全 文 ：·专论与综述·
Rev iew on an ticancer m echan ism of som e plan t a lka lo ids
CH EN G L ei, ZHOU X iu2jiaΞ
(Co llege of T radit ional Ch inese M ateria M edica, ShanghaiU niversity
of T radit ional Ch inese M edicine, Shanghai 201203, Ch ina)
Abstracts: A lkalo ids derived from natural p roducts have long been used as a fert ile source of cure fo r cancer,
w h ich is believed to be one of the m ajo r causes of death in th is cen tu ry. T h is art icle review s the recen t advances of
m any structu res of alkalo ids in understanding m echan ism of action at the mo lecu lar, cellu lar and physio logical lev2
els. T he impo rtan t mo lecu les discussed include vincrist ine, vinb last ine, camp to thecin, co lch icine, ellip t icine etc.
T he review also discussed the po ten tia l use of p lan t a lkalo ids on m ultidrug resistance.
Key words: m echan ism ; alkalo ids; an ticancer; cell cycle; DNA 2topo isom erase I; apop to sis; m ult idrug resistance
植物生物碱抗肿瘤机制
程　磊, 周秀佳
(上海中医药大学中药学院, 上海　201203)
摘　要: 生物碱中的一些种类用于治疗癌症已有相当长的一段时间。回顾了近年来在分子、细胞及生理水平上这些
生物碱抗肿瘤的作用机制, 包括长春花生物碱类、喜树碱、秋水仙碱、玫瑰树碱等。同时也涉及多药耐药现象。
关键词: 机制; 生物碱; 抗肿瘤; 细胞周期; DNA 2拓扑异构酶É ; 细胞凋亡; 多药耐药
中图分类号: R 282. 71; R 979119　　　文献标识码: A 　　　文章编号: 0253 2670 (2004) 02 0216 06
　　H erbal m edicine has been used fo r treatm ent of differ2
en t diseases in Ch ina fo r thousands of years. R ecen t studies
have demonstra ted that phytochem icals of m any classes in
herbal m edicine have therapeu tic use. N um erous in v itro
studies on differen t cell lines and in v ivo study of alkalo ids
have repo rted [1～ 3 ] that a lkalo ids po ssess an ticancer activi2
t ies. T h is review aim s to give an overview of the pharm aco2
logical effects of alkalo ids in the treatm ent of cancer. Po ssi2
ble m echan ism s of action of som e alkalo ids, including V inca
alkalo ids, camp to thecins, ellip t icine, w ere also discussed in
the paper.
1　M echan ism of action of d ifferen t a lka lo ids
1. 1　 V inca alkalo ids　V inblast ine and vincrist ine, com 2
monly term ed V inca alkalo ids, are iso la ted from Catharan2
thus roseus (L. G. Don) leaves in the la te 1950’s. V inca al2
kalo ids b inds to tubu lin, a dim eric cellu lar p ro tein p laying a
crucia l ro le in cell structu re and in the o rgan ization of ch ro2
mo som es. T h is b inding inh ib its the po lym erization of tubu2
lin in to m icro tubu les ra ther than in terferes w ith the m ito tic
p rocess and induces the arrest of cells in m ito sis.
T he tubu lin iso type compo stion of m icro tubu les is an
impo rtan t determ inan t in an tineop last ic activity of V inca al2
kalo ids. In v itro study has show n that Β2tubu lin iso type
compo sit ion affects m icro tubu le sensit ivity to V inca alka2
lo ids[4 ]. M o lecu lar app roaches using quan tita t ive sedim enta2
t ion velocity have already p roved that the tubu lin iso type
compo sit ion of various tissues o r tumours m ay also deter2
m ine the clin ically observed drug tox icity. T hermodynam ic
param eters fo r vincrist ine2, vinb last ine2 o r vino relb ine2
in teraction w ith differen t purified iso types of tubu lin had al2
so been determ ined. Sm all bu t sign ifican t differences in cer2
ta in individual thermodynam ic param eters w ere found fo r
vincrist ine and w ere no t observed w ith vinb last ine o r vi2
no relb ine. But in cells, m icro tubu les are compo sed of a
backbone of tubu lin dim ers and m icro tubu le2associa ted p ro2
teins, term ed M A P s w h ich have been show n to regu late
tubu lin po lym erization function and modulate the activity of
tubu lin2in teraction agen ts such as V inca alkalo ids.
O n the o ther hand, it had been show n that V inca alka2
lo ids also affected m icro tubu les in in terphase cells, w h ich is
associa ted w ith the cyto skeleton netw o rk influencing the in2
t racellu lar m igration of oncogenes. A nd such effects of V in2
ca alkalo ids on the m icro tubu les of in terphasic cells m ay also
influence their an titumour activity. A ctivit ies of four V inca
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Ξ 收稿日期: 2003205217
作者简介: 程　磊 (1976—) , 男, 江苏省阜宁人, 现为上海中医药大学中药学院在读博士生, 主要从事生药学研究, 已发表 15 篇论文。
T el: (021) 50808727　E2m ail: m r. chenglei@ 163. com
alkalo ids on the mo st dynam ic m icro tubu les w ere investigat2
ed in m ito sis and in in terphase by evaluating the distu rbance
of the m etaphase p late and the sp lit t ing of the dip lo som e,
respectively. Cyto tox icity, m ito tic distu rbance and dip lo2
som e sp lit t ing w ere observed in vinb last ine, vincrist ine,
vindesine and vino rlb ine, a lthough these even ts occurred at
ten tim es h igher concen tra t ions in the case of vinflun ine.
H ence, dynam ic modificat ions of bo th the m ito tic and in ter2
phasic m icro tubu le cyto skeleton are compatib le w ith in v itro
cyto tox icity of vinflun ine, ra ising questions abou t the con2
ven tional b iochem ical screen ing of these V inca alkalo ids.
In addit ion to their an tim ito tic effects, the effects of
vinb last ine on angiogenesis w ere specifically studied: in v it2
ro, vinb last ine had inh ib ito ry effect a t non2cyto tox ic do ses
and in a concen tra t ion2depeden t fash ion, on endo thelia l cell
p ro lifera t ion, chemo tax is, sp reading on fib ronectin and
mo rphogenesis on M atrigel; the an tiangiogen ic effects of
vinb last ine w ere confirm ed in v itro using the ch ick em bryo
cho rioallan to ic m em brane model and these effects w ere
rap idly abo lished w hen vinb last ine w as removed. T he an ti2
vascu lar effects of o ther new er V inca alkalo ids, such as vi2
no relb ine and vinflun ine, w ere also estab lished using the
M A C 15A transp lan tab le m urine co lon adenocarcinom a
model[5 ]. Furthermo re, it w as emphasized that fo r vinflu2
nine there w as a clear separat ion betw een the an tiangiogen ic
do se and the m axim um to lerated do se. In addit ion, reduced
tumour oxygenation by treatm ent w ith vinb last ine w as re2
cen tly observed in v ivo[6 ]. T h is study using non2invasive
techn iques such as m agnetic resonance im aging and electron
param agnetic resonance oxym etry, demonstra ted that vin2
blast ine caused a p rofound reduction in tumour b lood flow
and oxygenation w h ich cou ld have resu lted from the effects
of vinb last ine on tumour vascu latu re. N ew V inca alkalo ids
shou ld certa in ly be screened fo r any novel an tiangiogen ic
p ropert ies.
By flow cytom etry using nuclear sta in ing and annex in
V , vino relb ine and vincrist ine had been demonstra ted to in2
duce bo th m ito tic arrest and apop to sis in leukem ia and lym 2
phom a cells, in a drug expo sure tim e dependen t m anner.
CPP32 o r caspase23 w as a crit ical apop to sis inducer. Its ac2
t ive subun its p 20 and p 11 w ere up2regu lated in chemo2 and
apop to sis2sensit ive lymphom a and leukem ia cells treated
w ith vino relb ine. T hese observations suggested that w idely
divergen t exogenous st im uli and chemo therapeu tic agen ts
can affect apop to sis in cancer cells via differen t pathw ays in2
vo lving the caspases.
Fukuoka et a l. [7 ] repo rted that vino relb ine at a m in i2
m ally tox ic concen tra t ion moderately sensit ized hum an non2
sm all cell lung cancer cells to radia t ion by causing accum ula2
t ion of cells in the G2öM 2phase of the cell cycle. P ro logned
G2öM accum ulation concom itan t w ith con tinuous po ly2
p lo idization and increased suscep tib ility to induction of apop2
to sis m ay be associa ted w ith the cellu lar m echan ism of ra2
dio2sensit izat ion p roduced by vino relb ine.
1. 2　Camp to thecins　Camp to thecin (CT P ) is a natu rally
occurring cyto tox ic alkalo ids derived from the Ch inese tree
Cam p totheca acum ina ta D ecne. It is an effective inh ib ito r of
in tranuclear enzym e topo isom erase I, w h ich is invo lved in
reducing the to rsional stress of superco iled DNA during the
rep licat ion, recom bination, transcrip t ion, and repair of
DNA.
T he camp to thecins trap and stab ilize the no rm ally tran2
sien t DNA 2topo isom erase I cleavab le comp lex, w h ich leads
to the accum ulation of single2stranded break s of the DNA.
Co llision of the DNA rep licat ion fo rk w ith the ternary drug2
enzym e2DNA comp lex p roduces an irreversib le doub le2
strand break that u lt im ately leads to cell death. T he camp2
to thecins are S2phase2specific an ticancer agen ts. Irreversib le
DNA double2strand break s are p roduced during DNA syn2
thesis in the p resence of camp to thecin. A nd recen t studies
of low 2do se, p ro tracted adm in istra t ion of camp to thecin ana2
logues in m ice bearing xenografts of hum an tumo rs have
show n less tox icity and equal to o r better an titumo r activity
than sho rter, mo re in tense do sing schedu les. How ever,
camp to thecin2induced cyto tox icity had also been observed in
nondividing cells, such as neurons. It w as characteried by
ch rom atin condensation, cytop lasm ic sh rink ing, p lasm a
m em brane b lebb ing, and fragm entat ion of neurites. DNA
fragm entation w as also confirm ed by the use of the in situ
DNA end labeling assay.
CPT effectively k ills hum an gastric cancers by activa2
t ing cell cycle w ithdraw al and cell death th rough induction
of p 21W alf1öCip1 and dow n regu lat ion of Bcl22. M eanw h ile, the
transcrip t ion facto r comp lex E2F21öD P21 regu lates the G12
to2S2phase transit ion and has been associa ted w ith sensit ivi2
ty to the S2phase2specific an ticancer agen t camp to thecin.
Hofland et a l. [8 ] repo rted that camp to thecin2induced tox icity
in their experim ents w as due to the activation of an E2F21ö
D P212induced po st2DNA dam age pathw ay rather than an in2
crease in the num ber of rep licat ion fo rk s caused by the S2
phase in it ia t ion. In addit ion, A dam s et a l. [9 ] found that
CPT 2based drug developm ent and resu lt ing chemo therapy
cou ld benefit from evaluation of differen tia l act ivity at acidic
versus physio logical pH. It has been iden tified that ana2
logues cou ld have imp roved therapeu tic indices based on the
pH gradien t that select ively ex ists in hum an tumo rs. F inal2
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ly, recen t repo rts have suggested that the camp to thecins
m ay also have an an tiangiogenesis effect. T he pharm aco log2
ica l in terest of camp to thecin has generated a large num ber of
derivatives and analogues endow ed w ith po ten t cyto tox ic ac2
t ivity, including 92A C, 92N C, irino tecan, CPT 211, 72sub2
st itu ted camp to thecins, 102hydroxycamp to thecin, exatecan
m esylate, and karen itecin.
113 　Co lch icine 　Co lch icine exerts its b io logical effects
th rough b inding to the so lub le tubu lin heterodim er, the m a2
jo r componen t of the m icro tubu le. Specifically, it in terferes
w ith m icro tubu le grow th and therefo re affects m ito sis and
o ther m icro tubu le2dependen t functions. T he k inetic m echa2
nism s of the b inding to tubu lin of co lch icine and eigh t differ2
en t analogues had been studied. A ll of the analogues fo llow
a tw o step b inding m echan ism , i. e. b inding occurs via an
in it ia l step w ith low affin ity, fo llow ed by an isom erisat ion of
the in it ia l comp lex leading to the final h igh affin ity sta te.
M o rpho logical analysis of M CF27 ADR r cells revealed that
th ioco lch icone is ab le to induce apop to sis in th is m ult idrug
resistance (M DR ) 2bearing model and they also demonstra t2
ed that th ioco lch icone in teracts w ith Α2 and Β2tubu lin by us2
ing flow cytom etry. In addit ion, co lch icine also has sign ifi2
can t effects on tubu lin confo rm ation, bu t the regions w h ich
are affected have no t been iden tified. Chaudhuri et a l. [10 ] re2
po rted fo r the first t im e that the in teraction of the B 2ring of
co lch icine w ith the Α2 subun it affects a dom ain of tubu lin
w h ich appears to be far from its b inding site. Furthermo re,
they also found that the B 2ring of co lch icine p lays a m ajo r
ro le in the stab ility of tubu lin w h ile the A and the C2rings
have lit t le effect on it. L evchenko et a l. [11 ] used a po sitron2
em itt ing M DR tracer, 11C2co lch icine (CHC ) , to evaluate
M DR by PET im aging. T hey observed an app rox im ately 22
fo ld difference betw een 11C2CHC accum ulation in sensit ive
and resistan t tumo rs. T hese in v ivo experim ents p rovided
addit ional evidence fo r the indirect effect of P2gp action on
CHC2to2tubu lin b inding, w h ich in tu rn determ ines CHC up2
take in tumo rs.
1. 4　H arrington ine　H arrington ine (H T ) , homoharring2
ton ine (HH T ) and isoharrington ine ( IH T ) are cephalo ta2
xine alkalo ids w ith an ticancer activit ies w h ich w ere iso la ted
from Cep halotax us ha inanensis L. indigenous to Ch ina.
Since the 1970s, H T and HH T have been developed as ef2
fect ive an ticancer drugs in Ch ina and have been used w idely
in the treatm ent of acu te non lympho id leukem ia and ch ron ic
granu locyte leukem ia. T he Cep halotax us alkalo ids inh ib it
the elongation phase of transla t ion by p reven ting substra te
from binding to the accep to r site on the 602S ribo som e sub2
unit and therefo re b lock am inoacyl2tRNA binding and pep2
t ide bond fo rm ation. T he m echan ism of the an titumo r action
of harrington ine is considered to be an effect on p ro tein syn2
thesis and is characterized by breakdow n of po lysom es to
mono som es. In addit ion, IH T show s sign ifican t and rap id
apop to tic inductive effect on HL 260 cells in bo th concen tra2
t ion2 and tim e2dependen t fash ion. T yp ical DNA ladder in a2
garo se gel electropho resis and p re2G1 peak in flow cytom et2
ric analysis are also observed in the cells expo sed to IH T.
115　E llip t icine　E llip t icine is one of the simp lest natu rally
occurring alkalo ids iso la ted in 1959 from the leaves of
O ch rosia ellip tica (L ab ill. ) (A pocynaceae) , w h ich grow s
w ildly in O cean ia. Studies on the m echan ism s of cyto tox ici2
ty and an ticancer activity of the ellip t icine analogues indicate
a comp lex set of effects, including DNA in tercala t ion and
inh ib it ion of topo isom erase Ê . E llip t icine does no t impair
topo isom erase Ê 2m ediated DNA religation and p resum ably
increases levels of DNA cleavage comp lexes p rim arily by
stim ulating the fo rw ard rate of scission. W ild2type p 53
causes cell2cycle arrest a t la te G1 phase and induction of
apop to sis by up 2regu lat ion of WA F 1 and BA X, respective2
ly, bu t in m any cancer cells p 53 is frequen tly m utated and
lo ses its functions. M izumo to et a l. [12 ] suggests that 92hy2
droxy ellip t icine m ay cause G1 arrest and induction of G1
phase2restricted apop to sis by resto ring the w ild2type func2
t ion of m utan t p 53 p ro tein. R ecen tly, F rei et a l. found that
ellip t icine also fo rm s covalen t DNA adducts and that the
fo rm ation of the m ajo r adduct is dependen t on the activation
of ellip t icine by cytoch rom e P450 (CYP) [13, 14 ].
1. 6　Cepharan th in　Cepharan th in is one of the b iscoclau2
rine alkalo ids w idely used fo r treatm ent of m any acu te and
ch ron ic diseases; snakeb ite, b ronch ial asthm a, alopecia
areata, leukopen ia during radiat ion therapy o r an ticancer
treatm ent. R ecen tly, it has been repo rted that cepharan th in
exerts an titumour effects by increasing imm uno logical com 2
petence of the ho st o r apop to sis2inducing activity. Cepha2
ran th in induces G1 arrest via exp ression of p 21 (WA F1) and
apop to sis th rough caspase 3 against a hum an adeno squa2
mous cell carcinom a cell line (T YS) [15 ].
1. 7　So lam argine　So lam argine, a herbal and mo lluscicidal
m edicine derived from S olanum incanum L. , is a stero idal
a lkalo id glyco side. To characterize the an ticancer m echa2
nism of so lam argine on hum an hepatom a cells (H ep 3B ) ,
changes of cell mo rpho logy, DNA conten t, and gene ex2
p ression of cells after so lam argine treatm ent w ere studied.
T he appearance in so lam argine2t reated cells of ch rom atin
condensation, DNA fragm entation, and a sub2G1 peak in a
DNA h istogram suggest that so lam argine induce cell death
by apop to sis[16 ]. In addit ion, the gene exp ression of tumour
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necro sis facto r recep to r É (TN FR É ) is up2regu lated w ith
so lam argine treatm ent. Since TN FR É has been invo lved in
apop to sis, the overexp ression of TN FR É m ay be rela ted
w ith the m echan ism of cyto tox icity of so lam argine.
1. 8　Sanguinarine　Sanguinarine, w h ich is derived from
the roo t of S ang u inaria canad ensis L. and o ther poppy fu2
m aria species, is a benzophenath ridine alkalo id and a struc2
tu ra l homo logue of cheleryth rine. Sangu inarine has been
show n to po ssess an tim icrob ial, an tiox idan t, and an ti2in2
flamm ato ry p ropert ies. A recen t study has show n that san2
guinarine is a po ten t inh ib ito r of the activation of nuclear
transcrip t ion facto r N F2ϑB, w h ich has been imp licated to
p lay a key ro le in the regu lat ion of cell grow th, cell cycle
regu lat ion, and apop to sis. Bu t the an titumo r p ropert ies of
th is alkalo id are no t w ell estab lished. A hm ad et a l. [17 ] com 2
pared the an tip ro lifera t ive and apop to tic po ten tia l of san2
guinarine against hum an ep idermo id carcinom a (A 431) cells
and no rm al hum an ep iderm al kerat inocytes (N H EK s). San2
guinarine treatm ent w as found to resu lt in a do se2dependen t
decrease in the viab ility of A 431 cells as w ell as N H EK s al2
beit a t differen t levels because sangu inarine2m ediated lo ss of
viab ility occurred at low er do ses and w as m uch mo re p ro2
nounced in the A 431 carcinom a cells than in the no rm al ker2
atinocytes. W eerasinghe et a l. [18 ] demonstra ted that san2
guinarine treatm ent at a low level induces apop to sis o r p ro2
gramm ed cell death ( PCD ) in the Bcl22 low 2exp ressing
K562 hum an eryth ro leukem ia cells, and that a h igh level in2
duces b lister cell death (BCD ) ; w hereas the over2exp ression
of an ti2apop to tic Bcl22 m ay have p reven ted sangu inarine
from inducing PCD and BCD in JM 1 cells[19 ].
1. 9　O thers　 Inh ib it ion of cancer cell’s grow th in a com 2
mon app roach to treat cancer. R ecen tly, it w as repo rted
that the aqueous ex tract of R h iz om a Cop tid is and berberine
have po ten t inh ib ito ry effect on the p ro lifera t ion of
esophageal cancer cells (ECC s) lines[20 ]. Cell cycle analysis
of R h iz om a Cop tid is2t reated cancer cells show ed the accu2
m ulation of cells in the G0öG1 phase.
T etrandrine, a calcium channel an tagon ist, is a natu ral
lip id2so lub le alkalo id w ith a low mo lecu lar w eigh t, po ssess2
ing various pharm aco logical activit ies including an titumo r
activity. T etrandrine inh ib its bo th p ro lifera t ion and clono2
gen icity of hum an leukem ic U 937 cells a t an op tim al concen2
t ra t ion. T h is grow th inh ib it ion is do se2and tim e dependen t,
and is accompanied w ith evidence of apop to tic changes. T he
induction of apop to sis by tetrandrine w ould appear to p ro2
ceed via non2Ca2+ 2dependen t pathw ays. M o reover, tetran2
drine enhances the radio sensit ivity in hum an gliob lastom a
U 138M G cells and elim inated the cell cycle pertu rbation in2
duced by radiat ion.
C ryp to lep ine and neocryp to lep ine are tw o indo loqu ino2
line derivatives iso la ted from the roo ts of the A frican p lan ts
C ryp tolep is sang u inolen ta (L indl. ) Sch lech ter, w h ich dis2
p lay po ten t cyto tox ic activit ies agaist tumour cells. Studies
on mo lecu lar level indicated that these tw o natu ral p roducts
in tercala te in to DNA and in terfere w ith the cata lyt ic activity
of hum an topo isom erase Ê . W estern b lo tt ing analysis re2
vealed that cryp to lep ine induces cleavage of po ly (AD P2ri2
bo se) po lym erase bu t bo th alkalo ids induce the release of
cytoch rom e c from the m itochondria [21 ].
O riginally iso la ted from an A ustra lian p lan t, acro2
nycine in an an titumo r alkalo id w ih t poo r w ater so lub ility
and low po tency. T he modest an titumo r activity of th is
compound w as m arkedly imp roved by the to ta l syn thesis of
o riginal analogs resu lt ing in the selection of S2390621. T he
mo lecu lar m echan ism of action of S2390621 cou ld invo lve
DNA alkylat ion, modulat ion of cyclin E p ro tein levels and
inh ib it ion of DNA synthesis leading to apop to sis[22 ].
T he w ho le p lan t of S ed um sarm entosum Bunge has been
tradit ionally used fo r the treatm ent of ch ron ic vira l hepatit is
in Ch ina and South Ko rea. Certa in hepatit is virus causes
acu te and ch ron ic hepatit is and induces hepatocellu lar carci2
nom a (HC). A ntip ro lifera t ive effects of the crude alkalo id
fracion of S. sarm en tosum are associa ted w ith an increase in
the num ber of cells in the G1 phase of cell cycle. T h is study
suggests that S. sarm en tosum m ay imp rove survival of he2
patom a patien ts via the inh ib it ion of excessive grow th of
tumo r cells[23 ].
N o scap ine, a ph thalideisoqu ino line alkalo id derived
from op ium , has been used as an o ral an ti2tussive agen t and
has show n very few tox ic effects in an im als o r hum ans. R e2
cen tly, Ke et a l. [24 ] repo rted that no scap ine b inds sto ich io2
m etrically to tubu lin and p romo tes m icro tubu le po lym eriza2
t ion. N o scap ine causes grow th arrest of tumo r cells in m ito2
sis and induces apop to sis of tumo r cells in v itro. It is no te2
w o rthy that, no scap ine show s lit t le o r no tox icity to k idney,
liver, heart, bone m arrow , sp leen o r sm all in test ine at tu2
mo r2supp ressive do ses. Furthermo re, o ral no scap ine does
no t inh ib it p rim ary imm une responses, w h ich are crit ically
dependen t upon p ro lifera t ion of lympho id cells.
2　M ultidrug resistance
M ultidrug resistance (M DR ) is one of the m ain obsta2
cles in the chemo therapy of cancer. M DR ’s inh ib it ion effect
and com bination of chemo sensit izers w ith an titumo r com 2
pounds is an active field of research, since safe and po ten t
reversal agen ts w ould be beneficia l fo r clin ical use. T he
mo stly investigated m echan ism s w ith clin ical sign ificance
·912·中草药　Ch inese T radit ional and H erbal D rugs　第 35 卷第 2 期 2004 年 2 月
are: 1) activation of transm em brane p ro teins efflux ing dif2
feren t chem ical substances from the cells (P2glycop ro tein is
mo stly know n as efflux pump ) ; 2) activation of the en2
zym es of the glu ta th ione detox ificat ion system ; 3) alter2
ations of the genes and the p ro teins invo lves in to the con tro l
of apop to sis (especia lly p 53 and Bcl22).
P2glycop ro tein is a m em ber of the A T P2binding cas2
set te (ABC ) transpo rt superfam ily. It p lays an impo rtan t
ro le in the developm ent of M DR in cancers by efflux ing a
w ide variety of an ticancer drugs. Som e alkalo ids have lit t le
o r no cyto tox ic action by them selves, bu t inh ib it (P2gp ) o r
M R P (m ult idrug resistance2associa ted p ro tein ) 2m ediated
drug expo rt and are capab le of sensit izing M DR cells to the
cyto tox ic effects of chemo therapeu tic drugs. Kop siflo rine,
an indo le alkalo id of the asp idofractin ine2type iso la ted from
K op sia d asy rach is L. , in teracts direct ly w ith P2glycop ro tein
and inh ib its the efflux of an titumo r agen ts in drug2resistan t
cells. L avie et a l. [25 ] exam ined the ab ility of stero idal a lka2
lo ids of p lan t o rigin, nam ely the V era trum sp. a lkalo id cy2
clopam ine and the L y cop ersicon sp. a lkalo id tom atidine, to
act as po ten t and effective chemo sensit izers in M DR tumo r
cells. It is concluded that bo th of them act as inh ib ito rs of P2
gp2m ediated drug transpo rt and M DR and therefo re m ay
serve as chemo sensit izers in com bination chemo therapy w ith
conven tional cyto tox ic drugs fo r treat ing M DR cancer.
Pervilleine A , a novel tropane alkalo id ob tained from a ch lo2
rofo rm extract of E ry th roxy lum p erv illei Baill. as the resu lt
of b ioactivity2guided fractionation, w as found to resto re the
vinb last ine sensit ivity of cu ltu red M DR KB 2V 1 and CEM ö
VLB (100) cells[26 ]. T etrandrine inh ib its the P2gp2m ediated
drug efflux and low ered cell m em brane flu idity in a concen2
t ra t ion2dependen t m anner. It is an ex trem ely po ten t M DR
modulato r bo th in v itro and in v ivo, w ithou t apparen tly en2
hancing the tox icity of the co2adm in istered drugs. H ence, te2
t randrine ho lds great p rom ise as a M DR modulato r fo r the
treatm ent of P2gp2m ediated M DR cancers[27 ].
3　Perspectives
A lkalo ids derived from various p lan ts p roduces differ2
en t effects on the treatm ent of cancer, including reactions
w ith m icro tubu les, inh ib it ion of angiogenesis, inh ib it ion of
DNA 2topo isom erase É , m ito t ic arrest and induction of
apop to sis.
Furthermo re, studies on structu reöactivity rela t ion2
sh ip s (SA R ) of alkalo ids have discovered som e therapeu ti2
cally usefu l compounds and their sem isyn thetic derivatives,
including V inca alkalo ids, camp to thecins, ellip t icine, etc.
In o ther w o rds, p lan t a lkalo ids p rovided basic structu res of
b ioactivity and pharm acok inetic p ropert ies bu t mo re p racti2
cal app roach is the op tim ization of these structu res. M ean2
w h ile, a better understanding of SA R w ill lead to supp ress
o r circum vent M DR m echan ism s because the M DR tumo r
cells are resistan t to drugs w h ich are structu rally unrela ted
and functionally divergen t. N evertheless, the exact m echa2
nism s of som e alkalo ids st ill rem ain unclear. In view of the
above m entioned m echan ism s of action, com binationöparal2
lel m ethods shou ld be app lied in large2scale labo rato ry ex2
perim ents and detailed clin ical studies. F inally, p lan t a lka2
lo ids can be used as lead structu res fo r the developm ent of
fu rther an ticancer agen ts w ith imp roved physicochem ical
and pharm aco logical p ropert ies.
References:
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龙血树属植物化学成分及药理活性研究进展
何　兰1, 王竹红1, 屠鹏飞23 , 侯　辉3Ξ
(11 北京师范大学 化学系, 北京　100875; 　21 北京大学医学部药学院, 北京　100083;
31 蓝星化工科技总院, 北京　101300)
摘　要: 龙血树属植物含有黄酮类、酚类、三萜及其皂苷等化学成分。本属部分植物木质部分泌出的树脂在各产地
均做药用, 具有抗炎止痛、抗真菌、抗心律失常、抗血栓、止血等多种药理活性, 并可作为中药“血竭”的代用品。现对
龙血树属植物的化学成分及药理活性等方面进行概述。
关键词: 龙血树属植物; 化学成分; 药理活性
中图分类号: R 282. 71　　　文献标识码: A 　　　文章编号: 0253 2670 (2004) 02 0221 08
Advances in study on chem ica l con stituen ts and pharmacolog ica l
activ it ies in plan ts of D racaena Vand. ex L.
H E L an1, W AN G Zhu2hong1, TU Peng2fei2, HOU H u i3
(1. D epartm ent of Chem istry, Beijing N o rm al U niversity, Beijing 100875, Ch ina; 2. Co llege of Pharm acy, M edical
A cadem y of Beijing U niversity, Beijing 100083, Ch ina; 3. A cadem y of B lue Star Chem ical Industry
and Scien tific T echno logy, Beijing 101300, Ch ina)
Key words: p lan ts of D racaena V and. ex L. ; chem ical con st ituen t; pharm aco logica l act ivity
·122·中草药　Ch inese T radit ional and H erbal D rugs　第 35 卷第 2 期 2004 年 2 月
收稿日期: 2003203226
基金项目: 国家自然科学基金资助项目 (30070088)
作者简介: 何　兰 (1961—) , 女, 浙江省绍兴人, 副教授, 博士, 研究方向为天然产物化学。E2m ail: helan1961@ho tm ail. com3 通讯作者