來自加拿大皇后大學(xué)（Queen's University）生物化學(xué)系，多倫多大學(xué),，以及美國Palo Alto衛(wèi)生保健系統(tǒng)（Palo Alto Health Care System），印第安納州醫(yī)學(xué)院（Indiana University School of Medicine）等處的研究人員在實(shí)驗(yàn)室研究一種多肽分子（ANK）與抗乳腺癌藥物合用藥效的時(shí)候,，意外發(fā)現(xiàn)這種分子大大增強(qiáng)了藥力，從而希望能通過進(jìn)一步研究,，配合傳統(tǒng)抗乳腺癌藥物進(jìn)行分子療法,，給有抗藥性的乳腺癌病人使用，加強(qiáng)藥物藥效,。這一研究成果公布在1月15日的《Cancer Research》雜志上,。
領(lǐng)導(dǎo)這一研究的是加拿大皇后大學(xué)的賈宗超(Zongchao Jia)教授。
乳腺癌主要發(fā)生于女性,，是危害婦女健康的主要惡性腫瘤,，僅次于宮頸癌，在女性惡性腫瘤發(fā)病率中居第2位,。全世界每年約有120萬婦女發(fā)現(xiàn)乳腺癌,，有50萬婦女死于乳腺癌。北美,、北歐是乳腺癌的高發(fā)地區(qū),，其發(fā)病率約為亞,、非、拉美地區(qū)的4倍,。我國是乳腺癌的低發(fā)地區(qū),，但其發(fā)病率正逐年上升，尤其滬,、京,、津等大城市及沿海地區(qū)。
在對(duì)乳腺癌患者（advanced or metastatic diseases）的治療過程中,，經(jīng)常會(huì)使用抗微小管（Antimicrotubule）藥物,，但是病患對(duì)這種典型化療的反應(yīng)變化極大，不穩(wěn)定,。
在這篇文章中,，研究人員設(shè)計(jì)了一種新穎的多肽ANK，并利用一些生物學(xué)方法（熒光計(jì),，表面等離子共振技術(shù)（surface plasmon resonance）,，等溫滴定量熱法（isothermal titration calorimetry））證明了ANK與SNGG之間的關(guān)系。
Synuclein-γ (SNCG),，又稱為BCSG1 (breast cancer specific gene 1)或persyn,，屬于synuclein家庭成員，這類蛋白是一個(gè)廣泛分布于中樞神經(jīng)系統(tǒng)突觸前成分內(nèi)的小分子蛋白質(zhì)家族,，有α-synuclein,、β-synuclein和γ-synuclein三個(gè)成員，其中SNGG被發(fā)現(xiàn)與乳腺癌細(xì)胞的生長,、浸潤,、轉(zhuǎn)移和預(yù)后有關(guān)。
研究人員將ANK縮氨酸與標(biāo)準(zhǔn)藥物合并,，放入裝有乳癌細(xì)胞的培養(yǎng)皿中進(jìn)行效力測試,，他們也單獨(dú)使用藥物測試。結(jié)果發(fā)現(xiàn),，添加縮氨酸的藥物比不加縮氨酸藥物殺死的癌細(xì)胞多3.5倍,。
這說明這種縮氨酸可以促進(jìn)目前最廣泛應(yīng)用乳腺癌藥物的功效，這對(duì)于那些有嚴(yán)重抗藥問題的患者意義重大,。
不過研究人員也指出現(xiàn)在只是研究早期階段,，結(jié)果只限于實(shí)驗(yàn)室實(shí)驗(yàn)，下一步會(huì)在實(shí)驗(yàn)室老鼠身上實(shí)驗(yàn),。如果成功,，他們會(huì)進(jìn)入人體測試，這個(gè)過程可能需時(shí)幾年,。這一縮氨酸已申請(qǐng)了一項(xiàng)美國專利,。
附：
賈宗超,，北京師范大學(xué)長江學(xué)者講座教授。
生物化學(xué),。博士生導(dǎo)師,。
賈宗超，北京師范大學(xué)教授,，2004年受聘為國家教育部“長江學(xué)者獎(jiǎng)勵(lì)計(jì)劃講座教授”,，聘任崗位：生物化學(xué)。
部分英文原文：
Experimental Therapeutics, Molecular Targets, and Chemical Biology
Synuclein- Targeting Peptide Inhibitor that Enhances Sensitivity of Breast Cancer Cells to Antimicrotubule Drugs
Vinay K. Singh1, Yue Zhou2, Joseph A. Marsh3,4, Vladimir N. Uversky5, Julie D. Forman-Kay3,4, Jingwen Liu2 and Zongchao Jia1
1 Department of Biochemistry, Queen's University, Kingston, Ontario, Canada; 2 Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, California; 3 Molecular Structure and Function, Hospital for Sick Children; 4 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada; and 5 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
Requests for reprints: Zongchao Jia, Department of Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6. Phone: 613-533-6277; Fax: 613-533-2497; E-mail: [email protected] or Jingwen Liu, Department of Veterans Affairs, Palo Alto, CA 94304. Phone: 650-493-5000, ext. 64411; Fax: 650-849-0251; E-mail: [email protected] .
Synuclein- (SNCG) plays oncogenic roles in breast carcinogenesis. Although the expression of SNCG is abnormally high in advanced and metastatic breast carcinomas, SNCG is not expressed in normal or benign breast tissues. SNCG is an intrinsically disordered protein known to interact with BubR1, a mitotic checkpoint kinase. The SNCG-BubR1 interaction inhibits mitotic checkpoint control upon spindle damage caused by anticancer drugs, such as nocodazole and taxol. Antimicrotubule drugs that cause mitotic arrest and subsequent apoptosis of cancer cells are frequently used to treat breast cancer patients with advanced or metastatic diseases. However, patient response rates to this class of chemotherapeutic agents vary significantly. In this study, we have designed a novel peptide (ANK) and shown its interaction with SNCG using fluorometry, surface plasmon resonance, and isothermal titration calorimetry. Binding of the ANK peptide did not induce folding of SNCG, suggesting that SNCG can function biologically in its intrinsically disordered state. Microinjection of the ANK peptide in breast cancer cell line overexpressing SNCG (MCF7-SNCG) exhibited a similar cell killing response by nocodazole as in the SNCG-negative MCF7 cells. Overexpression of enhanced green fluorescent protein–tagged ANK reduces SNCG-mediated resistance to paclitaxel treatment by 3.5-fold. Our coimmunoprecipitation and colocalization results confirmed the intracellular association of the ANK peptide with SNCG. This is likely due to the disruption of the interaction of SNCG with BubR1 interaction. Our findings shed light on the molecular mechanism of the ANK peptide in releasing SNCG-mediated drug resistance. [Cancer Res 2007;67(2):626–33]
更多乳腺癌文獻(xiàn)資料...
http://cancerres.aacrjournals.org/cgi/content/abstract/67/2/626
