Increasing efficacy of antineoplastic drugs with gap junction enhancers

描述（由申请人提供）：乳腺癌是全球女性中最常见的癌症，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，疾病的无限制进展是不可避免的。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，随后需要替代性全身治疗。因此，针对乳腺肿瘤细胞的累加效应可以通过组合针对癌症中一种或多种改变的机制的抗肿瘤剂来实现。 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与药物敏感性和致瘤性的降低有关。癌症患者通常同时使用止痛药和抗抑郁药。最近，He et al.（2009）显示曲马多和氟比洛芬通过其缝隙连接抑制作用抑制顺铂的细胞毒性。因此，增加肿瘤细胞中的间隙连接活性或增强GJIC提供了增强肿瘤治疗的靶点。已经报道了几种GJIC增强剂;然而，目前还没有有效的靶向间隙连接的临床药物。最近，我们合成了一类新的取代喹啉（代号：PQ），并发现它们通过增强GJIC对T47 D乳腺癌细胞具有有效的抑制活性（PQ 11的IC 50值为16 nM，PQ 1为119 nM）。我们的数据表明，PQ 1显着增加间隙连接活性，抑制细胞活力和T47 D乳腺癌细胞的集落生长。此外，PQ 1和PQ 11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。PQ 1对正常的原代乳腺上皮细胞无影响。该提案将讨论间隙连接增强子（PQ）对三苯氧胺、紫杉醇和顺铂等抗肿瘤药物疗效的影响。因此，该提议的主要假设是间隙连接增强子（PQ）可以1）增加抗肿瘤药物的功效和2）减弱肿瘤生长。具体的目的是检查乳腺癌细胞中的抗肿瘤药物和间隙连接增强子的组合研究的效果，并确定在动物模型中存在间隙连接增强子的情况下抗肿瘤药物的疗效。 公共卫生相关性：癌症患者最初对三苯氧胺、帕唑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，随后需要替代性全身治疗。因此，针对乳腺肿瘤细胞的累加效应可以通过组合针对癌症中一种或多种改变的机制的抗肿瘤剂来实现。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中间隙连接细胞间通讯的方法。我们的目标是通过一种新的间隙连接增强子来增加细胞通讯，从而提高目前的抗肿瘤药物的疗效。

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.