Increasing efficacy of antineoplastic drugs with gap junction enhancers

使用间隙连接增强剂提高抗肿瘤药物的疗效

基本信息

批准号：
7980948
负责人：
THU ANNELISE NGUYEN
金额：
$ 37万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7980948
关键词：
ADME Study Ablation Address Adverse effects Analgesics Animal Model Antineoplastic Agents Attenuated Biological Availability Breast Breast Cancer Cell Cancer Patient Cell Communication Cell Proliferation Cell Survival Cells Cisplatin Clinical Code Connexins Data Defect Depressed mood Disease Disease Progression Drug Delivery Systems EGF gene Enhancers Epithelial Estrogen Therapy Estrogens Exhibits Fibroblast Growth Factor Flurbiprofen Gap Junctions Goals Growth Growth Factor Homeostasis Hormones Inhibitory Concentration 50 Intercellular Junctions Ions Link Longevity Maintenance Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Metabolism Molecular Weight Mus Names Neoplasm Metastasis Normal Cell Nude Mice Paclitaxel Phosphorylation Protein Kinase C Proteins Reporting Resistance Signal Transduction Surface Systemic Therapy T47D Tamoxifen Time Tissues Toxic effect Tramadol Tumorigenicity Woman Xenograft procedure absorption animal tissue anticancer activity antitumor agent cancer cell carcinogenesis cell growth regulation chemotherapy cytotoxicity dalton drug sensitivity extracellular gap junction channel improved intercellular communication malignant breast neoplasm mortality neoplastic cell novel public health relevance quinoline small molecule trafficking tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the most common cancer in women worldwide and mortality from breast cancer is consistent due to tumor metastasis. Breast cancer patients initially respond to estrogen ablation therapy, but estrogen-independent cells almost always aggressively emerge. The disease eventually progresses to estrogen-independent breast cancer. Tumor is no longer responsive to estrogen ablation therapy and unrestrained progression of the disease is inevitable. Furthermore, cancer patients initially respond to antineoplastic drugs such paxlitaxol and cisplatin but they gradually acquire resistance to the treatment and subsequently require alternative systemic therapies. Thus, the additive effects against mammary tumor cells might achieved by combining antitumor agents directed against one or more altered mechanisms in cancer. Most normal cells have functional gap junctional intercellular communication (GJIC), while most, if not all, tumors cells have dysfunctional GJIC. It is believed that restoring GJIC is linked to drug sensitivity and reduction of tumorigenicity. Cancer patients are often treated concurrently with analgesics and antineoplastic drugs. Recently, He et al. (2009) showed that tramadol and flurbiprofen depress the cytotoxicity of cisplatin through their effects of gap junction inhibition. Thus, increasing gap junction activity or enhancing GJIC in tumor cells provides the targets to enhance antineoplastic therapies. Several GJIC enhancers have been reported; however, an effective clinical drug targeting gap junction is not available at this time. Recently, we synthesized a new class of substituted quinolines (code name: PQ) and found that they possess potent inhibitory activities against T47D breast cancer cells (IC50 value of PQ11 is 16 nM and PQ1 is 119 nM) through the enhancement of GJIC. Our data showed that PQ1 significantly increases gap junction activity and inhibits cell viability and colony growth of T47D breast cancer cells. Moreover, PQ1 and PQ11 decrease 71% and 100%, respectively, of xenograft breast tumors and prolong the lifespan of cancer bearing mice. PQ1 has no effect on normal primary epithelial mammary cells. This proposal will address the effect of gap junction enhancers (PQs) on the efficacy of antineoplastic drugs such as tamoxifen, paclitaxel and cisplatin. Thus, the principle hypothesis of this proposal is that gap junction enhancers (PQs) can 1) increase the efficacy of antineoplastic drugs and 2) attenuate tumor growth. The specific aims are to examine the effect of combinational studies of antineoplastic drugs and gap junction enhancers in breast cancer cells and determine the efficacy of antineoplastic drugs in the presence of gap junction enhancers in animal models. PUBLIC HEALTH RELEVANCE: Cancer patients initially respond to antineoplastic drugs such tamoxifen, paxlitaxol and cisplatin; however, they gradually acquire resistance to the treatment and subsequently require alternative systemic therapies. Thus, the additive effects against mammary tumor cells might achieved by combining antitumor agents directed against one or more altered mechanisms in cancer. The loss of cell communication is a feature of cancer cells, and one approach to the treatment of breast and other cancers is to find ways to improve gap junctional intercellular communication in cancer cells. Our goal is to increase efficacy of the current antineoplastic drugs via increasing of cell communication by a novel gap junction enhancer.

描述（由申请人提供）：乳腺癌是全世界女性最常见的癌症，由于肿瘤转移，乳腺癌的死亡率是一致的。乳腺癌患者最初对雌激素消融疗法有反应，但雌激素非依赖性细胞几乎总是积极地出现。该疾病最终发展为不依赖雌激素的乳腺癌。肿瘤不再对雌激素消融治疗有反应，并且疾病的不受限制的进展是不可避免的。此外，癌症患者最初对紫杉醇和顺铂等抗肿瘤药物有反应，但他们逐渐对治疗产生耐药性，随后需要替代的全身治疗。因此，通过联合针对一种或多种癌症改变机制的抗肿瘤剂，可以实现针对乳腺肿瘤细胞的附加效应。大多数正常细胞具有功能性间隙连接细胞间通讯 (GJIC)，而大多数（如果不是全部）肿瘤细胞具有功能失调的 GJIC。据信恢复 GJIC 与药物敏感性和降低致瘤性有关。癌症患者通常同时使用镇痛药和抗肿瘤药进行治疗。最近，何等人。 (2009)表明曲马多和氟比洛芬通过间隙连接抑制作用来抑制顺铂的细胞毒性。因此，增加间隙连接活性或增强肿瘤细胞中的GJIC提供了增强抗肿瘤治疗的靶标。已报道了几种 GJIC 增强剂；然而，目前临床上尚无针对间隙连接的有效药物。最近，我们合成了一类新的取代喹啉（代号：PQ），发现它们通过增强GJIC对T47D乳腺癌细胞具有有效的抑制活性（PQ11的IC50值为16 nM，PQ1为119 nM）。我们的数据表明，PQ1 显着增加间隙连接活性并抑制 T47D 乳腺癌细胞的细胞活力和集落生长。此外，PQ1和PQ11分别使异种移植乳腺肿瘤减少71%和100%，并延长荷癌小鼠的寿命。 PQ1对正常的原代乳腺上皮细胞没有影响。该提案将解决间隙连接增强剂（PQ）对他莫昔芬、紫杉醇和顺铂等抗肿瘤药物疗效的影响。因此，该提案的主要假设是间隙连接增强剂（PQ）可以1）提高抗肿瘤药物的功效，2）减弱肿瘤的生长。具体目的是检查抗肿瘤药物和间隙连接增强剂的联合研究在乳腺癌细胞中的效果，并确定在动物模型中存在间隙连接增强剂的情况下抗肿瘤药物的功效。公共卫生相关性：癌症患者最初对他莫昔芬、紫杉醇和顺铂等抗肿瘤药物有反应；然而，他们逐渐对治疗产生耐药性，随后需要替代的全身疗法。因此，通过联合针对一种或多种癌症改变机制的抗肿瘤剂，可以实现针对乳腺肿瘤细胞的附加效应。细胞通讯的丧失是癌细胞的一个特征，治疗乳腺癌和其他癌症的一种方法是找到改善癌细胞间隙连接细胞间通讯的方法。我们的目标是通过新型间隙连接增强剂增加细胞通讯来提高当前抗肿瘤药物的功效。