Effect of anti-breast cancer agent , PQ 1 , on normal tissues

8 Gap junctions are intercellular channels connecting adjacent cells, allowing cells to transport 9 small molecules. Loss of gap junctional intercellular communication (GJIC) is one of the 10 important hallmarks of cancer. Restoration of GJIC is related to the reduction of tumorigenesis 11 and increase of drug sensitivity. Previous reports showed that PQ1, a quinoline derivative, 12 increases GJIC in T47D breast cancer cells, and subsequently attenuates xenograft breast tumor 13 growth. Combinational treatment of PQ1 and tamoxifen can lower the effective dose of 14 tamoxifen in cancer cells. In this study, effects of PQ1 were examined in normal C57BL/6J mice, 15 evaluating the distribution, toxicity and adverse effects. Distribution of PQ1 was quantified by 16 HPLC and mass spectrometry. Expressions of survivin, caspase-8, cleaved caspase-3, aryl 17 hydrocarbon receptor (AhR), and gap junction protein, connexin 43 (Cx43), were measured 18 using Western blot analysis. Our results showed that PQ1 absorbed and distributed to all tested 19 organs in 1 hour and the level of PQ1 diminished after 24 hours. PQ1 increased the expression of 20 survivin, whereas decreased the expression of caspase-8 and active caspase-3 in vital organs. 21 Furthermore, expression of AhR increased in the presence of PQ1, suggesting that PQ1 may be 22 involved in AhR-mediated response. Expression of Cx43 decreased after PQ1 treatment, which 23 is contrary to the effect of PQ1 on cancer cells. Hemotoxylin and eosin staining of the tissues 24 showed no histological change between treated and untreated organs (after 1 h or 24 h?). Our 25 studies indicate that PQ1 administration by oral gavage can be achieved with low toxicity to 26 normal vital organs. 27