Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells.
Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells.
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DOI：
10.1186/1471-2407-11-470
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发表时间：
2011-11-01
期刊：
影响因子：
3.8
通讯作者：
Rege K
中科院分区：
文献类型：
--
作者：
Taylor DJ;Parsons CE;Han H;Jayaraman A;Rege K
肿瘤坏死因子-α相关凋亡诱导配体（TRAIL）和死亡受体4和5的激动抗体是癌症治疗的有希望的候选者，因为它们能够在多种人类癌细胞中选择性地诱导细胞凋亡，而在正常细胞中显示出很少的细胞毒性。尽管TRAIL和针对DR4和DR5的激动抗体被认为是安全且有希望的癌症治疗候选药物，但许多恶性细胞对dr介导的TRAIL诱导的细胞凋亡具有耐药性。在目前的工作中，我们筛选了55种FDA和国外批准的抗肿瘤药物，以确定使耐药前列腺和胰腺癌细胞对trail诱导的凋亡敏感的候选药物。fda批准的药物通过MTT细胞活力测定法筛选其使TRAIL耐药前列腺癌细胞对TRAIL敏感的能力。方差分析用于鉴定与TRAIL具有协同作用的药物。选择具有最高协同作用的药物作为先导，在不同的前列腺癌和胰腺癌细胞系以及一种永生化的人胰腺上皮细胞系中进行了试验。研究了顺序和同步给药方式，并采用膜联蛋白V/碘化丙啶测定法，结合荧光显微镜，观察细胞凋亡过程。14种药物被确定为与TRAIL有协同作用，包括那些在前列腺或胰腺癌细胞或两者中TRAIL致敏活性未知的药物。在其他癌细胞系中测试了五种铅，其中阿霉素、米托蒽醌和米霉素在所有细胞系中都表现出协同作用。特别是，米托蒽醌和米霉素与TRAIL表现出显著的协同作用，并导致浓度低于1 μM时癌细胞活力降低。在这种低浓度下，米托蒽醌对恶性细胞的选择性优于正常胰腺上皮细胞。一些fda批准的TRAIL增敏剂的鉴定可以扩大前列腺癌和胰腺癌疾病联合治疗的化疗选择。
Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward malignant cells over normal pancreatic epithelial cells. The identification of a number of FDA-approved drugs as TRAIL sensitizers can expand chemotherapeutic options for combination treatments in prostate and pancreatic cancer diseases.
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影响因子：
2.7
作者：
Meinhold-Heerlein, I;Borges-Engeby, K;Bauknecht, T
通讯作者：
Bauknecht, T
影响因子：
3.8
作者：
El-Zawahry A;McKillop J;Voelkel-Johnson C
通讯作者：
Voelkel-Johnson C
影响因子：
11.2
作者：
Bai, JR;Sui, JH;Callery, MP
通讯作者：
Callery, MP
影响因子：
9.7
作者：
Barua, Sutapa;Linton, Rebecca S.;Rege, Kaushal
通讯作者：
Rege, Kaushal
影响因子：
3.6
作者：
Kelly, MM;Hoel, BD;Voelkel-Johnson, C
通讯作者：
Voelkel-Johnson, C