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.
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.
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