《天然药物化学》课程参考文献（天然药物研究与开发）Plants as a source of anti-cancer agents

Available online at www.sciencedirect.com SCIENCE孙IRECT· Journal of ELSEVIER Joumal of Ethnopharmacology 100(2005)72-79 www.ekevier.com/cate/jethpharm Perspective paper Plants as a source of anti-cancer agents Gordon M.Cragg*,David J.Newman er T Abstract Plant-derived com urce of several clinically useful anti-cancer 2005 Elsevier Ireland Ltd.All rights reserved. Keyrds:Camptothecins:Combretastatins Flavopiridol,Podophyllotoxin Taxanes.Vinca alkaloids,Cell cyele target inhibitors 1.Introduction Plants have a long history used ancover e way or another (Har well.1982).In hisr w.Ha and mi man et al than 3000 plant species that have reportedly been used in 2003). the treatment of cancer.but in many instances.the "can- The search for anti-cancer agents from plant sources cer"is undefined,or reference is made to conditions such as started inearnest in the 1950s with the discovery and develop- "hard swellings.abscesses.calluses,corns.warts,polyps. ment of the vinca alkaloids.vinblastine and vincristine.and or tumors,to name a few.Such symptoms would gener- the isolation of the cytotoxic podophyllotoxins.As a result ally apply to skin,"tangible",or visible conditions,and may the United States National Cancer Institute(NCI)initiated an indeed s etin erous conal on,bu extensive plant collect mny of the clain nempeaieegons.TisIdOhek60oeusedman likely to h s of folklor 980dd ditional medicine This is in contrast to other plant-based but their development into clinically active ag ned a therapies used in traditional medicine for the treatment of period of some 30 vears.from the early 1960s to the 1990s. afflictions such as malaria and pain.which are more eas- This plant collection program was terminated in 1982.but ily defined,and where the diseases are often prevalent in the development of new screening technologies led to the the regions where traditional medicine systems are exten revival of collections of plants and other organisms in 1986 sively used.Nevertheless,despite these observations,plants with a focus on the tropical and sub-tropical regions of the nave played an important role as a source of effective anti- world.It is inte resting to note,ho derive ve, s yet,reach 0378-8741/S-see front matter 2005 Elsevier Ireland Ltd.All rights reserved. do10.1016jjp2005.05.011

Journal of Ethnopharmacology 100 (2005) 72–79 Perspective paper Plants as a source of anti-cancer agents Gordon M. Cragg ∗, David J. Newman Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, P.O. Box B, Frederick, MD 21702-1201, USA Accepted 18 May 2005 Available online 11 July 2005 Abstract Plant-derived compounds have been an important source of several clinically useful anti-cancer agents. These include vinblastine, vin￾cristine, the camptothecin derivatives, topotecan and irinotecan, etoposide, derived from epipodophyllotoxin, and paclitaxel (taxol®). A number of promising new agents are in clinical development based on selective activity against cancer-related molecular targets, includ￾ing flavopiridol and combretastin A4 phosphate, while some agents which failed in earlier clinical studies are stimulating renewed interest. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Camptothecins; Combretastatins; Flavopiridol; Podophyllotoxins; Taxanes; Vinca alkaloids; Cell cycle target inhibitors 1. Introduction Plants have a long history of use in the treatment of cancer (Hartwell, 1982). In his review, Hartwell lists more than 3000 plant species that have reportedly been used in the treatment of cancer, but in many instances, the “can￾cer” is undefined, or reference is made to conditions such as “hard swellings”, abscesses, calluses, corns, warts, polyps, or tumors, to name a few. Such symptoms would gener￾ally apply to skin, “tangible”, or visible conditions, and may indeed sometimes correspond to a cancerous condition, but many of the claims for efficacy should be viewed with some skepticism because cancer, as a specific disease entity, is likely to be poorly defined in terms of folklore and tra￾ditional medicine. This is in contrast to other plant-based therapies used in traditional medicine for the treatment of afflictions such as malaria and pain, which are more eas￾ily defined, and where the diseases are often prevalent in the regions where traditional medicine systems are exten￾sively used. Nevertheless, despite these observations, plants have played an important role as a source of effective anti- ∗ Corresponding author. Tel.: +1 301 846 5387; fax: +1 301 846 6178. E-mail address: cragg@mail.nih.gov (G.M. Cragg). cancer agents, and it is significant that over 60% of currently used anti-cancer agents are derived in one way or another from natural sources, including plants, marine organisms and micro-organisms (Cragg et al., 2005; Newman et al., 2003). The search for anti-cancer agents from plant sources started in earnest in the 1950s with the discovery and develop￾ment of the vinca alkaloids, vinblastine and vincristine, and the isolation of the cytotoxic podophyllotoxins. As a result, the United States National Cancer Institute (NCI) initiated an extensive plant collection program in 1960, focused mainly in temperate regions. This led to the discovery of many novel chemotypes showing a range of cytotoxic activities (Cassady and Douros, 1980), including the taxanes and camptothecins, but their development into clinically active agents spanned a period of some 30 years, from the early 1960s to the 1990s. This plant collection program was terminated in 1982, but the development of new screening technologies led to the revival of collections of plants and other organisms in 1986, with a focus on the tropical and sub-tropical regions of the world. It is interesting to note, however that no new plant￾derived clinical anti-cancer agents have, as yet, reached the stage of general use, but a number of agents are in preclinical development. 0378-8741/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2005.05.011

colagv1002005723-79 73 The first agents to advance into clinical use were the nresandsuthseaucnlhsterefoundtobeactaeno .Don.(Apocyn Camptothecin 。 Fig1.Plant-deriv

G.M. Cragg, D.J. Newman / Journal of Ethnopharmacology 100 (2005) 72–79 73 2. Plant-derived anti-cancer agents in clinical use (Fig. 1) The first agents to advance into clinical use were the so-called vinca alkaloids, vinblastine (VLB) and vincristine (VCR), isolated from the Madagascar periwinkle, Catharan￾thus roseus G. Don. (Apocynaceae), which was used by vari￾ous cultures for the treatment of diabetes (Gueritte and Fahy, 2005). While under investigation as a source of potential oral hypoglycemic agents, it was noted that extracts reduced white blood cell counts and caused bone marrow depression in rats, and subsequently they were found to be active against lymphocytic leukemia in mice. This led to the isolation of VLB and VCR as the active agents, so their discovery may Fig. 1. Plant-derived anti-cancer agents in clinical use

g10020072-79 be indirectly attributed to the observation of an unrelated Another important addition to the anti-cancer drug arma- medicinal ohehcC eae (Rahier e collected in Jamaica and the Philippines.More recent semi ).Camptothecin(as its sodium salt)was advanced ind nare vinorelbine( se ag us for the ve Top treatment of a variety of cancers,including leukemias,lym- and Irinotecan (CPT-11:Camptosar).Topotecan is used for phomas,advanced testicular cancer,breast and lung cancers. the treatment of ovarian and small cell lung cancers,while and kaposi rin side (VM 26)and ringoine.isolated from the Chinese tree tives ofthe natural product,epipodophyllotoxin(nisomrof harringtonia var.drupacea (Sieb andu(Cephalotax )may be eing more closely wa et a (Lee and Xiao.2005).The aC.Sm a Fijian medicinal plant with reputed anti-cancer properties an mandrake or Mayapple).and Podophyllm na or the treatme and warts.The major active constituent,podophyllotoxin eukemia purified hHt has shown efficacy against various ndard treatment n to pro andunacceptable toxcityEteiv clinical trials.only on (CHRepo France for the treatment of breast cancer. mas and e and tes 3.Plant-derived anti-cancer agents in clinical A more recent addition to the armamentarium of plant development(Fig.2) ic agents are the taxanes (Kingston, olated from a random collection n been reported.while the eaves of the ove 100 analogs synthesized during structure-activity studies the traditional Asiatic Indian(Ayurvedic)medicine system and was found to possess tyrosine kinase activity and poten of“cancer'aba growth inhibitory agains catins),occurs in the leaves of various and the showed broad spectrum in vivo activity against human tumo ready semi-synthetic conversion of the relatively abundant ction for preclini ba ns to pac el analogs able natural source of this important class of drugs Paclitaxe clinical ials r in combination with other anti is used in the treatment of breast,ovarian,and non-small cell cancer agents,against a broad range of tumors,including lung eancer (NSCL against leukemias,lymp were (Combretaceae),collected in southern Africa in the 1970s en preclinical devnn velopment as potential anti-cance spart of a the NCI by the (05)

74 G.M. Cragg, D.J. Newman / Journal of Ethnopharmacology 100 (2005) 72–79 be indirectly attributed to the observation of an unrelated medicinal use of the source plant. It is interesting to note that though the plant was originally endemic to Madagascar, the samples used in the discovery of VLB and VCR were collected in Jamaica and the Philippines. More recent semi￾synthetic analogs of these agents are vinorelbine (VRLB) and vindesine (VDS). These agents are primarily used in com￾bination with other cancer chemotherapeutic drugs for the treatment of a variety of cancers, including leukemias, lym￾phomas, advanced testicular cancer, breast and lung cancers, and Kaposi’s sarcoma. The two clinically active agents, etoposide (VM 26) and teniposide (VP 16-213), which are semi-synthetic deriva￾tives of the natural product, epipodophyllotoxin (an isomer of podophyllotoxin), may be considered as being more closely linked to a plant originally used for the treatment of “cancer” (Lee and Xiao, 2005). The Podophyllum species (Podophyl￾laceae), Podophyllum peltatum Linnaeus (commonly known as the American mandrake or Mayapple), and Podophyllum emodii Wallich from the Indian subcontinent, have a long his￾tory of medicinal use, including the treatment of skin cancers and warts. The major active constituent, podophyllotoxin, was first isolated in 1880, but its correct structure was only reported in the 1950s. Many closely related podophyllotoxin￾like lignans were also isolated, and several of them were introduced into clinical trials, only to be dropped due to lack of efficacy and unacceptable toxicity. Extensive research led to the development of etoposide and teniposide as clin￾ically effective agents which are used in the treatment of lymphomas and bronchial and testicular cancers. A more recent addition to the armamentarium of plant￾derived chemotherapeutic agents are the taxanes (Kingston, 2005). Paclitaxel (taxol®) initially was isolated from the bark the Pacific Yew, Taxus brevifolia Nutt. (Taxaceae), as part of a random collection program for the NCI by the U.S. Depart￾ment of Agriculture (USDA). The use of various parts of Taxus brevifolia and other Taxusspecies (e.g., Taxus canaden￾sis Marshall, Taxus baccata L.) by several Native American tribes for the treatment of some non-cancerous conditions has been reported, while the leaves of Taxus baccata are used in the traditional Asiatic Indian (Ayurvedic) medicine system, with one reported use in the treatment of “cancer” (Hartwell, 1982). Paclitaxel, along with several key precursors (the bac￾catins), occurs in the leaves of various Taxus species, and the ready semi-synthetic conversion of the relatively abundant baccatins to paclitaxel, as well as active paclitaxel analogs, such as docetaxel (Taxotere®), has provided a major, renew￾able natural source of this important class of drugs. Paclitaxel is used in the treatment of breast, ovarian, and non-small cell lung cancer (NSCLC), and has also shown efficacy against Kaposi sarcoma, while docetaxel is primarily used in the treatment of breast cancer and NSCLC. Paclitaxel has also attracted attention in the potential treatment of multiple scle￾rosis, psoriasis and rheumatoid arthritis. In addition, 23 tax￾anes are in preclinical development as potential anti-cancer agents. Another important addition to the anti-cancer drug arma￾mentarium is the class of clinically active agents derived from camptothecin, which is isolated from the Chinese ornamental tree, Camptotheca acuminata Decne (Nyssaceae) (Rahier et al., 2005). Camptothecin (as its sodium salt) was advanced to clinical trials by the NCI in the 1970s, but was dropped because of severe bladder toxicity, but extensive research led to the development of more effective derivatives, Topotecan and Irinotecan (CPT-11; Camptosar). Topotecan is used for the treatment of ovarian and small cell lung cancers, while Irinotecan is used for the treatment of colorectal cancers. Other plant-derived agents in clinical use are homohar￾ringtonine, isolated from the Chinese tree, Cephalotaxus harringtonia var. drupacea (Sieb and Zucc.) (Cephalotax￾aceae) (Itokawa et al., 2005), and elliptinium, a derivative of ellipticine, isolated from species of several genera of the Apocynaceae family, including Bleekeria vitensis A.C. Sm., a Fijian medicinal plant with reputed anti-cancer properties. A racemic mixture of harringtonine and homoharringtonine (HHT) has been used successfully in China for the treatment of acute myelogenous leukemia and chronic myelogenous leukemia. Purified HHT has shown efficacy against various leukemias, including some resistant to standard treatment, and has been reported to produce complete hematologic remission (CHR) in patients with late chronic phase chronic myelogenous leukemia (CML). Elliptinium is marketed in France for the treatment of breast cancer. 3. Plant-derived anti-cancer agents in clinical development (Fig. 2) Flavopiridol is totally synthetic, but the basis for its novel flavonoid structure is a natural product, rohitukine, isolated as the constituent responsible for anti-inflammatory and immunomodulatory activity from Dysoxylum binectariferum Hook. f. (Meliaceae), which is phylogenetically related to the Ayurvedic plant, Dysoxylum malabaricum Bedd., used for rheumatoid arthritis. Flavopiridol was one of the over 100 analogs synthesized during structure–activity studies, and was found to possess tyrosine kinase activity and potent growth inhibitory activity against a series of breast and lung carcinoma cell lines (Sausville et al., 1999). It also showed broad spectrum in vivo activity against human tumor xenografts in mice, which led to its selection for preclini￾cal and clinical studies by the NCI in collaboration with the company, Hoechst. It is currently in 18 Phase I and Phase II clinical trials, either alone or in combination with other anti￾cancer agents, against a broad range of tumors, including leukemias, lymphomas and solid tumors. The combretastatins were isolated from the South African “bush willow”, Combretum caffrum (Eckl. & Zeyh.) Kuntze (Combretaceae), collected in southern Africa in the 1970s as part of a random collection program for the NCI by the USDA, working in collaboration with the Botanical Research Institute of South Africa (Pinney et al., 2005). Species of the

G.M Cragg.DJ Newman/Journal of 100(2005)7-79 Roscovitine(CYC202) Combretastatin A Flavopiridol Fig.Plant-derivsd r agents Combretum and Terminalia s both of which bel the plant-derived agents bru traditional medicine for the treatment of a variety of dis- their potential as"warheads"attached to monoclonal anti- ase is that of m avtansine Mavtansine act as anti-angiogenic agents,causing vascular shutdown in (Fig 3)was isolated in the early 1970s from the Ethiopian tumors and cros A water-soluble ana- SD developed.Three are in clincal ias while 11 are in preclinical development.This chemical class has served a a model of a host of an amwa the prodction of s quantities to pursue prec three atom bridges including heterocyclic rings and sulfon- 二 isplay of the power of rial e ere subsequently isolate Sham.2002). e d on ana ural product mode derive e,original时 between a mic the plant, was shown to inhibit eyelin-dependent kinases(Cdk),pro 一布r邮g which play amajor roe n ce ogether with their potency,has stimulated chem more potent n opment.A deriva Europe.Further development of this series,following syn hesledh purawhichor 99 ate known as SB408075 or huC242-DM1 (also known as Cantuzumab 24 4.Targeting natural products c b expre A recurring liability of natural products,at least in the nd gastric is n USA. (TG)(Fi

G.M. Cragg, D.J. Newman / Journal of Ethnopharmacology 100 (2005) 72–79 75 Fig. 2. Plant-derived anti-cancer agents in clinical development. Combretum and Terminalia genera, both of which belong to the Combretaceae family, are used in African and Indian traditional medicine for the treatment of a variety of dis￾eases, including hepatitis and malaria, and several Terminalia species have reportedly been used in the treatment of “can￾cer”. The combretastatins are a family of stilbenes which act as anti-angiogenic agents, causing vascular shutdown in tumors and resulting in tumor necrosis. A water-soluble ana￾log, combretastatin A4 phosphate (CA4), has shown promise in early clinical trials, and a number of combretastatin (CA4) mimics are being developed. Three are in clinical trials, while 11 are in preclinical development. This chemical class has served as a model for the synthesis of a host of analogs con￾taining the essential trimethoxy aryl moiety (Fig. 2) linked to substituted aromatic moieties through a variety of two or three atom bridges including heterocyclic rings and sulfon￾amides, and provides an impressive display of the power of a relatively simple natural product structure to spawn a pro￾lific output of medicinal and combinatorial chemistry (Li and Sham, 2002). Another synthetic agent based on a natural product model is roscovitine which is derived from olomucine, originally isolated from the cotyledons of the radish, Raphanus sativus L. (Brassicaceae) (Meijer and Raymond, 2003). Olomucine was shown to inhibit cyclin-dependent kinases (Cdk), pro￾teins which play a major role in cell cycle progression, and chemical modification resulted in the more potent inhibitor, roscovitine, which currently is in Phase II clinical trials in Europe. Further development of this series, following syn￾thesis of a focused library via combinatorial chemistry tech￾niques, has led to the purvalanols which were even more potent, and are in preclinical development (Chang et al., 1999). 4. Targeting natural products A recurring liability of natural products, at least in the area of cancer chemotherapy, is that while often very potent, they have limited solubility in aqueous solvents and exhibit narrow therapeutic indices. These factors have resulted in the demise of a number of pure natural products, such as the plant-derived agents, bruceantin and maytansine, but an alternative approach to utilizing such agents is to investigate their potential as “warheads” attached to monoclonal anti￾bodies specifically targeted to epitopes on tumors of interest (Sausville, 1997). A promising case is that of maytansine. Maytansine (Fig. 3) was isolated in the early 1970s from the Ethiopian plant, Maytenus serrata (Hochst. Ex A. Rich.) Wilczek (Celastraceae), again collected for the NCI through the USDA random collection program (Cassady et al., 2004). Despite very low yields (2 × 10−5% based on plant dry weight), its extreme potency in testing against cancer cell lines permitted the production of sufficient quantities to pursue preclini￾cal and clinical development. Unfortunately, very promising activity in preclinical animal testing did not translate into sig￾nificant efficacy in clinical trials, and it was dropped from further study in the early 1980s. Related compounds, the ansamitocins, were subsequently isolated from a microbial source, the Actinomycete,Actinosynnema pretiosum, and this posed the question as to whether the maytansines are actu￾ally plant products, or are produced through an association between a microbial symbiont and the plant; this is a topic of continuing study (Yu and Floss, 2005). The microbial source of closely related compounds has permitted the production of larger quantities of this class of compounds, and this factor, together with their extreme potency, has stimulated contin￾ued interest in pursuing their development. A derivative of maytansine, DM1, conjugated with a monoclonal antibody (mAb) targeting small cell lung cancer cells, is being devel￾oped as huN901-DM1 for the treatment of small-cell lung cancer, and another conjugate of DM1 to J591, a mAb tar￾geting the prostate specific membrane antigen (PSMA), is in clinical trials against prostate cancer. A conjugate known as SB408075 or huC242-DM1 (also known as Cantuzumab Mertansine), produced by the coupling of DM1 to huC242, a mAb directed against the muc1 epitope expressed in a range of cancers, including pancreatric, biliary, colorectal, and gastric cancers, is currently in Phase I clinical trials in the USA. Another case of considerable interest is that of thapsi￾gargin (TG) (Fig. 3), isolated from the umbelliferous plant, Thapsia garganica L. (Apiaceae), collected on the Mediter-

Cragg.D.J.Newmon ogr100200972-79 8em8amX:anX.N0oH Fig.3.Plant-derived anti-tum ents in preclinical development. ranean island of Ibiza(Denmeade).Thapsigargin bering that the development of effective drugs,such as pacli induces apoptosis PTOolaieCanCcTCelR,fhasbecncoanugaledioasnalpeptdte carrier to produce a water-soluble prodrug which is specifi- ultimately prove their efficacy as clinical agents. cally activated by prostate specific antigen(PSA)protease at Another example of of the met ic prostate cancer antin whimptot .Mill.(Simaroubaceae),used in Ethiopia human prostate cancer As often happens, observed in clinical trials and further development was ter 5.Plant-derived anti-tumor agents in preclinical minated.Recent observations of significant activity against development (Fig.3) panels of leuker mia,lymphoma an myeloma cell lines,as associated with the down-regulation of a key oncoprotein(c

76 G.M. Cragg, D.J. Newman / Journal of Ethnopharmacology 100 (2005) 72–79 Fig. 3. Plant-derived anti-tumor agents in preclinical development. ranean island of Ibiza (Denmeade et al., 2003). Thapsigargin induces apoptosis (cell death) in quiescent and proliferating prostate cancer cells, and while it does not show selectivity for prostate cancer cells, it has been conjugated to a small peptide carrier to produce a water-soluble prodrug which is specifi- cally activated by prostate specific antigen (PSA) protease at metastatic prostate cancer sites. Treatment of animals bear￾ing prostate cancer xenograft tumors demonstrated complete tumor growth inhibition without significant toxicity. Given that the prodrug is stable in human plasma, it holds promise as a treatment for human prostate cancer. 5. Plant-derived anti-tumor agents in preclinical development (Fig. 3) A number of naturally derived agents have been entered into clinical trials and terminated due to lack of efficacy or unacceptable toxicity. The case of maytansine (Section 4) illustrates how the emergence of novel technologies can revive interest in these “old” agents. It is also worth remem￾bering that the development of effective drugs, such as pacli￾taxel (taxol®) and the camptothecin derivatives, topotecan, and irinotecan (see Section 2), required 20–30 years of ded￾icated research and patience, and considerable resources, to ultimately prove their efficacy as clinical agents. Another example of an “old” drug of the same vintage as taxol® and camptothecin having a possibility of revival is bruceantin which was first isolated from a tree, Brucea antidysenterica J.F. Mill. (Simaroubaceae), used in Ethiopia for the treatment of “cancer” (Cuendet and Pezzuto, 2004). As often happens, activity was observed in animal models bearing a range of tumors, but no objective responses were observed in clinical trials, and further development was ter￾minated. Recent observations of significant activity against panels of leukemia, lymphoma and myeloma cell lines, as well as in animal models bearing early and advanced stages of the same cancers, has revived interest. This activity has been associated with the down-regulation of a key oncoprotein (c￾MYC), and these data are being presented as strong evidence supporting the development of bruceantin as an agent for the treatment of hematological malignancies