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Advance in treatment of pediatric leukemia through modulating signaling pathways induced by traditional Chinese medicine

从信号通路角度分析中药治疗儿童白血病的研究进展



全 文 :2016
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,Email:tanyuanguaiguai@126.com
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¨
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Advanceintreatmentofpediatricleukemiathroughmodulatingsignaling
pathwaysinducedbytraditionalChinesemedicine
TANYuan
(NeonatalDepartment,AfiliatedHospitalofGuilinMedicalUniversity,Guilin541001,China)
[Abstract] Leukemiaisthemostcommontypeofcancerinchildhood,whichisalsooneofthemalignanttumorsthatcanbe
curedbychemotherapyHowever,infectionandthesideefectsofchemotherapydrugsarethecausesofdeathinchildrenwith
leukemiaChemotherapycombinedwithtraditionalChinesemedicineisusedtotreatmentofpediatricleukemiainclinicAl
thoughtraditionalChinesemedicinehasextensiveclinicalexperienceinthetreatmentofleukemia,themechanismisnotclear
ThetargeteddrugsareatractivefortheadvantagesofthehighselectivityandlitlesideefectsTargetedtherapiesinpediatric
leukemiaaretargetingBCR/ABL,TARAandFLT3proteins,whichactivationresultsinthedownstreamactivationofmultiple
signalingpathways,includingthePI3K/AKT,JNK/STAT,Ras/ERKpathwaysInrecentyears,thetargetsiteorthesignaling
pathwaysareclearforthetraditionalChinesemedicineinthetreatmentofleukemiaInthispaper,wereviewrecentstudies,
summarythetraditionalChinesemedicineprescriptionsandefectiveingredientswhichcanregulatethesignalingpathwaysWe
viewtoprovideabasisforthetreatmentofchildhoodleukemiawithtraditionalChinesemedicinecombinedwithchemotherapy
drugsortargeteddrugs
[Keywords] leukemia;pediatricleukemia;signalingpathways;traditionalChinesemedicine
doi:10.4268/cjcmm20160603
  
QÇwòžŸÉ(ƒ!ü»¢
[1]。
 ¡¢
(leukaemi
a)
鞟7¸ƒÃ–/0

PžŸÃ–/0¢óƒ
30%,
 ¡¢œ‘ò?– ¡¢
(acuteleukaemia,AL)¨
>– ¡
¢
(chronicleukaemia,CL),
žŸ ¡¢«˜>ò
AL[2]。
F
G„´¨œIJƒ£´m‡

žŸ ¡¢«˜ƒœˆ=
r?‡ƒpø

«˜ƒ

y°ý¬Ý
70%~90% [34]。

¡¢«˜ƒm–

<œ–e°ý¬HƒøùI£œ:‡

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d:‘3ç;,‹b4

[d
éhi°\à]“
(retinoicacidreceptors,RARs)
ƒwÒ
£\à]
(altransretinoicacid,ATRA),
„…më
ATRA
ƒ
ôShiçÑ ò
Pin1
Ñ 
[5];
r[dòhi°
BCR/ABL
ƒT’]ÒÓ±ù1UsVY
(imatinib)¨
ÝmVY
(dasat
inib)[67]。


d,‹²žŸ ¡¢œ€÷ZGÖüh
i

åæ¥(ãÿґãäpžŸ ¡¢«˜ƒx»¢°
ý}
[89]。
7E
,FMS
‚T’]ÒÓ
3(FMSliketyrosineki
nase3,FLT3)
² ¡¢œ$hò&ƒœçèS“ô
 
[10],FLT3
±ù1”
Lestaurtinib
œ™ ¡¢Bãä
‚
[11],
F~

­žŸ ¡¢«˜ˆ—núåænJ„…
[10]。
xãé
BCR/ABL
êé
FLT3,¯
Ð:Òêë>‹v<@N”
Ras/Raf,PI3K,JAK
ö
[1214],
q
1,
1,
,¯
Јµ¶
Hedgehog(Hh)
@N¨
Wnt
@N
[12]。
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Bçè{‚¨‚‚%ƒ8>

6éQÄÅ­“Ø,–Ié
£œŒ4ƒøù

q
1 
 ¡¢;’ƒÖüçè’v<@N
Fig1 Themaintargetpointandsignalingpathwaysinleukemia
$A,hò3%ƒ%W

² ¡¢œ$mÚÖüh
i

”$,XYƒ•–‘Lt_8Z
(arsenictrioxide,
ATO)
›=_,‹X ¡¢«˜ƒ

yx¢°ý¬˜
25%
pr
95%。
7°$,ƒ-–X=$,ƒ,‚‹´Ôä
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fùˆFð{‚

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28
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B
21
Ì­

î.þÌ­

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iƒÃ>ƒòÈ
ï

]¨”¡€1ö
[15]。
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?Š^ƒCD–

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6
é_ƒ&LhiÑ飜Œ4ƒ

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1 
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1。
11 
_&d$,
 ATO
é$,XYƒÖü•–‘

XY
B_&
,¸
œ[þÖ»¢
。ATO
²œ ¡¢$q=ú
[$`

åæ$›=“|_,‹ÒãäpžŸ ¡¢
ƒý•¬
[4345]。
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ATO
ґµ¶QÄŃ(


¦

¡°ö

Òî×
PML/RARαÑ 、Ûê Bcl2ƒÜ
Ý

•_
Caspase3/8、
±ù
NFκB•–ö,²hi@N€÷­
PI3K/Akt
@N¨
JNK
@NBµ¶
[16,4649],
ˆù{
ATO
›
=UsVY­ ¡¢«˜B‚hi

¤O­UsVYØ,
ƒ ¡¢«˜ŠŸB‚
[5051]。
r[8B_&ƒ$,D‚
ˆi°œ»¢

åæ$¸hò45±ù1œd@A–ô
ë†

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[

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,¯
é
HSP90
ƒ±ù1

­ ¡¢QÄŃ
AKT
@N¨
Notch/NF
κB@N:B±ùhi[3840],­BCR/ABL[¯ƒ ¡¢«˜


cœÞáUsVYØ,ƒhi
[52]。
Ü
1 
œ ¡¢ƒ$,’“êëƒv<@N
Table1 TraditionalChinesemedicinefortreatmentofleukemiaandthesignalingpathways
€W¦ •–$, •–‘ v<@N *Ë^Þ
Lt_8Z ¡¢ XY
 
Lt_8Z
(ATO) PI3K/AKT
@N
;JNK
@N
[16]
€Qdü

½¡ÎFe Qd
 
f¬Ë
SFK/STAT5
@N
;FLT3 [1718]
­*º ¡¢ ­*
 
­*º
JAK/STAT3
@N
;MAPK
@N
[1923]
‡ËgíØ ‡Ë
 
‡ËO
PI3K/AKT
@N
;BCR/ABL [2425]
wËOFe wË
 
wËO
MMP
@N
;AKT/mTOR
@N
;Raf/ERK
@N
;MAPK
@N
;;FLT3 [2629]
Ëð×&ñ Ëï
 
Ëï
PI3K/AKT
@N
;Notch
@N
; [3032]
vhi ¡¢ vh
 
vhi
GSK3β;Wnt@N [33]
€m* ¡¢ m*
  m*7ⅡA JAK/STAT3/5@N;AMPK/mTOR@N;Raf/ERK@N; [3435]
Ëj ¡¢ Ëj
 
Ëj>Å
MICA [36]
Mö¡ñ Mö
 
Mö>Å
JAK/STAT3 [37]
D‚ D‚ËO
BCR/ABL;AKT
@N
;Notch/NFκB@N [3840]
Ój
 
ܓÍ3žjO“Í3]³
JNK
@N
;AKT
@N
;FLT3 [4142]
·099·
ò 


˜v<@N™š‘›$,œžŸ ¡¢ƒ„…—‡
12 
Èïd,
 
f¬Ëé$,Qdƒ•–‘

ìQdò
֕ƒ$,€Qdüåæ¥($­žŸ ¡¢«˜
‚‚%
[53],
¤Of¬Ë›=_,‹ˆÒ*× ¡¢«˜
ƒåæÜ/
[54],
fù€÷f¬Ë@òêë
SFK/STAT5
@N
±ù
BCL/ABL
[¯­¨_°­ ¡¢Äя¦
[17],
¤O
¯ˆé
FLT3
ƒ±ù1
[18]。
­*ºé$,­*ƒÖü•–
‘

­*‰°Èï×&d,

i° ¡¢ƒÈï×&¨l
¡¼¥

ì­*òփb4,‹€­* ¡¢åæ¥(
ãÿґµ¶ ¡¢«˜_Oƒ&Lhi
[55]。
­°­*
ºƒ„…Ã>
,¯
ÒÞá
ATRA
ƒØ,–
[5657],
êë ¡¢
QÄŃ
JAK/STAT3
@N¨
AKT
@N
[20,2334]。
þhif
ùÜ{­*º†UsVYö,‹›=DB‚hi

Ëï
ò$,ËïƒÖü•–‘

²åæ¥($

/sBËï


ËïO

ãËãËïOƒËïpq‹i°œž
Ÿ ¡¢«˜

më“DB45mÊhi
[58]。
Ë 
¡¢QÄŃ
PI3K/AKT
@N¨
Notch
@NB±ùhi

ˆ
Ò±ùØ,ƒÄÅ°°±
[3032],
²›=€÷„…ƒÃu

6
˜hi@N$œìƒ$“†UsVY
、ATO
ö›=DB*¤
‚hi

13 
•¡d,
 
‡ËOé$,‡ËƒÖü•–‘ð[

‡ËDB>?,”•–

­ ¡¢«˜_~ƒmï



nÅöDB?$ƒ‚
[59],¯
é‡Ëgí؃Öü•

„…më‡ËODBe/0

%

e†öhi

Ô䄅Ü
{­ ¡¢cB,‚
[60]。
‡ËOƒhifùÃ>

­
BCR/
ABL
[¯ƒ ¡¢QÄÅB±ùhi

Òêë
BCR/ABL
2
ZƒÛO@N”
PI3K/AKT
@N¨
MEK
@Nö
[24];
†
AT
RA
=iODB*¤‚ƒhi
[61];
ˆÒÞáQÄÅ­Us
VYƒØ,–
[62]。
wËOé$,w˃•–‘
,¯
ƒ,
”•–Ã>

„…ˆ?>

wËODB>hiçè

ґ
±ù
AKT/mTOR
@N¨
Raf/ERK/MAPK
@N

˜êŠU
sVYƒ,‚hi

ˆÒ±ù­UsVYØ,ƒQÄÅ°
±

1,

wËOˆé
FLT3
ƒ±ù1

­QÄŃáâˆB
±ùhi

wËOƒ>ç;­X=“XiO>†“|_,
‹›=Xi

˜êÝr‚µ&ƒhi
[2729]。
vhiò$,
vhƒÖü•–‘

còvhi ¡¢ƒÖü‘

åæ
¥($vhi ¡¢†_,›=~ґÐѨ*× ¡¢
«˜ƒåæÇ®
[63]。
vhiœÛê
GSK3βƒÜÝ,—êÛ
ê
NFκBƒÜÝ,—ê±ùQÄŃ°±[33]。m*7ⅡA
ò$,m*ƒ•–‘ð[

m*òb4,‹€m* ¡
¢ƒÖü‘

€m* ¡¢³=_œ™ ¡¢¨
žŸ ¡¢Òp‚

îH&Lhi¨ÐÑ«˜°ý´
ö
[6465]。
m*7ⅡA­ BCR/ABL2ZƒÛOv<@N”
JAK/STAT3/5
@N
、MPK/mTOR
@N
、Raf/ERK
@NöD
Bêëhi

Ò±ùØUsVYƒQÄÅ°±
[3435],
†Us
VY
、TARA
¨
ATO
›=DB*¤‚hi
[6667]。
14 
Û¡d
 
Ëj>Åò$,Ëjƒ•–‘ð[

Ëjò$]Ûd$,

霝 ¡¢Û,$7¸iƒ[
8,
[15],
éËj ¡¢ƒÖü•

åæ¥($

Ëj ¡
¢›=_œŠe/0hi

pžŸ ¡¢«˜ƒåæ
‚

Ðѓ:~
[68]。
Ëj>ÅÖüZr45êëhi

@
òbê
MICA
ÜݏŠ“­
NK
ÄÅì˜CD–
[36]。
r[
Z45êëhiƒ>ÅòMö>Å
,¯
é$,Möƒ•–
‘

Möé7¸iƒ¡d,‹

Mö>Å@òÛê
JAK/STAT3
v<@N­ ¡¢QÄÅZr±ùhi
[37]。
15 
“|d
 
ܓÍ3žjO“Í3]³òÓjƒ•–
‘ð[

òj>”$7B‚ƒ•–‘

ґ±ù
FLT3
Ć
Ý

œìêë
JNK
@N¨
AKT
@Nƒ•–
[4142],
†wËO=
iDB*¤‚hi
[69],
†_,‹”nÌO›=DB
‚µ&‚
[70]。
2 
<ㆇ†
FG‘3°‹()ƒm‡

‡öƒ¥(„…Ìú>Q
Ç«˜ý²[¯ÔÕ

X=·ì·>ƒç;,‹uo|b
4

íîuo|œ ¡¢ƒç;:‘3,‹éœ
BCR/
ABL
[¯ƒ«˜

ê~­“|ÔÕ[¯ƒ,‹ÊI°åæe
åæînJ

²1Ôäb

$A,ˆFðm‡

67° ¡
¢«˜ƒ$A/Z‘­-ç÷$,•€£´ƒ¯_

—ê
X=•–‘<‘›

‰ð3%&„ÔäpÛ

³ì

$,²
‘3€÷ƒÔ䄅I°¹^nJ

žŸ ¡¢é@ò_
œìœƒÃ–/0»¢

6_,‹ƒ&Lhi¨œ
$ƒDhˆéç÷žŸ ¡¢«˜ƒÉ(ÐÕð[

ê$,
q$ÒÃòB‚rþ–è

Õ1

å渵i$,³=
_,‹ƒ€£œ ¡¢

ÖüZr‚µ&

Þá>,
Ø,–

Šf45@¨*× ¡¢«˜ƒåæÇ®öh
i

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N^u<úv<@
NÃò{‚ƒ$,

˜êò“›=_,‹p)Š.


žŸ ¡¢«˜ƒœ

ÔV_,ƒ„…5­­$,,‚‘ƒhi’hif
ù—nôõ‘›

‘›$mëú>$,~­
PI3K/AKT,
JNK/STAT,Ras/ERK
öv<@NBêëhi

BþˆÒêë
>‹v<@N

ê9>=ґÞá_,ƒØ,–hi


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ATO
¨D‚,

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þ{‚hifù
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yg?z

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