Abstract 4397: Bioavailability of substituted quinoline, a gap junction enhancer

Abstract

Abstract Breast cancer is one of the most malignant diseases that threaten the health of women all over the world, especially in western countries. It ranks the second leading cause of cancer deaths among women in the United States. Several drugs have been discovered to target different pathways of breast cancer cells; however, drug resistance and side effects have increasingly become a major concern. One of the effective methods is combinational treatment of different drugs. Loss of gap junctional intercellular communication (GJIC) is thought as one of the important hallmarks of cancer. It is believed that restoration of GJIC in cancer cells is related to reduction of tumorigenesis and increase of drug sensitivity. Gap junctions are intercellular channels connecting adjacent cells, allowing cells to transport small molecules (< 1.2kDa) from one cell to the next. This ordination of communication keeps cells at homeostasis. Previous report showed that combinational treatment of substituted quinoline (PQ1, a gap junction enhancer) and tamoxifen (a common used chemotherapeutic agent for breast cancers) can lower the concentration of tamoxifen in T47D breast cancer cells. It was also reported that PQ1 could increase 70% GJIC in T47D cells, whereas had no effect on GJIC in normal human mammary epithelial cells (HMECs) in vitro. However, the toxicity of PQ1 in vivo is still unknown. In this study, bioavailability of PQ1 was studied in mice. Twenty-five micrograms/kg body weight of PQ1 was administered orally to 5 week old mice. After 1, 12, or 24 hours of treatment, mice were sacrificed, and amounts of PQ1 in different organs were tested by HPLC and mass spectrometry. Expressions of connexin 43 and different protein markers (survivin, caspase-8, cleaved caspase-3, and aryl hydrocarbon receptor (AhR)) in organs were tested by western blot analysis. Hematoxylin and eosin staining was performed. Our results showed that compared to control, the expression of Cx43 in normal organs of the mice treated with PQ1 decreased, which is contrary to the effect of PQ1 on cancer cells. We also found that PQ1 can increase the expression of survivin and decrease the expression of caspase-8 and cleaved caspase-3 in nearly all the tested organs. Expression of AhR in liver was directly related with PQ1 amount, which means PQ1 is mediated through AhR and can be metabolized by liver. Histological results of the liver implied that PQ1 is not toxic to the tissue structure. Our studies demonstrate that PQ1 is a promising anti-cancer drug as well as in combinational treatment with other antineoplastic drugs with high specificity to cancer cells and low toxicity to normal organs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4397. doi:10.1158/1538-7445.AM2011-4397