The heat shock proteins as targets for radiosensitization and chemosensitization in cancer

The heat shock proteins (HSPs) represent a class of proteins which are induced under physiologic stress to promote cell survival in the face of endogenous or exogenous injury. HSPs function predominantly as molecular chaperones, maintaining their "client" proteins in the correct conformational state in order to withstand a biologic stressor. Elevated HSP expression is also found in a range of pathologic conditions, notably malignancy. Cancer cells exploit the pro-survival phenotype endowed by HSPs to bolster their proliferative potential. Consequently, developing means of abrogating HSP expression may provide a way to render cancer cells more susceptible to radiation or chemotherapy. Here, we review the members of the HSP class and their roles in malignancy. We focus on attempts to target these proteins, particularly the small HSPs, in developing potent radiation and chemotherapy sensitizers, as well as proposed mechanisms for this sensitization effect.     

Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells

Medulloblastoma is an aggressive primary brain tumor that arises in the cerebellum of children and young adults. The Sonic Hedgehog (Shh) signaling pathway that plays important roles in the pathology of this aggressive disease is a promising therapeutic target. In the present report we have shown that curcumin has cytotoxic effects on medulloblastoma cells. Curcumin suppressed also cell proliferation and triggered cell‐cycle arrest at G₂/M phase. Moreover, curcumin inhibited the Shh–Gli1 signaling pathway by downregulating the Shh protein and its most important downstream targets GLI1 and PTCH1. Furthermore, curcumin reduced the levels of β‐catenin, the activate/phosphorylated form of Akt and NF‐κB, which led to downregulating the three common key effectors, namely C‐myc, N‐myc, and Cyclin D1. Consequently, apoptosis was triggered by curcumin through the mitochondrial pathway via downregulation of Bcl‐2, a downstream anti‐apoptotic effector of the Shh signaling. Importantly, the resistant cells that exhibited no decrease in the levels of Shh and Bcl‐2, were sensitized to curcumin by the addition of the Shh antogonist, cyclopamine. Furthermore, we have shown that curcumin enhances the killing efficiency of nontoxic doses of cisplatin and γ‐rays. In addition, we present clear evidence that piperine, an enhancer of curcumin bioavailability in humans, potentiates the apoptotic effect of curcumin against medulloblastoma cells. This effect was mediated through strong downregulation of Bcl‐2. These results indicate that curcumin, a natural nontoxic compound, represents great promise as Shh‐targeted therapy for medulloblastomas. © 2009 Wiley‐Liss, Inc.     

甘氨双唑钠在Ⅲ期非小细胞肺癌三维适形放疗中的应用

目的观察甘氨双唑钠(CMNa)对Ⅲ期非小细胞肺癌(NSCLC)三维适形放疗(3-DCRT)的放射增敏作用及其安全性。方法经病理和细胞学证实的Ⅲ期NSCLC病人42例,随机分为试验组(A组)22例和对照组(B组)20例,B组采用全身伽玛刀放疗,每周5次,每次3.5Gy,总剂量为70Gy。A组采用全身伽玛刀放疗,同时使用CMNa800mgm2,每周5次。结果A组CR率和总有效率(CR PR)均明显高于B组;A组病人治疗达到PR和CR时的中位照射剂量均低于B组;两组病人不良反应发生率比较无统计学意义。结论CMNa对Ⅲ期非小细胞肺癌三维适形放疗有较肯定的放射增敏作用,明显提高了NSCLC的近期疗效,不增加不良反应。     

纳米复合材料GO@AgPt对非小细胞肺癌的放射增敏作用

目的:制备新型纳米复合材料GO@AgPt,探究其对非小细胞肺癌的放射增敏效果。方法:通过改进型的水热法合成纳米复合材料GO@AgPt,通过透射电子显微镜、原子力显微镜、X射线光电子能谱分析、傅里叶红外光谱仪等方法对材料进行形貌及组分分析。应用细胞活性检测试剂盒CCK-8检测材料对肺癌细胞A549和人肺微血管细胞HPMEC的细胞活性的影响;然后通过流式检测及细胞克隆形成实验探究材料对于A549细胞的放射增敏效果。结果:成功制备出粒径大小均匀、化学成分稳定的纳米复合材料GO@AgPt。在一定浓度范围内该材料对肺癌细胞A549有毒性而对正常细胞HPMEC没有明显毒性。该材料能促进癌细胞产生活性氧,与X射线联合作用能促进细胞的凋亡。细胞克隆形成的结果也显示该材料对肺癌细胞具有放射增敏效果。结论:成功制备了纳米复合材料GO@AgPt,证明了该材料对于非小细胞肺癌有明显的放疗增敏效果。     

组蛋白去乙酰化酶抑制剂对宫颈癌细胞的放射增敏作用

目的探讨组蛋白去乙酰化酶抑制剂SAHA对宫颈癌SiHa细胞的毒性和放射增敏作用。方法 2009年10月至2010年6月在河北联合大学医学院采用MTT法检测SAHA对SiHa细胞的毒性并计算IC50。选择20%IC50的SAHA与放疗联合,克隆形成实验分析SAHA对SiHa细胞的放射增敏作用,采用Sigma Plot 2000 Demo版软件,利用多靶单击模型S=1-(1-eD0/D)n拟合细胞存活曲线,计算放射相关参数和放射增敏比,评价增敏效果。结果 MTT结果显示SAHA对SiHa细胞的毒性反应呈浓度和时间依赖性,SAHA作用SiHa细胞48h的IC50为4.80μmol/L。克隆形成实验结果显示,SAHA联合放疗组细胞的克隆形成率明显低于单独放疗组,二者的平均致死剂量(D0)分别为2.329、1.213,准阈剂量Dq分别为1.721、0.823。放射增敏比(SER)为1.92。结论 SAHA对宫颈癌SiHa细胞有良好的细胞毒性和放射增敏作用。     

石上柏联合放疗治疗鼻咽癌临床观察

目的 观察中药石上柏对晚期鼻咽癌的放射增敏作用。方法 选择180例鼻咽癌患者随机分为A、B、C三组：A组患者仅接受单纯放疗；B组从放疗第1天开始，每日用石上柏30g煎水50ml口服，至放疗结束；C组在疗程的后半段开始服用石上柏。结果 B组或C组鼻咽原发灶的完全缓解率（CR）高于A组（P〈0．05）；B组或C组颈淋巴结CR率高于A组（P〈0．05）。B、C组的急性放射反应较A组轻，但差异无统计学意义。结论 石上柏可能对晚期鼻咽癌有一定的放射增敏作用，并且不会增加正常组织的急性放射反应。     

Anginex synergizes with radiation therapy to inhibit tumor growth by radiosensitizing endothelial cells

We have demonstrated that the designed peptide anginex displays potent antiangiogenic activity. The aim of our study was to investigate the effect of anginex on established tumor vasculature as an adjuvant to radiation therapy of solid tumors. In the MA148 human ovarian carcinoma athymic mouse model, anginex (10 mg/kg) in combination with a suboptimal dose of radiation (5 Gy once weekly for 4 weeks) caused tumors to regress to an impalpable state. In the more aggressive SCK murine mammary carcinoma model, combination of anginex and a single radiation dose of 25 Gy synergistically increased the delay in tumor growth compared to the tumor growth delay caused by either treatment alone. Immunohistochemical analysis also demonstrated significantly enhanced effects of combined treatment on tumor microvessel density and tumor or endothelial cell proliferation and viability. In assessing physiologic effects of anginex, we observed a reduction in tumor perfusion and tumor oxygenation in SCK tumors after 5-7 daily treatments with anginex with no reduction in blood pressure. To test anginex as a radiosensitizer, additional studies using SCK tumors were performed. Three daily i.p. injections of anginex were able to enhance the effect of 2 radiation doses of 10 Gy, resulting in 50% complete responses, whereas the known antiangiogenic agent angiostatin did not enhance the radiation response of SCK tumors. Mechanistically, it appears that anginex functions as an endothelial cell-specific radiosensitizer because anginex showed no effect on in vitro radiosensitivity of SCK or MA148 tumor cells, whereas anginex significantly enhanced the in vitro radiosensitivity of 2 endothelial cell types. This work supports the idea that the combination of the antiangiogenic agent anginex and radiation may lead to improved clinical outcome in treating cancer patients.