-
放射增敏剂是一类可以增加肿瘤细胞放射敏感性、加大射线杀伤力的药物。研究发现，除传统亲电子类放射增敏剂（如硝基咪唑类亲电子化合物、硝基苯类氧利用抑制剂等）之外，部分化疗药物也可作为放射增敏剂使用[1-2]。此外分子靶向增敏剂可以在优化治疗效果的同时降低对正常组织细胞的伤害[3]，具有更为广阔的临床应用前景。
-
5-氟尿嘧啶是一种最常用的肿瘤化疗药物，为胸苷酸合成酶抑制剂，通过干扰肿瘤DNA的合成产生细胞毒作用[4]。它与电离辐射的组合疗法对多种临床肿瘤均具有增效作用，是目前放化疗的主要药物。
-
顺铂类是另一种常用的化疗药物，通过与肿瘤DNA交联，干扰细胞分裂而产生细胞毒性。研究发现，新型铂类衍生物奥沙利铂，因显示出更优的增敏效果在临床上渐渐取代顺铂，常与放疗联合应用以提高治疗效果[5]。
-
吉西他滨是一种核苷类似物，通过阻止肿瘤DNA复制产生细胞毒性，可作为放射增敏剂应用[6]。吉西他滨通过干扰Rad51（一种同源重组修复蛋白）的功能和同源重组修复，同时与细胞周期检测点激酶1（checkpoint kinase 1，Chk1）和Chk2结合使细胞进入S期而产生增敏作用[7]。
-
伊立替康、拓扑替康、喜树碱与拓扑异构酶相互作用，干扰DNA复制和修复过程中的螺旋化和解螺旋化。电离辐射导致DNA双链断裂，而拓扑异构酶1抑制剂干扰DNA修复，二者具有协同作用，但是具体的机制尚不明了。而且，临床试验表明，这种组合疗法对多种实体瘤（如头颈部癌、肺癌等）均有效[8]。
-
几种小分子以及单抗靶向药物（靶标分别为表皮生长因子受体、原癌基因人类表皮生长因子受体2、血管内皮生长因子受体）已应用于临床，而且研究者们已设计出多种类型的分子靶向制剂，目前正处于临床试验阶段[9-10]。以下是具有增敏活性的分子靶向制剂。
-
HDAC是一类调控组蛋白去乙酰化的蛋白酶，在基因表达调控中发挥着重要作用。有临床前研究表明HDAC抑制剂可选择性诱导肿瘤细胞凋亡，抑制肿瘤生长；而且有临床试验表明HDAC抑制剂单独使用或与化疗药物联用均呈现出明显的增敏效果[11]。HDAC抑制剂诱导的组蛋白高度乙酰化可增强电离辐射对肿瘤细胞的杀伤性，因此，可作为放射增敏剂使用，多项临床试验正测试该类抑制剂对多种肿瘤的增敏活性[12-13]。Chen等[14]的研究表明，HDAC抑制剂伏立诺他通过抑制受照射的骨髓瘤细胞中Rad51的形成，阻断Rad51对电离辐射的响应，从而达到增敏效果，这种抑制作用不受细胞周期分布的影响；此外，伏立诺他还可通过一种新机制——选择性抑制HDAC受体途径来增敏骨髓瘤细胞。
-
肿瘤细胞放射敏感性的提高与放射诱导两面神激酶/STAT通路的激活相关，因此抑制STAT应该可以达到增敏效果。Kim等[15]研究表明，STAT-3介导的增敏作用是通过下调抗凋亡生存素的表达而实现的。Johnson等[16]研究表明，白藜芦醇（一种多酚类植物抗毒素）可选择性地作用于多种细胞信号通路，启动凋亡机制，降低细胞存活率；在黑色素瘤细胞中，白藜芦醇在激活促分裂素原活化蛋白激酶和毛细血管扩张共济失调突变基因（ataxia-telangiectasia mutated gene，ATM）-Chk2-p53通路的同时，可抑制STAT-3和核转录因子kappa B（nuclear factor kappa-light-chain-enhancer of activated B cells，NF-κB）介导的转录过程，最终抑制细胞型Fas相关死亡区域蛋白样白介素1β转换酶抑制蛋白和B细胞淋巴瘤（B-cell lymphoma，Bcl）-XL的表达；白藜芦醇还可以上调肿瘤坏死因子凋亡相关诱导配体启动子的活性，诱导肿瘤坏死因子凋亡相关诱导配体在某些黑色素瘤细胞系中的表达，导致快速凋亡的发生；并且这两种机制可以协同发挥作用。氯化胡椒碱（一种从花椒属植物中提取的天然生物碱）为有效的STAT-3信号通路抑制剂，可抑制胃癌血管的生成[17]。
-
PARP在DNA的复制和修复中发挥着重要作用。PARP既可与单链DNA结合又可与双链DNA结合，但主要影响单链DNA修复；因此，PARP抑制剂主要阻断单链DNA的修复，并不直接影响对细胞存活至关重要的双链DNA修复。尽管如此，PARP抑制剂导致的同源重组缺陷仍具有明显的增敏效果，尤其是对存在双链修复缺陷和非同源末端连接的肿瘤细胞[18-19]。某些PARP抑制剂已进入临床试验阶段，如ABK-888[20]。
-
PGHS-2抑制剂对多种肿瘤具有增敏效果。如N-（2-甲氧基环己烷-4-硝基）甲砜胺可增强食管癌肿瘤干细胞样放射抗拒Eca109R50Gy细胞的放射敏感性，其机制可能是通过下调β-连环蛋白的表达，抑制蛋白激酶B的激活，诱导肿瘤细胞凋亡[21-22]。N-（2-甲氧基环己烷-4-硝基）甲砜胺对黑色素瘤细胞亦有增敏效果，主要是通过坏死机制使细胞分裂停留在G2或M期[16]。另一种PGHS-2抑制剂——塞来昔布，抑制非PGHS-2依赖性表皮生长因子受体调节的放射抗拒，可增强支气管癌和结肠癌细胞的放射敏感性，这表明即使患者的放射抗拒不依赖于PGHS-2，PGHS-2抑制剂仍可改善放疗的效果[23]。鉴于此，在PGHS-2缺乏的情况下，PGHS-2抑制剂也可以增强肿瘤辐射敏感性。尼美舒利是一种PGHS-2选择性抑制剂，可以增强非小细胞肺癌细胞的放疗效果，可能是通过抑制NF-κB调节辐射诱导细胞保护基因的表达实现的[24]。
但是，高剂量PGHS-2选择性抑制剂存在诱发心血管疾病的风险[25]，可采用低剂量PGHS与从绿茶中提取的表没食子儿茶素没食子酸酯联合应用的方法解决该问题[26-27]。其他的植物提取物如染料木素、姜黄素、白藜芦醇、水飞蓟素、咖啡酸苯乙基酯、夫拉平度、大黄素、茶多酚、胡椒碱、夹竹桃苷、熊果酸和桦木酸等，也具有同样的作用，它们通过抑制放射抗拒通路达到放射增敏效果[28-29]。从姜的根茎中提取的姜黄素的作用机制如下：阻断NF-κB通路，下调抗凋亡Bcl-XL和生存素的表达，增加G2和M期细胞数，从而改善伯基特淋巴瘤的疗效[30]；姜黄素还可以通过抑制放射诱导的NF-κB激活途径，促进胰腺癌细胞凋亡[31]。
-
HIF-1是乏氧信号通路的重要调节因子，在乏氧诱导的肿瘤放射抵抗中发挥重要作用。而且最近N-myc（在成神经细胞瘤中发现的一类myc癌基因）下游调节基因2被证实是HIF-1的下游靶标基因，通过抑制Bax（一种促进细胞凋亡的蛋白）的表达提高宫颈癌细胞的放射抵抗性[32]。因此，HIF-1和N-myc下游调节基因2抑制剂可作为肿瘤治疗的放射增敏剂。向经60Co照射的来源于喉鳞状细胞癌组织的乏氧细胞中注射HIF-1抑制剂3-（5'-羟甲基-2'-呋喃基）-1-苯甲基吲唑，可明显抑制HIF-1α的表达、增强肿瘤细胞的放射敏感性以及降低乏氧细胞的存活率[33]；与单独放疗相比，3-（5'-羟甲基-2'-呋喃基）-1-苯甲基吲唑的使用使HIF-1的激活受到抑制，明显抑制了肿瘤生长[34]。另一种HIF-1抑制剂——吖啶黄，在前列腺癌的一种移植模型中，通过阻碍HIF-1的二聚化抑制肿瘤的生长和血管生成[35]。在放射抗拒肺癌细胞中，热休克蛋白（heat shock protein，HSP）90功能的抑制也会导致HIF-1α表达的下降[36]。HSP90与HIF-1α竞争结合活化C激酶受体1，并抑制非氧依赖性HIF-1α的降解[37]。Singh-Gupta等[38]用大豆异黄酮对前列腺癌细胞进行预处理，发现其可抑制c-Src/STAT-3/HIF-1α（其中，Src即鸡肉瘤病毒基因组中的基因）的激活以及HIF-1的核转运，这与脱嘌呤/脱嘧啶核酸内切酶或氧化还原因子1的表达以及HIF-1α和NF-κB与DNA的结合活性下降相关。使用HIF-1拮抗剂也可以抑制HIF的表达：HIF-1通过上调生存素的表达增强细胞的放射抵抗性，并且辐射可以激活并增强HIF-1信号通路从而上调血管内皮生长因子和碱性成纤维细胞生长因子的表达，达到对血管内皮细胞放射损伤的保护作用。因此，HIF-1拮抗剂与HIF-1相互竞争，减少了血管的生成，增敏了肿瘤细胞[39]。抑制HIF-1的上游途径也可以达到增敏效果。磷脂酰肌醇3-激酶/蛋白激酶B/雷帕霉素靶蛋白通路是最重要的增敏靶点，该通路可影响NF-κB介导PGHS-2的表达[40]，以及辐射诱导基质金属蛋白酶9的表达[41]。该方面的抑制剂主要有erufosine[42]、LY294002[43]等。
-
近年来，多种NF-κB抑制剂被批准为放射增敏剂，尤其是天然的植化成分，因其广谱抗瘤和抗炎特性以及低毒性而应用得更为广泛。其中，姜黄素是研究最为充分的植物多酚类物质。姜黄素可下调NF-κB、PGHS-2和磷酸化STAT-3的表达；姜黄素还可以增敏前列腺癌细胞，通过抑制肿瘤坏死因子介导NF-κB的激活，导致Bcl-2蛋白表达下调，并伴随着细胞色素C和细胞凋亡酶9和3的激活[44]。最近，姜黄素被发现可增敏结直肠癌细胞，通过抑制辐射诱导的NF-κB的抑制蛋白α的磷酸化和降解来抑制蛋白激酶B的磷酸化和NF-κB的激活，最终导致致瘤因子表达的下调[45]。相似地，腰果酸（6-十五烷基水杨酸）通过抑制辐射诱导的NF-κB的抑制蛋白α的磷酸化和降解，抑制p65的乙酰化和核转运，抑制NF-κB的激活[46]。此外，许多其他化合物也可以通过抑制NF-κB增敏肿瘤细胞，包括二十二碳六烯酸[47]以及有机硒硫氧还原蛋白还原酶抑制剂乙烷硒啉[48]等。
-
HSP的过度表达可抗衰亡，在肿瘤发生中发挥着重要的作用，采用有效手段抑制HSP表达是增强癌细胞敏感性的又一途径。HSP抑制剂KNK437为亚苄基内酰胺类化合物，在KLM1-R细胞（一种抗吉西他滨的细胞）中可显著降低HSP27的表达，从而增强吉西他滨的抗癌作用[49]；KNK437还可以通过下调热诱导HSP70 mRNA的表达增敏前列腺癌细胞[50]。
-
ATM属于磷脂酰肌醇3-激酶蛋白家族，在DNA修复信号通路中发挥着重要的作用，DNA损伤后，ATM可立即激活DNA修复通路。KU55933是一种ATM专一性抑制剂，不作用于其同家族蛋白，如ATP、雷帕霉素靶蛋白、DNA依赖蛋白激酶等，通过阻碍磷酸化组蛋白、N-溴代丁二酰亚胺-1和Chk1的磷酸化来增敏肿瘤细胞[51]。CGK733可选择性抑制ATM与ATM和Rad3相关蛋白，阻碍细胞周期关卡转换通路达到增敏效果[52]。CP466722与KU55933相似，可抑制ATM及其下游途径，而且ATM的短暂抑制（4 h以内）已足够提高肿瘤细胞的敏感性[53]。
-
此外，一些表皮生长因子受体酪氨酸蛋白激酶抑制剂如埃罗替尼、吉非替尼，血管内皮生长因子抑制剂如贝伐单抗等抗肿瘤药物也在临床前或者临床试验中显示出增敏效果[54]，主要通过抑制肿瘤细胞增殖、促进肿瘤细胞凋亡、抑制血管生成以及降低肿瘤转移等途径发挥放射增敏作用。
-
部分化疗药物（如紫杉醇、奥沙利铂等）在发挥抑瘤作用的同时，还可以增强射线对肿瘤细胞的杀伤效应，因此，可与放疗联合应用增强临床治疗效果。而分子靶向增敏剂则可以选择性地作用于肿瘤细胞，降低对正常组织细胞的伤害，优化治疗效果。HDAC、STAT-3、PARP、PGHS-2、HIF-1、NF-κB、HSP、ATM等均是有效的分子靶点，并且随着对肿瘤生物学研究的不断深入，新的增敏靶点也会不断地被开发利用，但这些成果还远不能满足人类治愈肿瘤的愿望，目前绝大多数的靶向药物都是针对单一靶点，而细胞中信号转导是一个复杂、多因素、多水平的分子网络系统，阻断一个节点并无法阻断全部信息的传导。因此，如能将肿瘤发生发展中的多个相关靶点同时加以抑制，则有可能在肿瘤临床化疗和放疗增敏方面取得更好的治疗效果[55]。
肿瘤放射治疗增敏剂研究新进展
Radiosensitizers development and the pathways
-
摘要: 目前除传统的亲电子放射增敏剂硝基咪唑类、硝基苯等之外，还发现了部分化疗药物也具有肿瘤放射治疗增敏效果。分子靶向药物的研究方兴未艾，分别作用于组蛋白去乙酰化酶、信号转导子和转录激活因子3、聚腺苷二磷酸核糖基聚合酶、前列腺素H合成酶2、缺氧诱导因子1、核转录因子、热休克蛋白、毛细血管扩张共济失调突变基因等分子靶点，通过各种不同的途径干扰肿瘤DNA修复、抑制肿瘤细胞增殖、促进其凋亡、抑制血管生成从而达到放射增敏效果。Abstract: Except for the traditional radiotherapy sensitization agents such as nitro imidazoles and nitrobenzene, some chemotherapeutics also showed sensitization effect. Molecular targeted drug research is in the ascendant, respectively interacting with histone deacetylase, signal transducer and activator of transcription 3, poly(adenosine diphosphate-ribose)polymerase, prostaglandin H synthase-2, (hypoxia inducible factor-1, nuclear factor kappa-light-chain-enhancer of activated B cells, heat shock protein, ataxia-telangiectasia mutated gene and so on, through various ways such as interfering DNA repair, inhibiting tumor cell proliferation, promoting tumor cell apoptosis and inhibiting angiogenesis to improve the sensitivity of cancer cells to iron radiation.
-
[1] Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med, 2004, 350(19): 1937-1944. [2] Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med, 2004, 350(19): 1945-1952. [3] Zhukov NV, Tjulandin SA. Targeted therapy in the treatment of solid tumors: practice contradicts theory. Biochemistry(Mosc), 2008, 73(5): 605-618. [4] Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer, 2003, 3(5): 330-338. [5] Spalding AC, Lawrence TS. New and emerging radiosensitizers and radioprotectors. Cancer Invest, 2006, 24(4): 444-456. [6] Morgan MA, Parsels LA, Maybaum J, et al. Improving gemcitabine-mediated radiosensitization using molecularly targeted therapy: a review. Clin Cancer Res, 2008, 14(21): 6744-6750. [7] Morgan MA, Parsels LA, Parsels JD, et al. Role of checkpoint kinase 1 in preventing premature mitosis in response to gemci-tabine. Cancer Res, 2005, 65(15): 6835-6842. [8] Murphy BA. Topoisomerases in the treatment of metastatic or recurrent squamous carcinoma of the head and neck. Expert Opin Pharmacother, 2005, 6(1): 85-92. [9] Press MF, Lenz HJ. EGFR, HER2 and VEGF pathways: validated targets for cancer treatment. Drugs, 2007, 67(14): 2045-2075. [10] Janku F, Stewart DJ, Kurzrock R. Targeted therapy in non-small-cell lung cancer--is it becoming a reality?. Nat Rev Clin Oncol, 2010, 7(7): 401-414. [11] Marks PA. The clinical development of histone deacetylase inhibitors as targeted anticancer drugs. Expert Opin Investig Drugs, 2010, 19(9): 1049-1066. [12] Ree AH, Dueland S, Folkvord S, et al. Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat(PRAVO)phase 1 study. Lancet Oncol, 2010, 11(5): 459-464. [13] Shabason JE, Tofilon PJ, Camphausen K. Grand rounds at the National Institutes of Health: HDAC inhibitors as radiation modifiers, from bench to clinic. J Cell Mol Med, 2011, 15(12): 2735-2744. [14] Chen X, Wong P, Radany EH, et al. Suberoylanilide hydroxamic acid as a radiosensitizer through modulation of RAD51 protein and inhibition of homology-directed repair in multiple myeloma. Mol Cancer Res, 2012, 10(8): 1052-1064. [15] Kim KW, Mutter RW, Cao C, et al. Inhibition of signal transducer and activator of transcription 3 activity results in down-regulation of Survivin following irradiation. Mol Cancer Ther, 2006, 5(11): 2659-2665. [16] Johnson GE, Ivanov VN, Hei TK. Radiosensitization of melanoma cells through combined inhibition of protein regulators of cell survival. Apoptosis, 2008, 13(6): 790-802. [17] Chen J, Wang J, Lin L, et al. Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer. Mol Cancer Ther, 2012, 11(2): 277-287. [18] Löser DA, Shibata A, Shibata AK, et al. Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose)polymerase is enhanced in cells deficient in DNA double-strand break repair. Mol Cancer Ther, 2010, 9(6): 1775-1787. [19] Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 2005, 434(7035): 917-921. [20] Chalmers AJ, Lakshman M, Chan N, et al. Poly(ADP-ribose)polymerase inhibition as a model for synthetic lethality in developing radiation oncology targets. Semin Radiat Oncol, 2010, 20(4): 274-281. [21] Che SM, Zhang XZ, Hou L, et al. Cyclooxygenase-2 inhibitor NS398 enhances radiosensitivity of radioresistant esophageal cancer cells by inhibiting AKT activation and inducing apoptosis. Cancer Invest, 2010, 28(7): 679-688. [22] Che SM, Zhang XZ, Liu XL, et al. The radiosensitization effect of NS398 on esophageal cancer stem cell—like radioresistant cells. Dis Esophagus, 2011, 24(4): 265-273. [23] Dittmann KH, Mayer C, Ohneseit PA, et al. Celecoxib induced tumor cell radiosensitization by inhibiting radiation induced nuclear EGFR transport and DNA-repair: a COX-2 independent mechanism. Int J Radiat Oncol Biol Phys, 2008, 70(1): 203-212. [24] Grimes KR, Warren GW, Fang F, et al. Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo. Oncol Rep, 2006, 16(4): 771-776. [25] Solomon SD, Wittes J, Finn PV, et al. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation, 2008, 117(16): 2104-2113. [26] Cerella C, Sobolewski C, Dicato M, et al. Targeting COX-2 expression by natural compounds: a promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy. Biochem Pharmacol, 2010, 80(12): 1801-1815. [27] Härdtner C, Multhoff G, Falk W, et al. (-)-Epigallocatechin-3-gallate, a green tea-derived catechin, synergizes with celecoxib to inhibit IL-1-induced tumorigenic mediators by human pancreatic adenocarcinoma cells Colo357. Eur J Pharmacol, 2012, 684(1-3): 36-43. [28] Garg AK, Buchholz TA, Aggarwal BB. Chemosensitization and radiosensitization of tumors by plant polyphenols. Antioxid Redox Signal, 2005, 7(11-12): 1630-1647. [29] Nambiar D, Rajamani P, Singh RP. Effects of phytochemicals on ionization radiation-mediated carcinogenesis and cancer therapy. Mutat Res, 2011, 728(3): 139-157. [30] Qiao Q, Jiang Y, Li G. Curcumin improves the antitumor effect of X-ray irradiation by blocking the NF-κB pathway: an in-vitro study of lymphoma. Anticancer Drugs, 2012, 23(6): 597-605. [31] Veeraraghavan J, Natarajan M, Lagisetty P, et al. Impact of curcumin, raspberry extract, and neem leaf extract on rel protein-regulated cell death/radiosensitization in pancreatic cancer cells. Pancreas, 2011, 40(7): 1107-1119. [32] Liu J, Zhang J, Wang X, et al. HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells. Exp Cell Res, 2010, 316(12): 1985-1993. [33] Moon SY, Chang HW, Roh JL, et al. Using YC-1 to overcome the radioresistance of hypoxic cancer cells. Oral oncol, 2009, 45(10): 915-919. [34] Harada H, Itasaka S, Zhu Y, et al. Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy. Br J Cancer, 2009, 100(5): 747-757. [35] Lee K, Zhang H, Qian DZ, et al. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc Natl Acad Sci USA, 2009, 106(42): 17910-17915. [36] Kim WY, Oh SH, Woo JK, et al. Targeting heat shock protein 90 overrides the resistance of lung cancer cells by blocking radiation-induced stabilization of hypoxia-inducible factor-1alpha. Cancer Res, 2009, 69(4): 1624-1632. [37] Semenza GL. Hypoxia-inducible factor 1(HIF-1)pathway. Sci STKE, 2007, 2007(407): cm8. [38] Singh-Gupta V, Zhang H, Banerjee S, et al. Radiation-induced HIF-1alpha cell survival pathway is inhibited by soy isoflavones in prostate cancer cells. Int J Cancer, 2009, 124(7): 1675-1684. [39] Shi M, Guo XT, Shu MG, et al. Cell-permeable hypoxia-inducible factor-1(HIF-1)antagonists function as tumor radiosensitizers. Med Hypotheses, 2007, 69(1): 33-35. [40] Yang CM, Lee IT, Lin CC, et al. Cigarette smoke extract induces COX-2 expression via a PKCalpha/c-Src/EGFR, PDGFR/PI3K/Akt/NF-kappaB pathway and p300 in tracheal smooth muscle cells. Am J Physiol Lung Cell Mol Physiol, 2009, 297(5): L892-902. [41] Cheng JC, Chou CH, Kuo ML, et al. Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. Oncogene, 2006, 25(53): 7009-7018. [42] Rudner J, Ruiner CE, Handrick R, et al. The Akt-inhibitor Erufosine induces apoptotic cell death in prostate cancer cells and increases the short term effects of ionizing radiation. Radiat Oncol, 2010, 5: 108. [43] Kao GD, Jiang Z, Fernandes AM, et al. Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem, 2007, 282(29): 21206-21212. [44] Chendil D, Ranga RS, Meigooni D, et al. Curcumin confers radio-sensitizing effect in prostate cancer cell line PC-3. Oncogene, 2004, 23(8): 1599-1607. [45] Sandur SK, Deorukhkar A, Pandey MK, et al. Curcumin modulates the radiosensitivity of colorectal cancer cells by suppressing constitutive and inducible NF-kappaB activity. Int J Radiat Oncol Biol Phys, 2009, 75(2): 534-542. [46] Sung B, Pandey MK, Ahn KS, et al. Anacardic acid(6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-kappaB-regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-kappa Balpha kinase, leading to potentiation of apoptosis. Blood, 2008, 111(10): 4880-4891. [47] Zand H, Rahimipour A, Salimi S, et al. Docosahexaenoic acid sensitizes Ramos cells to Gamma-irradiation-induced apoptosis through involvement of PPAR-gamma activation and NF-kappaB suppression. Mol Cell Biochem, 2008, 317(1-2): 113-120. [48] Wang L, Fu JN, Wang JY, et al. Selenium-containing thioredoxin reductase inhibitor ethaselen sensitizes non-small cell lung cancer to radiotherapy. Anticancer Drugs, 2011, 22(8): 732-740. [49] Taba K, Kuramitsu Y, Ryozawa S, et al. KNK437 downregulates heat shock protein 27 of pancreatic cancer cells and enhances the cytotoxic effect of gemcitabine. Chemotherapy, 2011, 57(1): 12-16. [50] Sahin E, Sahin M, Sanliolu AD, et al. KNK437, a benzylidene lactam compound, sensitises prostate cancer cells to the apoptotic effect of hyperthermia. Int J Hyperthermia, 2011, 27(1): 63-73. [51] Hickson I, Zhao Y, Richardson CJ, et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res, 2004, 64(24): 9152-9159. [52] Won J, Kim M, Kim N, et al. Small molecule-based reversible reprogramming of cellular lifespan. Nat Chem Biol, 2006, 2(7): 369-374. [53] Rainey MD, Charlton ME, Stanton RV, et al. Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res, 2008, 68(18): 7466-7474. [54] Tofilon PJ, Camphausen K. Molecular targets for tumor radiosensitization. Chem Rev, 2009, 109(7): 2974-2988. [55] 王浩, 周晓靓, 施培基, 等.靶向放射增敏剂的研究进展.中华放射医学与防护杂志, 2011, 31(2): 243-245.
-
点击查看大图
计量
- 文章访问数: 2779
- HTML全文浏览量: 1832
- PDF下载量: 5
下载: