符策崗，趙紅衛(wèi)，劉揚(yáng)，陳海丹

(三峽大學(xué)第一臨床醫(yī)學(xué)院宜昌市中心人民醫(yī)院脊柱外科，湖北宜昌443000)

·綜述·

骨肉瘤直接抑制化療藥物療效的分子機(jī)制

符策崗，趙紅衛(wèi)，劉揚(yáng)，陳海丹

(三峽大學(xué)第一臨床醫(yī)學(xué)院宜昌市中心人民醫(yī)院脊柱外科，湖北宜昌443000)

骨肉瘤(Osteosarcoma，OS)是一種發(fā)病率在兒童和青少年惡性腫瘤中居首位的腫瘤，目前臨床治療方式以外科手術(shù)聯(lián)合藥物化療為主。骨肉瘤對(duì)化療藥物的耐藥性是影響臨床骨肉瘤治療效果的重要原因之一，了解骨肉瘤細(xì)胞的耐藥機(jī)制，從而研發(fā)新的化療藥物對(duì)提高骨肉瘤的治療效果具有重要意義。OS可以通過直接抑制化療藥物或增強(qiáng)自身抗藥性等兩種方式達(dá)到耐藥的目的。本綜述側(cè)重介紹骨肉瘤直接影化療藥物療效的3種分子機(jī)制：骨肉瘤細(xì)胞阻滯化療藥物進(jìn)入胞內(nèi)、骨肉瘤細(xì)胞排出胞內(nèi)的化療藥物以及促使化療藥物失活。

骨肉瘤；耐藥性；分子機(jī)制

骨肉瘤(Osteosarcoma，OS)好發(fā)于15～25歲的青少年，并以男性患者居多，其發(fā)病率在兒童和青少年惡性腫瘤中居首位。OS好發(fā)于長骨干骺端、股骨遠(yuǎn)端和脛骨近端[1]，具有很強(qiáng)的侵蝕性，多見肺部轉(zhuǎn)移[2]。視網(wǎng)膜細(xì)胞瘤和p53基因突變的患者更容易罹患OS，表明相關(guān)基因可能介入了OS的發(fā)病。OS主要是梭形細(xì)胞的惡性增殖，也存在軟骨母細(xì)胞和成纖維細(xì)胞等亞型，這些肉瘤細(xì)胞只要在骨組織內(nèi)被發(fā)現(xiàn)即可確診OS[3]。臨床方面，OS患者的主要臨床癥狀是疼痛和軟組織腫脹，并且高達(dá)20%～25%患者發(fā)現(xiàn)有肺部轉(zhuǎn)移灶，給予OS患者及時(shí)有效的治療能緩解病情的發(fā)展。OS患者僅行手術(shù)切除的存活率不足20%，但與化學(xué)治療聯(lián)用后，局部病變OS患者存活率增加了70%，這說明了化學(xué)治療的有效性和重要性[4]。目前國內(nèi)外以順鉑、多柔比星和甲氨蝶呤(Methotrexate， MTX)為基礎(chǔ)抗化療藥物治療OS。由于骨肉瘤對(duì)化療藥物的耐藥性存在，使得OS患者存活率在過去的30年里沒有發(fā)生變化[5]。探索骨肉瘤抗化學(xué)治療的分子機(jī)制并找到相應(yīng)的克服方式，對(duì)提高OS患者的生存率具有重要價(jià)值。OS可以通過直接抑制化療藥物療效和增強(qiáng)自身耐藥性等兩種主要方式產(chǎn)生對(duì)化療藥物的耐藥性，本文將對(duì)OS如何直接抑制化療藥物的分子機(jī)制做一簡要綜述。

1 阻滯化療藥物進(jìn)入細(xì)胞內(nèi)

目前尚不清楚腫瘤細(xì)胞吸收化療藥物的分子機(jī)制。據(jù)了解，二氫葉酸還原酶抑制劑MTX常被用于治療OS，實(shí)驗(yàn)發(fā)現(xiàn)，MTX轉(zhuǎn)入細(xì)胞需要通過細(xì)胞膜上的還原型葉酸載體(Reduced folate carrier，RFC)，減少細(xì)胞膜上RFC能抑制MTX轉(zhuǎn)運(yùn)入細(xì)胞內(nèi)，從而降低MTX在細(xì)胞內(nèi)的濃度，這一現(xiàn)象在OS細(xì)胞內(nèi)普遍存在(圖1)[6-7]。研究發(fā)現(xiàn)，65%的OS病患RFC表達(dá)減少，并且RFC水平越低化療敏感性越差，這表明RFC的表達(dá)水平能直接影響化療藥物的作用[8]。也有研究表明，原發(fā)病灶RFC的表達(dá)水平比轉(zhuǎn)移病灶和復(fù)發(fā)病灶RFC的表達(dá)水平都要低，說明RFC水平與腫瘤病變程度有關(guān)。在此，值得一提的是，伴隨腫瘤好轉(zhuǎn)RFC表達(dá)隨之增加，反向驗(yàn)證腫瘤病變程度與RFC表達(dá)水平的關(guān)系[9-10]。研究發(fā)現(xiàn)，變異的RFC失去了或者在一定程度上降低了轉(zhuǎn)運(yùn)MTX的能力，一種名為Leu291Pro的變異RFC蛋白失去了承載底物穿過細(xì)胞膜的能力，另外三種變異型Ser46Asn、Ser4Pro和Gly259Trp的轉(zhuǎn)運(yùn)能力都有不同程度的下降，說明RFC變異會(huì)降低RFC的轉(zhuǎn)運(yùn)能力，進(jìn)而影響化療藥物的轉(zhuǎn)運(yùn)，最終引起腫瘤對(duì)化療藥物耐藥[11]。此外，研究發(fā)現(xiàn)，RFC基因復(fù)制在親本細(xì)胞系與MTX耐藥細(xì)胞系內(nèi)并無不同，表明RFC表達(dá)的減少并不是因?yàn)榛蛉笔Ф鸬腫12]。

圖1 OS抗化療機(jī)制

為了克服RFC引起的耐藥，目前研發(fā)了一種新型的抗葉酸劑三甲曲沙，它最大的優(yōu)勢(shì)在于轉(zhuǎn)運(yùn)人細(xì)胞內(nèi)不需要借助RFC。目前，三甲曲沙已經(jīng)被列入惡性或頑固性O(shè)S患者的Ⅱ期研究中，并取得了一定的成果。此外，目前正在嘗試聯(lián)用三甲曲沙與高劑量MTX治療復(fù)發(fā)性O(shè)S，這有望提高化療療效[13]。

2 排出細(xì)胞內(nèi)的化療藥物

細(xì)胞膜上的膜泵P糖蛋白(P-glycoprotein，P-GP)能非特異性的泵出腫瘤細(xì)胞內(nèi)的化療藥物從而降低細(xì)胞內(nèi)藥物濃度，從而抑制化療藥物的作用[14]。P-GP由人類多重抗藥(Multidrug-resistant，MDR)基因MDR1所編碼，它是一種70 kD的ATP結(jié)合(ATP-binding cassette，ABC)轉(zhuǎn)運(yùn)蛋白，也是細(xì)胞排出藥物的外排泵(圖1)[15]。研究發(fā)現(xiàn)，P-GP表達(dá)增多與OS細(xì)胞對(duì)化療藥物耐藥有著密不可分的關(guān)系[16-18]。此外，回顧性研究發(fā)現(xiàn)，P-GP表達(dá)增多能促進(jìn)腫瘤的發(fā)展和惡變[19-20]。

相反的研究發(fā)現(xiàn)，P-GP的表達(dá)水平與腫瘤的發(fā)展和生存率沒有內(nèi)在聯(lián)系[21-22]。類似的研究發(fā)現(xiàn)，P-GP mRNA的表達(dá)水平并不能反映腫瘤的發(fā)展或惡變程度[23]。因此綜合分析，P-GP并不影響化療藥物在腫瘤細(xì)胞內(nèi)的作用[24]。也有研究發(fā)現(xiàn)，不能用P-GP的表達(dá)水平作為指標(biāo)去預(yù)測(cè)OS患者的化療效果或存活率[25]。此外，當(dāng)MDR基因轉(zhuǎn)染進(jìn)入OS細(xì)胞系內(nèi)后，在一種低侵蝕性表型內(nèi)可發(fā)現(xiàn)P-GP表達(dá)增多，這表明P-GP能抑制腫瘤轉(zhuǎn)移[26]。

雖然目前對(duì)于P-GP的作用存在爭(zhēng)議，但為了克服P-GP引起耐藥的分子機(jī)制，目前正在開發(fā)一種新型的藥物傳遞載體，即具備生物溶性和脂溶性的納米顆粒。前期研究證實(shí)，這種納米顆粒能有效地把化療藥物送入已經(jīng)產(chǎn)生耐藥性的OS細(xì)胞內(nèi)，這能提高化療藥物在細(xì)胞內(nèi)的濃度，甚至扭轉(zhuǎn)細(xì)胞內(nèi)藥物低濃度的局面[27-29]。

3 促使化療藥物失活

谷胱甘肽S-轉(zhuǎn)移酶P1(Glutathione S-transferase P1，GSTP1)是一種細(xì)胞質(zhì)谷胱甘肽S-轉(zhuǎn)移酶，它屬于Ⅱ期解毒酶系，參與滅活一系列外源性化學(xué)物質(zhì)，其中包括誘變劑、抗癌劑以及它們的代謝物(圖1)[30]。研究表明，GSTP1表達(dá)增多與多種腫瘤抵抗化療藥物的作用有關(guān)[31]。進(jìn)一步研究證實(shí)，GSTP1表達(dá)增多能明顯縮短藥物的半衰期和存在時(shí)間，這能很快降低藥物在體內(nèi)的濃度，進(jìn)而抑制化療藥物對(duì)腫瘤細(xì)胞的殺傷作用[32]。類似的研究發(fā)現(xiàn)，隨著GSTP1表達(dá)的增多，化療藥物對(duì)腫瘤細(xì)胞的殺傷作用隨之減弱[33]。研究發(fā)現(xiàn)，化療藥物能刺激GSTP1表達(dá)增多，而GSTP1表達(dá)增多會(huì)促進(jìn)腫瘤的發(fā)展[34]。針對(duì)性研究發(fā)現(xiàn)，OS耐藥細(xì)胞系內(nèi)GSTP1表達(dá)增多，這表明GSTP1表達(dá)增多能促進(jìn)OS細(xì)胞對(duì)化療藥物耐藥[35]。綜上所述，GSTP1在體內(nèi)能有效滅活化療藥物，這不利于化療藥物發(fā)揮藥效，從而促進(jìn)腫瘤繼續(xù)發(fā)展。Windsor等[36]研究發(fā)現(xiàn)一種變異的GSTP1基因(c.313A＞G p. lle(105)Val)，它能促進(jìn)OS細(xì)胞對(duì)化療藥物的耐藥性，這說明變異的GSTP1也能引起細(xì)胞產(chǎn)生化療耐藥性。Zhang等[37]研究發(fā)現(xiàn)，GSTP1 Val基因型患者比GSTP1 IIe基因型患者生存率要低。但是Yang等[38]卻發(fā)現(xiàn)，GSTP1 Val基因型患者對(duì)化療藥物更加敏感。GSTP1基因的多樣性是一種表觀遺傳學(xué)變化，目前對(duì)表觀遺傳學(xué)的研究還存在矛盾和不成熟，因此更深入的研究可能會(huì)為治療OS帶來新的視角。

為了抑制GSTP1的解毒作用，并提高化療藥物對(duì)OS細(xì)胞的殺傷作用，近期正在體外測(cè)試一種高效的GSTP1抑制劑NBDHEX[6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol]。研究發(fā)現(xiàn)，NBDHEX在化療藥物耐藥細(xì)胞系內(nèi)極度活躍[39]。進(jìn)一步研究發(fā)現(xiàn)，NBDHEX能誘導(dǎo)OS細(xì)胞凋亡并能抑制OS細(xì)胞轉(zhuǎn)移，這表明NBDHEX有助于治療OS[40]。蛋白組學(xué)研究結(jié)果顯示，NBDHEX能通過分解GSTP1腫瘤壞死因子受體相關(guān)因子(Tumor necrosis factor receptor-associated factor，TRAF)2復(fù)合體恢復(fù)TRAF2/ ASK1信號(hào)轉(zhuǎn)導(dǎo)，從而延長c-Jun氨基末端激酶(JNK)和P38的活性，進(jìn)一步增強(qiáng)JNK促進(jìn)細(xì)胞凋亡和P38引起P21增多而發(fā)揮抑癌作用，這最終能促進(jìn)腫瘤細(xì)胞死亡[41]。這些研究表明，NBDHEX抑制GSTP1后能有助于治療OS，這可能是一種有效的新型療法，并值得進(jìn)一步去發(fā)掘。

4 結(jié)論

雖然手術(shù)治療和化療藥物聯(lián)合治療OS已經(jīng)在很大程度上提高了OS患者的生存率。但從1980年至今，局部病變OS患者的生存率還停留在70%，伴隨轉(zhuǎn)移和復(fù)發(fā)的OS患者長期生存率依然不足20%[42]。了解骨肉瘤細(xì)胞的耐藥機(jī)制，并找到相應(yīng)的處理方式，能在很大程度上提高骨肉瘤的治療效果，進(jìn)而提高OS患者生存率。本綜述簡要介紹了OS直接抑制化療藥物的三種分子機(jī)制，以及相應(yīng)的處理方式，但這些研究都尚處于初期。并且還存在其他機(jī)制能引起OS細(xì)胞的耐藥性，例如APE1或ERCC增強(qiáng)DNA修復(fù)，干擾mTOR或IGF-IR信號(hào)轉(zhuǎn)導(dǎo)通路，細(xì)胞凋亡和細(xì)胞自噬相關(guān)的抗化療機(jī)制，miRNA失調(diào)和OSC介導(dǎo)的抗化療作用等等。

目前已經(jīng)證實(shí)三甲曲沙轉(zhuǎn)運(yùn)入細(xì)胞內(nèi)不需要借助RFC，但是抗腫瘤作用依然不夠理想。因此有必要對(duì)三甲曲沙進(jìn)行改良，這可以從藥物的殺傷作用本身著手，也可以著手于化療藥物聯(lián)用方面，以提高療效。具備生物溶性和脂溶性的新型納米顆粒能有效提高藥物在腫瘤內(nèi)傳遞，有助于扭轉(zhuǎn)P-GP藥物外排[43]。在未來，更應(yīng)該研究納米顆粒和外排泵抑制劑聯(lián)聯(lián)合治療OS的效果，這些藥物之間的相互作用機(jī)制值得進(jìn)一步研究。GSTP1能引起化療藥物失活，NBDHEX能高效的抑制GSTP1，這表明NBDHEX有助于治療OS[40]。研究NBDHEX與其他化療藥物聯(lián)用對(duì)提高骨肉瘤的治療效果具有重要的意義。目前對(duì)這所有機(jī)制了解尚淺，進(jìn)一步的探索骨肉瘤細(xì)胞的耐藥機(jī)制，從而研發(fā)新的化療藥物對(duì)提高骨肉瘤的治療效果具有重要意義。

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Molecular mechanisms of osteosarcoma inhibiting chemotherapeutical efficacy directly.

FU Ce-gang,ZHAO Hong-wei,LIU Yang,CHEN Hai-dan.Department of Spinal Surgery,the First College of Clinical Medical Sciences, China Three Gorges University,Yichang 443000,Hubei,CHINA

Osteosarcoma(OS)is the most common malignant primary bone tumor in children and adolescents.Currently,the combination of surgical resection and chemotherapy is the chief method for treating OS.OS resistance to the anti-OS drugs plays an important role in decreasing the chemotherapeutical efficacy.Therefore,elucidation of the mechanisms of chemoresistance and implementation of strategies to overcome chemoresistance will definitely play a pivotal role in developing novel chemotherapeutics and improving the survival rate of OS patients.There are two major mechanisms contribute to drug resistance of OS:osteosarcoma inhibiting chemotherapeutical efficacy directly and improving the cell ability to resistance chemotherapeutics.This article reviewed three methods of osteosarcoma inhibiting chemotherapeutical efficacy directly:inhibiting chemotherapeutics transport into cell,removal of chemotherapeutics from tumor cells and promoting chemotherapeutics inactivation.

Osteosarcoma;Chemoresistance;Molecular mechanisms

R738.1

A

1003—6350（2015）01—0070—04

10.3969/j.issn.1003-6350.2015.01.0022

2014-08-06)

國家自然科學(xué)基金（編號(hào)：81302346）

陳海丹。E-mail：wenquanchd@sina.com