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      蛋白激酶C抑制劑的研究新進(jìn)展

      2016-02-10 16:17:59吳靜楊睿劉樹(shù)業(yè)
      天津醫(yī)藥 2016年1期
      關(guān)鍵詞:綜述腫瘤

      吳靜,楊睿,劉樹(shù)業(yè)△

      ?

      蛋白激酶C抑制劑的研究新進(jìn)展

      吳靜1,楊睿2,劉樹(shù)業(yè)1△

      摘要:蛋白激酶C(PKC)是一組磷脂依賴性的絲氨酸/蘇氨酸蛋白激酶,與蛋白激酶A(PKA)和蛋白激酶G (PKG)共同構(gòu)成絲氨酸/蘇氨酸蛋白激酶AGC超家族。PKC包括傳統(tǒng)型PKC、新型PKC、非典型PKC和與PKC相關(guān)的一些激酶(PRK)成員。PKC廣泛分布于哺乳動(dòng)物的組織和細(xì)胞中,對(duì)細(xì)胞的生長(zhǎng)代謝、增殖分化等起著重要的生物學(xué)作用。研究表明,多種細(xì)胞的變異和疾病的發(fā)生發(fā)展都與PKC的異常表達(dá)有關(guān)。因此,設(shè)計(jì)和尋找高效的PKC抑制劑對(duì)于多種有效藥物的合成和臨床上包括腫瘤、心血管疾病、高血壓等多種疾病的治療都具有非常重要的意義。近年來(lái),關(guān)于PKC抑制劑的研究已經(jīng)成為國(guó)內(nèi)外研究的焦點(diǎn)。大量文獻(xiàn)報(bào)道了多種有效的PKC抑制劑,并對(duì)其作用位點(diǎn)、作用機(jī)制以及臨床試驗(yàn)數(shù)據(jù)等進(jìn)行了分析。這些PKC抑制劑的發(fā)現(xiàn)對(duì)于PKC的結(jié)構(gòu)分析和疾病的治療具有重要的意義。因此,本文對(duì)這些高效的PKC抑制劑進(jìn)行綜述。

      關(guān)鍵詞:蛋白激酶C;酶抑制劑;胰蛋白酶抑制劑;蛋白激酶抑制劑;腫瘤;綜述

      蛋白激酶C(protein kinase C,PKC)是由Nishizaka等于1977年首次發(fā)現(xiàn)的一組磷脂依賴性的蛋白絲氨酸/蘇氨酸激酶,廣泛分布于哺乳動(dòng)物的器官、組織和細(xì)胞中,對(duì)細(xì)胞的代謝生長(zhǎng)、增殖和分化起著重要的調(diào)節(jié)作用[1]。它與蛋白激酶A(cAMP- dependent protein kinase,PKA)和蛋白激酶G (cGMP-dependent protein kinase,PKG)共同構(gòu)成絲氨酸/蘇氨酸蛋白激酶AGC(PKA、PKG和PKC)超家族。

      PKC由單一多肽鏈組成,其結(jié)構(gòu)由高度同源性的4個(gè)保守區(qū)(C1~C4)和低度同源性的5個(gè)可變區(qū)(V1~V5)組成,可變區(qū)在特定PKC同工酶亞型的識(shí)別和激活中起作用。因此,在不同的外界刺激下有不同的亞型被選擇性地激活。迄今為止,根據(jù)同工酶的結(jié)構(gòu)、特性及激活劑的不同將其分為4大類(12種亞型):傳統(tǒng)型PKC包括PKCα[2]、βⅠ、βⅡ、γ;新型PKC包括PKCδ、ε、η、θ和μ亞型;非典型PKC包括PKCζ 和ι(或λ);3個(gè)PRK成員(PRK1~3)。正常情況下,PKC處于失活狀態(tài),當(dāng)受到外界刺激時(shí),PKC被激活。激活的PKC可使多種蛋白的絲氨酸、蘇氨酸發(fā)生磷酸化,從而影響各種內(nèi)、外分泌腺的分泌、神經(jīng)遞質(zhì)的釋放、細(xì)胞凋亡、心肌收縮和代謝途徑調(diào)節(jié)等。

      一系列研究表明,多種疾病的發(fā)生發(fā)展都與PKC的異常表達(dá)有關(guān)。比如在人乳腺癌[3]、結(jié)腸癌、肝癌細(xì)胞中存在著PKCα表達(dá)的明顯增加;在甲狀腺病變細(xì)胞[4]中發(fā)現(xiàn)PKCα、PKCβⅡ、PKCδ的異常表達(dá);前列腺癌和結(jié)腸癌細(xì)胞[5]中PKCβ的表達(dá)增多,而膀胱癌中表達(dá)降低。此外,在高分化級(jí)別的膀胱癌[6]、前列腺癌和子宮內(nèi)膜癌細(xì)胞中,PKCα的表達(dá)增加;反之,在低分化級(jí)別腫瘤和正常上皮細(xì)胞中PKCα表達(dá)明顯減少。同時(shí),PKC可以被某些促癌劑和佛波脂所激活,也可以被某些抗癌劑所抑制[1]。因此,開(kāi)發(fā)新型強(qiáng)效的PKC抑制劑不僅有助于研究其生物療效,而且對(duì)于重大疾病的治療有著非常重要的意義。

      近些年來(lái),尋找新型特異性的PKC抑制劑已成為國(guó)內(nèi)外研究關(guān)注的焦點(diǎn)。已有大量從植物、微生物以及動(dòng)物的代謝物中分離提取出的PKC抑制劑或天然產(chǎn)物中的PKC抑制劑被發(fā)現(xiàn)。本文就近年來(lái)新發(fā)現(xiàn)的PKC抑制劑加以綜述。

      1 Enzastaurin(LY317615.HCl)

      Enzastaurin(LY317615.HCl)是一種新型有效的口服PKC抑制劑[7]。Enzastaurin通過(guò)與三磷酸腺苷(ATP)競(jìng)爭(zhēng)PKC的核苷酸三磷酸鹽的結(jié)合位點(diǎn),從而阻滯PKC的激活。Enzastaurin的主要靶標(biāo)是PKCβ,除此之外,它也可以有效抑制其他PKC亞型[8],包括PKCδ、PKCα、PKCγ、PKCε和磷酸酰肌醇3激酶/Akt/肝糖合酶激酶-3信號(hào)途徑。Enzastau?rin主要是經(jīng)過(guò)CYP3A代謝,產(chǎn)生的代謝產(chǎn)物和Enzastaurin具有相似作用,也是PKC抑制劑。盡管Enzastaurin最開(kāi)始應(yīng)用于抗血管增生的腫瘤治療,近來(lái)的臨床前研究證實(shí)它對(duì)于卵巢癌[9]、結(jié)腸癌(HCT116)、惡性膠質(zhì)瘤(U87MG)、前列腺癌(PC-3)、皮膚T細(xì)胞淋巴瘤(HH,HuT-78)、白血?。↘562 和MOLT-4)和非小細(xì)胞肺癌(HOP-92)等多種腫瘤細(xì)胞系均具有顯著的抗腫瘤活性。Ⅰ期臨床研究發(fā)現(xiàn),患有進(jìn)行性肺癌和頭頸癌的腫瘤患者口服Enzastaurin后顯示了較小的相關(guān)毒性,最常見(jiàn)的不良反應(yīng)是疲勞和胃腸道反應(yīng)(惡心嘔吐、腹瀉),臨床上沒(méi)有出現(xiàn)嚴(yán)重的3或4級(jí)毒性反應(yīng)發(fā)生[10]。其他不良反應(yīng)包括血小板減少、咳嗽、轉(zhuǎn)氨酶升高、呼吸困難、外周性水腫和頭昏眼花等。多中心的Ⅱ期臨床研究也證實(shí)Enzastaurin對(duì)于治療復(fù)發(fā)性彌漫性大B細(xì)胞性淋巴瘤(DLBCL)和濾泡性淋巴瘤具有很好的相容性,并可防止部分患者的病情進(jìn)展[11]。Enzastaurin可以抑制多發(fā)性骨髓瘤(MM)細(xì)胞的PKC活化,從而抑制了多藥耐藥MM細(xì)胞的生長(zhǎng)增殖、存活和遷移[12]。此外,Enzastaurin還可以協(xié)同增強(qiáng)紫杉醇[13]、阿霉素、硼替佐米、利妥昔單抗、氟達(dá)拉濱、地塞米松等的抗癌作用。

      2 苔蘚蟲(chóng)素

      苔蘚蟲(chóng)素是來(lái)自于海洋無(wú)脊椎動(dòng)物苔蘚蟲(chóng)類的一個(gè)大環(huán)內(nèi)酯物,可以有效地結(jié)合PKC的調(diào)節(jié)區(qū)域。它的抗腫瘤作用歸功于它與PKC的相互作用[14]。與佛波醇酯相似,苔蘚蟲(chóng)素-1也是PKC活性的一個(gè)調(diào)節(jié)器,但它不是促腫瘤因子。苔蘚蟲(chóng)素可以促進(jìn)或抑制PKC的活性,取決于細(xì)胞背景和暴露的時(shí)間。短期暴露于苔蘚蟲(chóng)素可以促進(jìn)PKC活化,而長(zhǎng)期暴露則顯著抑制了PKC。臨床前研究已經(jīng)證實(shí)苔蘚蟲(chóng)素對(duì)于固體腫瘤和血液病腫瘤細(xì)胞均具有顯著抗腫瘤作用[15]。苔蘚蟲(chóng)素的Ⅱ期臨床研究證實(shí)在復(fù)發(fā)性多發(fā)性骨髓瘤患者和上皮卵巢癌患者中無(wú)顯著不良反應(yīng)[16]。Ⅰ期和Ⅱ期研究顯示苔蘚蟲(chóng)素對(duì)于急性白血病[17]、轉(zhuǎn)移性腎癌[18]和惰性血液病腫瘤[19]均有療效。此外,研究發(fā)現(xiàn)苔蘚蟲(chóng)素與傳統(tǒng)化療藥物合用(如三苯氧胺[20]、胞核嘧啶、氟達(dá)拉濱、紫杉醇等)治療胰腺癌、白血病和卵巢癌細(xì)胞時(shí)具有顯著的化療增敏療效。因此,苔蘚蟲(chóng)素的多項(xiàng)臨床前研究證實(shí)了它對(duì)多種腫瘤模型具有抗癌作用,然而其確切的抗癌機(jī)制仍不清楚,可能也包括PKC依賴性途徑。

      3 米哚妥林(PKC-412)

      米哚妥林(PKC-412)是一種生物堿的星形孢菌素衍生物,是一個(gè)口服的多靶標(biāo)的激酶抑制劑[21]。盡管米哚妥林最初的設(shè)計(jì)是抑制傳統(tǒng)PKC和新型PKC亞型的活性,它同樣也可以阻斷血管內(nèi)皮生長(zhǎng)因子(VEGF)受體Flt-1和突變型Flt-3[22]、成纖維細(xì)胞生長(zhǎng)因子受體FGFR1、突變型FGFR3以及Ⅲ型酪氨酸激酶的激活。多種臨床前試驗(yàn)?zāi)P桶毙粤<?xì)胞性白血病、急性淋巴細(xì)胞性白血病、柱狀細(xì)胞白血病、T細(xì)胞淋巴瘤和固體腫瘤等的研究已經(jīng)證實(shí)了PKC-412具有明顯的抗腫瘤作用[23]。此外,PKC-412對(duì)MM細(xì)胞系如RPMI8226、U266、NCI-929等也具有顯著抗腫瘤活性。研究證實(shí),PKC-412是JNK依賴性地通過(guò)c-Jun的上調(diào)和c-Fos的下調(diào)而發(fā)揮作用[24]。

      4 Aprinocarsen(ISIS-3521,LY-9000003)

      Aprinocarsen是一段含有20個(gè)堿基對(duì)的反義寡聚脫氧核甘酸,可以與PKCα基因的3′非翻譯區(qū)互補(bǔ)結(jié)合,從而抑制PKCα的表達(dá)。研究證實(shí),PKCα在多種腫瘤類型包括非小細(xì)胞肺癌(NSCLC)的發(fā)生和發(fā)展中都起到了重要作用,因此Aprinocarsen具有一定的抗癌意義[25]。研究證實(shí),Aprinocars?en在進(jìn)展性卵巢癌患者的臨床試驗(yàn)中沒(méi)有發(fā)生明顯的不良反應(yīng)[26]。此外,許多Ⅱ期和Ⅲ期臨床試驗(yàn)正在研究Aprino?carsen聯(lián)合其他化療藥物的抗癌療效。

      5 姜黃素

      姜黃素來(lái)自于姜黃屬植物的根莖。近年來(lái)臨床數(shù)據(jù)證實(shí)姜黃素具有廣泛的生物學(xué)效果[27],包括抗氧化、抗炎、抗病毒和抗感染作用。最重要的是,姜黃素被證實(shí)具有抗血管增生和抗癌作用,在包括對(duì)結(jié)腸癌[28]、卵巢癌[29]和胰腺癌等多種腫瘤中都具有化療增敏作用。此外,姜黃素在人MM細(xì)胞也具有抗腫瘤活性[30]。研究證實(shí),姜黃素是通過(guò)與鈣離子競(jìng)爭(zhēng)結(jié)合PKC調(diào)節(jié)區(qū)從而抑制PKC信號(hào)途徑來(lái)發(fā)揮生物學(xué)作用的[31]。一些Ⅱ期和Ⅲ期的臨床試驗(yàn)正在研究姜黃素的抗癌療效。

      6 其他PKC抑制劑

      三苯氧胺在雌激素受體(ER)陽(yáng)性的乳腺癌細(xì)胞中一直被認(rèn)為是通過(guò)抑制ER發(fā)揮抗癌作用,然而現(xiàn)在認(rèn)為三苯氧胺也通過(guò)非ER介導(dǎo)機(jī)制發(fā)揮作用,包括通過(guò)抑制PKC的活性。研究發(fā)現(xiàn),在ER表達(dá)陰性的乳腺癌細(xì)胞中,三苯氧胺是通過(guò)氧化應(yīng)激來(lái)調(diào)節(jié)PKC的活性[32]。因此,在ER表達(dá)陰性的腫瘤,包括乳腺癌[33]、黑色素瘤、卵巢癌、神經(jīng)膠質(zhì)瘤[34]和肝細(xì)胞癌中,三苯氧胺依然具有抗癌活性作用。

      Aplidin(plitidepsin)來(lái)自于地中海中有被膜的aplidium念珠菌,在胃癌、前列腺癌、膀胱癌和伯基特式淋巴瘤中顯示出抗腫瘤的作用[35]。Aplidin通過(guò)誘導(dǎo)線粒體凋亡途徑,抑制VEGF的分泌和下調(diào)Flt-1而發(fā)揮抗癌、抗血管生成的作用。Aplidin可以通過(guò)切割PKCδ來(lái)誘導(dǎo)MM細(xì)胞凋亡。目前Aplidin對(duì)復(fù)發(fā)性MM患者的臨床試驗(yàn)還在進(jìn)行中。

      目前,尋找PKC抑制劑的研究已經(jīng)取得了很大的進(jìn)展,一些具有特異激酶抑制活性的化合物也逐漸被發(fā)現(xiàn),如chel?erythrine、LY317615、PKCzI257.3[36]等。除此之外,許多天然化合物,包括抗氧化維生素A、C、E和白藜蘆醇都可以調(diào)節(jié)PKC的活性。另外,胡蘿卜素和類維生素A可以對(duì)抗強(qiáng)氧化劑對(duì)PKC的生物學(xué)作用。新型PKC抑制劑的發(fā)現(xiàn)對(duì)于進(jìn)一步研究PKC的結(jié)構(gòu)功能、篩選出更加高效的抑制劑,并進(jìn)一步設(shè)計(jì)出抗癌、抗病毒、抗炎等疾病的制劑具有重要的臨床意義。

      參考文獻(xiàn)

      [1] ZhanghT, Zhang D, Zha ZG, et al.Transcriptional activation of PRMT5 by NF-Y is required for cell growth and negatively regulat?ed by the PKC/c-Fos signaling in prostate cancer cells[J].Biochim Biophys Acta, 2014, 1839(11):1330-1340.doi: 10.1016/j.bbagrm.2014.09.015.

      [2]maillard L, Saito N,hlawatyh, et al.RANTES/CCL5mediated-bi?ological effects depend on the syndecan-4/PKCα signaling pathway [J].Biol Open, 2014, 3(10):995-1004.doi: 10.1242/bio.20148227.

      [3] Kim S, Lee J, Lee SK, et al.Protein kinase C-α downregulates estro?gen receptor-α by suppressing c-Jun phosphorylation in estrogen receptor- positive breast cancer cells[J].Oncol Rep, 2014, 31(3): 1423-1428.doi: 10.3892/or.2013.2936.

      [4] Knauf JA, Ward LS, Nikiforov YE, et al.Isozyme-specific abnormalities of PKC in thyroid cancer: evidence for post-transcriptional changes in PKC epsilon[J].J Clin Endocrinolmetab, 2002, 87(5):2150-2159.

      [5] Graff JR,mcNulty AM,hanna KR, et al.The protein kinase Cbetaselective inhibitor, Enzastaurin (LY317615.HCl), suppresses signal?ing through the AKT pathway, induces apoptosis, and suppresses growth ofhuman colon cancer and glioblastoma xenografts[J].Can?cer Res, 2005, 65(16):7462-7469.

      [6] Jiang Z, Kong C, Zhang Z, et al.Reduction of protein kinase C α (PKC-α) promote apoptosis via down-regulation of Dicer in blad?der cancer[J].J Cellmolmed, 2015, 19(5):1085- 1093.doi: 10.1111/jcmm.12503.

      [7]mattoo AR, Pastan I, Fitzgerald D.Combination treatments with the PKC inhibitor, enzastaurin, enhance the cytotoxicity of the anti-me?sothelin immunotoxin, SS1P[J].PLoS One, 2013, 8(10):e75576.doi: 10.1371/journal.pone.0075576.

      [8] Kheirallah S, Fruchon S, Ysebaert L, et al.The serine-threonine ki?nase p90RSK is a new target of enzastaurin in follicular lymphoma cells[J].Br J Pharmacol, 2013, 170(7):1374- 1383.doi: 10.1111/bph.12351.

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      (2015-07-29收稿2015-09-06修回)

      (本文編輯李鵬)

      New progress in the study of protein kinase C(PKC)inhibitors

      WU Jing1, YANG Rui2, LIU Shuye1△
      1 Department of Clinical Laboratory, Tianjin Third Centralhospital, Tianjin 300170,China; 2 Research Center of Basicmedical Science, Tianjinmedical University△Corresponding Author E-mail:lshye@163.com

      Abstract:Protein kinase C (PKC) is a group of phospholipid-dependent serine/threonine protein kinases, which togeth?er with protein kinase A (PKA) and protein kinase G (PKG) constitute a superfamily of serine/threonine protein kinase AGC.PKC includes classic PKC, novel PKC, atypical PKC and somemembers of kinase associated with PKC (PRK).PKC is wide?ly distributed inmammalian tissues and cells, which plays an important biological role in growth andmetabolism, prolifera?tion and differentiation of cells.A series of studieshave demonstrated that variations ofmultiple cells, occurrence and devel?opment of diseases are related to the abnormal expression of PKC.Therefore, designing and searching for efficient PKC inhib?itorshave very important implications for synthesis ofmany kinds of effective drugs and treatment of a variety of clinical dis?eases including cancer, cardiovascular, andhypertension, et al.In recent years, the research on PKC inhibitorshas become the focus of domestic and foreign research.A large number of literatureshave reportedmany kinds of effective PKC inhibi?tors, and analyzed their function site,mechanism, clinical trial data and so on.The discovery of these PKC inhibitorshas im?portant implications for structural analysis of PKC and the treatment of diseases.So in this paper, the efficient PKC inhibi?tors are summarized.

      Key words:protein kinase C;enzyme inhibitors;trypsin inhibitors;protein kinase inhibitors;neoplasms; review

      通訊作者△E-mail:lshye@163.com

      作者簡(jiǎn)介:吳靜(1982),女,博士,助理研究員,主要從事腫瘤分子生物學(xué)方面研究

      基金項(xiàng)目:國(guó)家自然科學(xué)基金資助項(xiàng)目(81301985);天津市應(yīng)用基礎(chǔ)與前沿技術(shù)研究計(jì)劃青年項(xiàng)目(14JCQNJC14000)

      中圖分類號(hào):R730.53

      文獻(xiàn)標(biāo)志碼:A

      DOI:10.11958/20150079

      作者單位:1天津市第三中心醫(yī)院檢驗(yàn)科(郵編300170);2天津醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)研究中心轉(zhuǎn)化腫瘤學(xué)實(shí)驗(yàn)室

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