with DES Oh et al., 2004 2004 APL 12 Arsenic trioxide 0.06 to 0.2 mg/(kg·d), cumulative doses, 160~515 mg Herb Complete remission: 92% Soignet et al., 1998 1998 APL 61 Arsenic trioxide ATRA: 25 mg/m 2 per day; Arsenic trioxide: 0.16 mg/kg per day Arsenic trioxide+ATRA (appropriate chemotherapy) The time to achieve complete rates was the shortest one in the combination group Shen et al., 2004 2004 Breast cancer 272 sME 0.5 ml (10, 30, 70 ng/ml) twice weekly subcutaneously for 15 consecutive weeks Herb+CMF chemotherapy QoL was significantly improved ( P < 0.01) with the medium dose (30 ng/ml) Semiglasov et al., 2004 2004 Breast cancer 68 3 sME 3 1 mg up to 200 mg, subcutaneously, 3 times per week 3 Herb+chemotherapy (Breast cancer: CAP, CAF; Ovarian cancer: CP, IcP; NSCLC: VP, MViP) 3 QoL was significantly ( P < 0.05) improved 3 Piao et al., 2004 2004 Ovarian cancer 71 NSCLC 94 Sample sizes in the clinical trials ranged from 12 to 272. Dropouts and withdrawals were mentioned in (Wheeler et al., 2003 2003 ; Oh et al., 2004 2004 ; Soignet et al., 1998 1998 ; Shen et al., 2004 2004 ; Semiglasov et al., 2004 2004 ; Piao et al., 2004 2004 ). Adverse effects of CHM were reported in all of the clinical trials. In these trials, patients received herbal medicine alone (Wheeler et al., 2003 2003 ; Mabed et al., 2004 2004 ; Oh et al., 2004 2004 ; Soignet et al., 1998 1998 ) or along with standard tumor destructive treatment (Shen et al., 2004 2004 ; Semiglasov et al., 2004 2004 ; Piao et al., 2004 2004 ). The phase I trial (Wheeler et al., 2003 2003 ) focusing on Semen coicis demonstrated the safety of the drug. The six phase II trials (Mabed et al., 2004 2004 ; Oh et al., 2004 2004 ; Soignet et al., 1998 1998 ; Shen et al., 2004 2004 ; Semiglasov et al., 2004 2004 ; Piao et al., 2004 2004 ) showed that these herbs were helpful against cancer, alone or in combination with chemotherapy. It is demonstrated that herbs could improve survival (Mabed et al., 2004 2004 ; Shen et al., 2004 2004 ), increase tumor response (Mabed et al., 2004 2004 ; Oh et al., 2004 2004 ; Soignet et al., 1998 1998 ; Shen et al., 2004 2004 ), improve quality of life or reduce chemotherapy toxicity (Semiglasov et al., 2004 2004 ; Piao et al., 2004 2004 ). DISCUSSION 1 Benefits and concerns 2 Science has long acknowledged the value of healing substances found in nature, such as digitalis, aspirin, penicillin, insulin, steroids, etc. There has been a resurgence of interest, both scientifically and popularly, in the utilization of natural approaches. Experiments in test tubes and in animals demonstrated that CHM played its anticancer role by inducing apoptosis and differentiation, enhancing the immune system, inhibiting angiogenesis, reversing multidrug resistance (MDR), etc. However, the mechanism of the anticancer role of CHM has not yet been fully elucidated. Further research is needed to explore the molecular mechanism of CHM. The pharmacological effects of CHM are still not clear although it is proved to be effective against disease, which is also the major reason preventing CHM from being accepted worldwide. Although the clinical trials showed that herbs were helpful against cancer, these outcomes require further confirmation with rigorously controlled trials. In China, many clinical trials focusing on the anticancer effects of herbal formulas have been conducted. Though many of them demonstrated that herbs are helpful against cancer, especially useful in improving survival and quality of life in patients suffering from advanced cancer, the lack of controls and reporting bias have been severe flaws. Researchers must pay attention to the scientific rigor of studies of CHM in the future to improve the status. Some Chinese herbs may be harmful to the human body if they are used improperly. Some herbs may cause serious toxicity when taken excessively or under inappropriate circumstances (Chan et al., 2005 2005 ). Herbal remedies should be prescribed carefully by qualified practitioners according to the herb character and the whole body condition of the patient. Also, potential herb-drug interactions should be taken into consideration if multiple drugs are prescribed simultaneously (Cheng et al., 2003b 2003b ). Herbal therapies have already led to the development of a number of anticancer drugs. The key to choosing the anticancer CHM is to optimize an effective formula. With the development of modern science and medicine, CHM modernization is on the way. Using state-of-the-art technology in CHM extraction, purification and drug production can efficiently improve the CHM industry. Traditionally, herbs have been made into pills, powders and astopical plasters. Today, herbal companies have developed other forms like capsules, tablets and injections which are more convenient and palatable. Kanglaite injection is an extract produced from coix seed ( Semen coicis ). The anticancer mechanisms of Kanglaite injection have been widely explored in China. It has been proven to play its anticancer role through inhibition of the mitosis of tumor cells during G2/M phases, induction of apoptosis and inhibition of the formation of newly generated blood vessels (Li, 2001 2001 ). This botanical drug, which is approved in China for treatment of lung cancer, hepatic cancer and gastric cancer, has been extensively used in more than 2000 hospitals around the country. After one year of clinical experiments which proved its beneficial effects in the treatment of lung cancer and gastric cancer, it has been recently permitted by the Russian health authorities for clinical application for cancer treatment. A phase I trial for Kanglaite in Salt Lake City, USA, has been completed, verifying the safety of the drug (Wheeler et al., 2003 2003 ). The phase II trial, approved by the United States Food and Drug Administration (FDA), will pair Kanglaite with another chemotherapy to treat NSCLC. The global market of CHM for anticancer therapy will probably be prosperous from this new start. However, caution should be used. Due to contamination with undeclared prescription drugs, such as DES, indomethacin and warfarin, PC-SPES was withdrawn from the market in 2002. The withdrawal of PC-SPES can be viewed as due to inadequate quality control in the production of the herb remedies. The product should be fully characterized and standardized, properly labelled for its contents. It is unclear whether these prescription drugs account for the anticancer effect of the herb remedies. Future research is required to determine which ingredients are effective. However, PC-SPES did have anticancer effects against prostate cancer. If PC-SPES free of contaminating drugs is not as effective as the drug-containing PC-SPES, the original mixture (combining herbs and drugs) may provide valuable clues for researching and developing anticancer drugs in the future. Combination of CHM and chemotherapy 2 Although much remains to be determined regarding the objective effects of CHM in vitro and in human in the context of clinical trials, Arsenic trioxide has confirmed efficacy against APL. Arsenic trioxide has proven to be very effective in obtaining high clinically complete remission rates in APL patients (Soignet et al., 1998 1998 ). This drug has been widely used on APL patients around the world. Recent study showed that the ATRA/Arsenic trioxide combination for remission/maintenance therapy of APL lead to much better results than either of the two drugs alone in terms of the quality of complete remission and the status of the disease-free survival (Shen et al., 2004 2004 ). The authors also conducted experiments to explore the possible underlying molecular mechanisms. As a result, ATRA and Arsenic trioxide were shown to have synergistic effect on apoptosis and degradation of PML-PARα oncoprotein. This successful research, together with other studies demonstrating the enlarged efficacy and lowered toxicity of the combination therapy in vitro (Huang et al., 2004 2004 ; Ikezoe et al., 2003a 2003a ; Plouzek et al., 1999 1999 ) and in clinical trials (Shen et al., 2004 2004 ; Semiglasov et al., 2004 2004 ; Piao et al., 2004 2004 ) holds the promise of better treatment of cancer. However, the possibility of detrimental effects from the combination cannot be ruled out. Further studies, including basic experiments conducted in different systems and rigorously controlled clinical trials, are required to better define the objective effects of the combination therapy. Western therapies, including surgery, chemotherapy, and radiotherapy are tumor destructive. From the Chinese practitioners’ viewpoint, the whole unhealthy condition should be treated successfully to cure the patients suffering from cancer. The two different systems of medicine target “cancer” from different perspective. This is due to difference in the way of thinking. Westerner usually use the direct thinking way. When they want to target “A”, they usually try their best to target “A” itself, with that requisite, they will impair the factors related to “A”-B, C, D. Chinese usually use the indirect way of thinking. When they want to target “A”, they are apt to first target the factors related to “A”-B, C, D, to change the environment and conditions of “A”, which ultimately leads to change in “A”. It is difficult to draw a conclusion about which one is superior to the other. They are two ways from different perspective to solve the problem. One might provide a complementary remedy to the other. Chinese practitioners hold the belief that western therapy strongly targets the cancer foci and CHM strongly targets the unhealthy condition of the whole body. Combination therapy, bringing together the advantages of each type of medicine for an overall enhancement of cancer treatment, is regarded as one of the most important principles for the treatment of cancer in China (Fig. 1 1 ). However, due to the culture difference, the philosophy accepted in China needs further research to verify its scientific basis from the perspective accepted all around the world, which needs the effort from Chinese practitioners and oncologists worldwide. References AS Attele , JA Wu , CS Yuan . Ginseng pharmacology: multiple constituents and multiple actions . Biochem Pharmacol , 1999 . 58 ( 11 ): 1685 - 1693 . 10571242 DOI: 10.1016/S0006-2952(99)00212-9 http://doi.org/10.1016/S0006-2952(99)00212-9 . Ginseng pharmacology: multiple constituents and multiple actions YY Cha , EO Lee , HJ Lee , YD Park , SG Ko , DH Kim , HM Kim , IC Kang , SH Kim . Methylene chloride fraction of Scutellaria barbata induces apoptosis in human U937 leukemia cells via the mitochondrial signaling pathway . Clin Chim Acta , 2004 . 348 ( 1-2 ): 41 - 48 . 15369734 DOI: 10.1016/j.cccn.2004.04.013 http://doi.org/10.1016/j.cccn.2004.04.013 . Methylene chloride fraction of Scutellaria barbata induces apoptosis in human U937 leukemia cells via the mitochondrial signaling pathway TY Chan , HP Tam , CK Lai , AY Chan . A multidisciplinary approach to the toxicologic problems associated with the use of herbal medicines . Ther Drug Monit , 2005 . 27 ( 1 ): 53 - 57 . 15665747 DOI: 10.1097/00007691-200502000-00011 http://doi.org/10.1097/00007691-200502000-00011 . A multidisciplinary approach to the toxicologic problems associated with the use of herbal medicines GQ Chen , J Zhu , XG Shi , JH Ni , HJ Zhong , GY Si , XL Jin , W Tang , XS Li , SM Xong , 等 . In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As 2 O 3 ) in the treatment of acute promyelocytic leukemia: As 2 O 3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins . Blood , 1996 . 88 ( 3 ): 1052 - 1061 . 8704214 . In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins RC Chen , JH Su , GL Ouyang , KX Cai , JQ Li , XG Xie . Induction of differentiation in human hepatocarcinoma cells by isoverbascoside . Planta Med , 2002 . 68 ( 4 ): 370 - 372 . 11988868 DOI: 10.1055/s-2002-26759 http://doi.org/10.1055/s-2002-26759 . Induction of differentiation in human hepatocarcinoma cells by isoverbascoside Q Chen , W Peng , S Qi , A Xu . Apoptosis of human highly metastatic lung cancer cell line 95-D induced by acutiaporberine, a novel bisalkaloid derived from Thalictrum acutifolium . Planta Med , 2002 . 68 ( 6 ): 550 - 553 . 12094304 DOI: 10.1055/s-2002-32546 http://doi.org/10.1055/s-2002-32546 . Apoptosis of human highly metastatic lung cancer cell line 95-D induced by acutiaporberine, a novel bisalkaloid derived from Thalictrum acutifolium YL Cheng , WL Chang , SC Lee , YG Liu , HC Lin , CJ Chen , CY Yen , DS Yu , SZ Lin , HJ Harn . Acetone extract of Bupleurum scorzonerifolium inhibits proliferation of A549 human lung cancer cells via inducing apoptosis and suppressing telomerase activity . Life Sci , 2003 . 73 ( 18 ): 2383 - 2394 . 12941440 DOI: 10.1016/S0024-3205(03)00648-9 http://doi.org/10.1016/S0024-3205(03)00648-9 . Acetone extract of Bupleurum scorzonerifolium inhibits proliferation of A549 human lung cancer cells via inducing apoptosis and suppressing telomerase activity KF Cheng , KS Leung , PC Leung . Interactions between modern and Chinese medicinal drugs: a general review . Am J Chin Med , 2003 . 31 ( 2 ): 163 - 169 . 12856855 DOI: 10.1142/S0192415X0300093X http://doi.org/10.1142/S0192415X0300093X . Interactions between modern and Chinese medicinal drugs: a general review T Efferth , M Davey , A Olbrich , G Rucker , E Gebhart , R Davey . Activity of drugs from traditional Chinese medicine toward sensitive and MDR1- or MRP1-overexpressing multidrug-resistant human CCRF-CEM leukemia cells . Blood Cells Mol Dis , 2002 . 28 ( 2 ): 160 - 168 . 12064912 DOI: 10.1006/bcmd.2002.0492 http://doi.org/10.1006/bcmd.2002.0492 . Activity of drugs from traditional Chinese medicine toward sensitive and MDR1- or MRP1-overexpressing multidrug-resistant human CCRF-CEM leukemia cells S Frese , F Pirnia , D Miescher , S Krajewski , MM Borner , JC Reed , RA Schmid . PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2 . Oncogene , 2003 . 22 ( 35 ): 5427 - 5435 . 12934102 DOI: 10.1038/sj.onc.1206842 http://doi.org/10.1038/sj.onc.1206842 . PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2 I Hayashi , M Ohotsuki , I Suzuki , T Watanabe . Effects of oral administration of Echinacea purpurea (American herb) on incidence of spontaneous leukemia caused by recombinant leukemia viruses in AKR/J mice . Nihon Rinsho Meneki Gakkai Kaishi , 2001 . 24 ( 1 ): 10 - 20 . 11280896 . Effects of oral administration of Echinacea purpurea (American herb) on incidence of spontaneous leukemia caused by recombinant leukemia viruses in AKR/J mice L Hong-Fen , T Waisman , Y Maimon , K Shakhar , E Rosenne , S Ben-Eliyahu . The effects of a Chinese herb formula, anti-cancer number one (ACNO), on NK cell activity and tumor metastasis in rats . Int Immunopharmacol , 2001 . 1 ( 11 ): 1947 - 1956 . DOI: 10.1016/S1567-5769(01)00120-5 http://doi.org/10.1016/S1567-5769(01)00120-5 . The effects of a Chinese herb formula, anti-cancer number one (ACNO), on NK cell activity and tumor metastasis in rats TC Hsieh , X Lu , J Guo , W Xiong , J Kunicki , Z Darzynkiewicz , JM Wu . Effects of herbal preparation Equiguard on hormone-responsive and hormone-refractory prostate carcinoma cells: mechanistic studies . Int J Oncol , 2002 . 20 ( 4 ): 681 - 689 . 11894110 . Effects of herbal preparation Equiguard on hormone-responsive and hormone-refractory prostate carcinoma cells: mechanistic studies CC Hsieh , WC Lin , MR Lee , SL Hsu , HS Liu , ST Kao , MT Hsieh . Dang-Gui-Bu-Xai-Tang modulated the immunity of tumor bearing mice . Immunopharmacol Immunotoxicol , 2003 . 25 ( 2 ): 259 - 271 . 12784917 DOI: 10.1081/IPH-120020474 http://doi.org/10.1081/IPH-120020474 . Dang-Gui-Bu-Xai-Tang modulated the immunity of tumor bearing mice YH Huang , SH Zhang , RX Zhen , XD Xu , YS Zhen . Asiaticoside inducing apoptosis of tumor cells and enhancing anti-tumor activity of vincristine . Ai Zheng , 2004 . 23 ( 12 ): 1599 - 1604 . (in Chinese) 15601545 . Asiaticoside inducing apoptosis of tumor cells and enhancing anti-tumor activity of vincristine JE Huh , KS Kang , KS Ahn , DH Kim , I Saiki , SH Kim . Mylabris phalerlata induces apoptosis by caspase activation following cytochrome c release and Bid cleavage . Life Sci , 2003 . 73 ( 17 ): 2249 - 2262 . 12927594 DOI: 10.1016/S0024-3205(03)00568-X http://doi.org/10.1016/S0024-3205(03)00568-X . Mylabris phalerlata induces apoptosis by caspase activation following cytochrome c release and Bid cleavage N Iizuka , S Hazama , K Yoshimura , S Yoshino , A Tangoku , K Miyamoto , K Okita , M Oka . Anticachectic effects of the natural herb Coptidis rhizoma and berberine on mice bearing colon 26/clone 20 adenocarcinoma . Int J Cancer , 2002 . 99 ( 2 ): 286 - 291 . 11979446 DOI: 10.1002/ijc.10338 http://doi.org/10.1002/ijc.10338 . Anticachectic effects of the natural herb Coptidis rhizoma and berberine on mice bearing colon 26/clone 20 adenocarcinoma T Ikezoe , S Chen , T Saito , H Asou , T Kyo , S Tanosaki , D Heber , H Taguchi , HP Koeffler . PC-SPES decreases proliferation and induces differentiation and apoptosis of human acute myeloid leukemia cells . Int J Oncol , 2003 . 23 ( 4 ): 1203 - 1211 . 12964005 . PC-SPES decreases proliferation and induces differentiation and apoptosis of human acute myeloid leukemia cells T Ikezoe , SS Chen , Y Yang , D Heber , H Taguchi , HP Koeffler . PC-SPES: molecular mechanism to induce apoptosis and down-regulate expression of PSA in LNCaP human prostate cancer cells . Int J Oncol , 2003 . 23 ( 5 ): 1461 - 1470 . 14532991 . PC-SPES: molecular mechanism to induce apoptosis and down-regulate expression of PSA in LNCaP human prostate cancer cells DP Li . Progresses in basic studies of anticancer mechanisms of Kanglaite injection (KLT) . Zhong Yao Xin Yao Yu Lin Chuang Yao Li , 2001 . 12 ( 2 ): 122 - 124 . (in Chinese) . Progresses in basic studies of anticancer mechanisms of Kanglaite injection (KLT) SY Lin , JD Liu , HC Chang , SD Yeh , CH Lin , WS Lee . Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhibiting DNA synthesis and activating apoptosis . J Cell Biochem , 2002 . 84 ( 3 ): 532 - 544 . 11813258 DOI: 10.1002/jcb.10059 http://doi.org/10.1002/jcb.10059 . Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhibiting DNA synthesis and activating apoptosis J Lin , HF Dong , JJ Oppenheim , OM Howard . Effects of astragali radix on the growth of different cancer cell lines . World J Gastroenterol , 2003 . 9 ( 4 ): 670 - 673 . 12679907 . Effects of astragali radix on the growth of different cancer cell lines J Ma , NY Fu , DB Pang , WY Wu , AL Xu . Apoptosis induced by isoliquiritigenin in human gastric cancer MGC-803 cells . Planta Med , 2001 . 67 ( 8 ): 754 - 757 . 11731922 . Apoptosis induced by isoliquiritigenin in human gastric cancer MGC-803 cells M Mabed , L El-Helw , S Shamaa . Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma . Br J Cancer , 2004 . 90 ( 1 ): 65 - 69 . 14710208 DOI: 10.1038/sj.bjc.6601463 http://doi.org/10.1038/sj.bjc.6601463 . Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma WK Oh , PW Kantoff , V Weinberg , G Jones , BI Rini , MK Derynck , R Bok , MR Smith , GJ Bubley , RT Rosen , 等 . Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer . J Clin Oncol , 2004 . 22 ( 18 ): 3705 - 3712 . 15289492 DOI: 10.1200/JCO.2004.10.195 http://doi.org/10.1200/JCO.2004.10.195 . Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer BK Piao , YX Wang , GR Xie , U Mansmann , H Matthes , J Beuth , HS Lin . Impact of complementary mistletoe extract treatment on quality of life in breast, ovarian and non-small cell lung cancer patients. A prospective randomized controlled clinical trial . Anticancer Res , 2004 . 24 ( 1 ): 303 - 309 . 15015612 . Impact of complementary mistletoe extract treatment on quality of life in breast, ovarian and non-small cell lung cancer patients. A prospective randomized controlled clinical trial CA Plouzek , HP Ciolino , R Clarke , GC Yeh . Inhibition of P-glycoprotein activity and reversal of multidrug resistance in vitro by rosemary extract . Eur J Cancer , 1999 . 35 ( 10 ): 1541 - 1545 . 10673984 DOI: 10.1016/S0959-8049(99)00180-X http://doi.org/10.1016/S0959-8049(99)00180-X . Inhibition of P-glycoprotein activity and reversal of multidrug resistance in vitro by rosemary extract CB Powell , P Fung , J Jackson , J Dall′Era , D Lewkowicz , I Cohen , K Smith-McCune . Aqueous extract of herba Scutellaria barbatae, a chinese herb used for ovarian cancer, induces apoptosis of ovarian cancer cell lines . Gynecol Oncol , 2003 . 91 ( 2 ): 332 - 340 . 14599863 DOI: 10.1016/j.ygyno.2003.07.004 http://doi.org/10.1016/j.ygyno.2003.07.004 . Aqueous extract of herba Scutellaria barbatae, a chinese herb used for ovarian cancer, induces apoptosis of ovarian cancer cell lines VF Semiglasov , VV Stepula , A Dudov , W Lehmacher , U Mengs . The standardised mistletoe extract PS76A2 improves QoL in patients with breast cancer receiving adjuvant CMF chemotherapy: a randomised, placebo-controlled, double-blind, multicentre clinical trial . Anticancer Res , 2004 . 24 ( 2C ): 1293 - 1302 . 15154663 . The standardised mistletoe extract PS76A2 improves QoL in patients with breast cancer receiving adjuvant CMF chemotherapy: a randomised, placebo-controlled, double-blind, multicentre clinical trial ZX Shen , ZZ Shi , J Fang , BW Gu , JM Li , YM Zhu , JY Shi , PZ Zheng , H Yan , YF Liu , 等 . All-trans retinoic acid/As 2 O 3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia . Proc Natl Acad Sci USA , 2004 . 101 ( 15 ): 5328 - 5335 . 15044693 DOI: 10.1073/pnas.0400053101 http://doi.org/10.1073/pnas.0400053101 . All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia SL Soignet , P Maslak , ZG Wang , S Jhanwar , E Calleja , LJ Dardashti , D Corso , A DeBlasio , J Gabrilove , DA Scheinberg , 等 . Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide . N Engl J Med , 1998 . 339 ( 19 ): 1341 - 1348 . 9801394 DOI: 10.1056/NEJM199811053391901 http://doi.org/10.1056/NEJM199811053391901 . Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide Y Takeda , H Togashi , T Matsuo , H Shinzawa , Y Takeda , T Takahashi . Growth inhibition and apoptosis of gastric cancer cell lines by Anemarrhena asphodeloides Bunge . J Gastroenterol , 2001 . 36 ( 2 ): 79 - 90 . 11227675 DOI: 10.1007/s005350170135 http://doi.org/10.1007/s005350170135 . Growth inhibition and apoptosis of gastric cancer cell lines by Anemarrhena asphodeloides Bunge YJ Tsai , IL Chen , LY Horng , RT Wu . Induction of differentiation in rat C6 glioma cells with Saikosaponins . Phytother Res , 2002 . 16 ( 2 ): 117 - 121 . 11933111 DOI: 10.1002/ptr.752 http://doi.org/10.1002/ptr.752 . Induction of differentiation in rat C6 glioma cells with Saikosaponins M Wartenberg , P Budde , M de Marees , F Grunheck , SY Tsang , Y Huang , ZY Chen , J Hescheler , H Sauer . Inhibition of tumor-induced angiogenesis and matrix-metalloproteinase expression in confrontation cultures of embryoid bodies and tumor spheroids by plant ingredients used in traditional chinese medicine . Lab Invest , 2003 . 83 ( 1 ): 87 - 98 . 12533689 DOI: 10.1097/01.LAB.0000049348.51663.2F http://doi.org/10.1097/01.LAB.0000049348.51663.2F . Inhibition of tumor-induced angiogenesis and matrix-metalloproteinase expression in confrontation cultures of embryoid bodies and tumor spheroids by plant ingredients used in traditional chinese medicine RH Wheeler , L Busby , W Samlowski , 等 . Phase I Study of Kanglaite (KLT) a Botanical Product Based on Traditional Chinese Medicine . 2003 . Presented at American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL . Phase I Study of Kanglaite (KLT) a Botanical Product Based on Traditional Chinese Medicine T Xue , R Roy . Studying traditional Chinese medicine . Science , 2003 . 300 ( 5620 ): 740 - 741 . 12730581 DOI: 10.1126/science.300.5620.740 http://doi.org/10.1126/science.300.5620.740 . Studying traditional Chinese medicine LL Yang , CY Lee , KY Yen . Induction of apoptosis by hydrolyzable tannins from Eugenia jambos L. on human leukemia cells . Cancer Lett , 2000 . 157 ( 1 ): 65 - 75 . 10893444 DOI: 10.1016/S0304-3835(00)00477-8 http://doi.org/10.1016/S0304-3835(00)00477-8 . Induction of apoptosis by hydrolyzable tannins from Eugenia jambos L. on human leukemia cells CW Yeh , WJ Chen , CT Chiang , SY Lin-Shiau , JK Lin . Suppression of fatty acid synthase in MCF-7 breast cancer cells by tea and tea polyphenols: a possible mechanism for their hypolipidemic effects . Pharmacogenomics J , 2003 . 3 ( 5 ): 267 - 276 . 12931129 . Suppression of fatty acid synthase in MCF-7 breast cancer cells by tea and tea polyphenols: a possible mechanism for their hypolipidemic effects DY Zhang , J Wu , F Ye , L Xue , S Jiang , J Yi , W Zhang , H Wei , M Sung , W Wang , 等 . Inhibition of cancer cell proliferation and prostaglandin E2 synthesis by Scutellaria baicalensis . Cancer Res , 2003 . 63 ( 14 ): 4037 - 4043 . 12874003 . Inhibition of cancer cell proliferation and prostaglandin E2 synthesis by Scutellaria baicalensis L Zhong , F Chen , J Han , N Shao , R Ouyang . Effects of red orpiment on cell morphology and expression of PML mRNA and protein in NB4 and HL-60 cells . Chin Med J , 2003 . 116 ( 1 ): 148 - 150 . 12667410 . Effects of red orpiment on cell morphology and expression of PML mRNA and protein in NB4 and HL-60 cells We thank Mari Swift (University of Washington, USA), Janice Lee (Harvard University, USA) for the serious proofreading work, Bingjian Lv, Weiqun Xu, Xiuxu Chen, Jing Deng and Lina Shao for helpful discussion in revising the article, Richard T. Penson (Massachusetts General Hospital, USA), Mohammed Mabed (Mansoura University, Egypt) for critical comments, Peng Fang for help with figure preparation. 10.1631/jzus.2006.B1006 Project (No. 011107607) supported by the Science and Technology Foundation Grant of Zhejiang Province, China 2006-07-17 2006-09-26 2006-11-17 2022-01-05 Copyright © 2006, Journal of Zhejiang University Science 2006 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 12 07