Increasing efficacy of antineoplastic drugs with gap junction enhancers

描述(申请人提供)：乳腺癌是世界上最常见的女性癌症，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治疗有反应，但雌激素非依赖性细胞几乎总是积极出现。这种疾病最终会发展为雌激素非依赖性乳腺癌。肿瘤对雌激素消融治疗不再有反应，疾病的无节制发展是不可避免的。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抗药性，随后需要替代系统治疗。因此，针对癌症中的一个或多个改变的机制联合使用抗肿瘤药物可能实现对乳腺肿瘤细胞的相加作用。大多数正常细胞具有功能性缝隙连接细胞间通讯(GJIC)，而大多数(如果不是全部)肿瘤细胞具有功能失调的GJIC。据认为，恢复GJIC与药物敏感性和降低致瘤性有关。癌症患者经常同时服用止痛药和抗肿瘤药物。最近，他等人。(2009)发现曲马多和氟比洛芬通过抑制缝隙连接抑制顺铂的细胞毒性。因此，增加肿瘤细胞的缝隙连接活性或增强GJIC为加强抗肿瘤治疗提供了靶点。已经报道了几种GJIC增强剂；然而，目前还没有一种有效的针对缝隙连接的临床药物。最近，我们合成了一类新的取代喹啉类化合物(代号：PQ)，通过增强GJIC发现它们对T47D乳腺癌细胞具有很强的抑制活性(PQ11的IC50值为16 nM，PQ1的IC50值为119 nM)。我们的数据显示，PQ1显著增加了T47D乳腺癌细胞的缝隙连接活性，抑制了细胞活力和集落生长。此外，PQ1和PQ11分别减少了异种乳腺肿瘤的71%和100%，并延长了荷瘤小鼠的寿命。PQ1对正常乳腺原代上皮细胞无影响。这项提案将讨论缝隙连接增强剂(PQs)对他莫昔芬、紫杉醇和顺铂等抗肿瘤药物疗效的影响。因此，这一建议的基本假设是，缝隙连接增强剂(PQs)可以1)提高抗肿瘤药物的疗效，2)抑制肿瘤生长。其具体目的是检验抗肿瘤药物和缝隙连接增强剂在乳腺癌细胞中的联合研究的效果，并在动物模型中确定存在缝隙连接增强剂的抗肿瘤药物的疗效。 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抗药性，随后需要替代系统疗法。因此，针对癌症中的一个或多个改变的机制联合使用抗肿瘤药物可能实现对乳腺肿瘤细胞的相加作用。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寻找方法来改善癌细胞的缝隙连接通讯。我们的目标是通过一种新型的缝隙连接增强剂增加细胞通讯来提高现有抗肿瘤药物的疗效。

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.