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.
Highlights
We 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
The influence of 1,4-DMP on the onset and metastasis of spontaneously formed prostate tumors To establish whether 1,4-DMP might prevent the development of prostate tumors, the compound was continuously given to male TRAMP mice that during their life span spontaneously develop mild intraepithelial hyperplasia to malignant neoplasia within prostate gland
Histopathological analysis demonstrated that metastases in TRAMP mice prostate adenocarcinomas were developed in lymph nodes, lungs, liver and kidneys (Fig. 1d)
Summary
We 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. We aimed to investigate whether the previously observed activity of pyridine compounds pertains to the prevention and the treatment of metastatic prostate tumors, in a combined chemotherapy with docetaxel. While the risk of developing prostate cancer might be beneficially influenced by proper diet and physical activity [2], there are no confirmed pharmacological means for the prevention of these types of tumors. The majority of prostate cancer cases are diagnosed at the localized stage enabling effective treatment; a significant fraction of patients develops. Initial treatment of prostate cancer usually comprises hormone therapy; when tumors are irresponsive to hormonal treatment (i.e., in case of castrateresistant prostate cancer), the most common first-line treatment includes the simultaneous use of docetaxel and prednisone. It was shown to inhibit cell proliferation and induce apoptosis in prostate cancer
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