The effects of 1,4-dimethylpyridine in metastatic prostate cancer in mice

Abstract

BackgroundWe previously showed that 1-methylnicotinamide (1-MNA) and its analog 1,4-dimethylpyridine (1,4-DMP) could inhibit the formation of lung metastases and enhance the efficacy of cyclophosphamide-based chemotherapy in the model of spontaneously metastasizing 4T1 mouse mammary gland tumors. In the present study, we aimed to investigate whether the previously observed activity of pyridine compounds pertains also to the prevention and the treatment of metastatic prostate tumors, in a combined chemotherapy with docetaxel.MethodsCancer-preventing activity of 1,4-DMP was studied in the model of prostate tumors spontaneously arising in C57BL/6-Tg (TRAMP)8247Ng/J (TRAMP) mice. The efficacy of the combined chemotherapy, comprising simultaneous use of 1,4-DMP and docetaxel, was evaluated in the orthotopic mouse model of human PC-3M-luc2 prostate cancer. The toxicity of the applied treatment was also determined.ResultsThe development of prostate tumors in TRAMP mice remained unaffected after administration of 1,4-DMP. Similarly, no effect of 1,4-DMP was found on the growth of orthotopically transplanted PC-3M-luc2 tumors. However, when 1,4-DMP was administered along with docetaxel, it enhanced the anticancer activity of the chemotherapy. As a result, in PC-3M-luc2-bearing mice statistically significant inhibition of the tumor growth and lower metastases incidence were observed. The decreased metastatic yield is probably related to the diminished platelet activity observed in mice treated with combined therapeutic regimen. Finally, the combined treatment exhibited lowered side effects accompanying docetaxel administration.ConclusionsResults presented herein confirm previously published data on the anticancer activity of pyridine compounds and demonstrate that 1,4-DMP may be beneficially implemented into chemotherapy utilizing various cytotoxic agents, directed against multiple metastatic tumor types.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3161-4) contains supplementary material, which is available to authorized users.

Dynamic CTC phenotypes in metastatic prostate cancer models visualized using magnetic ranking cytometry

“…The second theory is backed by a body of research showing that EpCAM is downregulated in prostate cancer cells under docetaxel treatment 38 . Following the decreased cell heterogeneity, treated mice exhibited a decline in metastasis incidence and survived longer which correlates with literature studies 39 . After the third dose of docetaxel, a much lower number of CTCs were remained which had mesenchymal phenotypes (Figure 4C).…”

Endothelial SIRT1 as a Target for the Prevention of Arterial Aging: Promises and Challenges

“…Although not affecting the NAD levels, MNA triggers prostacyclin (PGI2)-mediated antithrombotic, 290,291 antiinflammatory, 292 gastroprotective, 293 hepatoprotective, 294,295 and neuroprotective activity, 296,297 as well as antimetastatic effects. 298,299 The antiatherosclerotic activity of MNA is associated with an improvement in PGI2-and NO-dependent endothelial function. 300 Administration of MNA improves endothelial dysfunction in aorta of apolipoprotein E-or lowdensity lipoprotein receptor-deficient mice.…”