Endothelium and cancer metastasis: Perspectives for antimetastatic therapy

Błażejczyk, Agnieszka; Papiernik, Diana; Porshneva, Kseniia; Sadowska, Joanna; Wietrzyk, Joanna

doi:10.1016/j.pharep.2015.05.014

Cited by 51 publications

(37 citation statements)

References 102 publications

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“…Platelets, in turn, contribute to metastases formation by several mechanisms as comprehensively reviewed in the literature [45, 46]. To confirm that increased anticancer efficacy of docetaxel observed when cytotoxic drug was given with 1,4-DMP was associated with diminished platelets activity, we have analyzed morphological and biochemical parameters reflecting platelet activation status.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…PCD induced by AGR2 could also explain the absence of CD104 + basal epithelial cells in prostate tumor glands [32], which is a diagnostic criterion for prostate cancer. Additionally, cancer-secreted AGR2 could facilitate tumor spread by inducing PCD in endothelial cells of the vessel lining, making blood vessels leaky to allow access by the cancer cells [33]. …”

Section: Discussionmentioning

confidence: 99%

Cancer-secreted AGR2 induces programmed cell death in normal cells

et al. 2016

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Anterior Gradient 2 (AGR2) is a protein expressed in many solid tumor types including prostate, pancreatic, breast and lung. AGR2 functions as a protein disulfide isomerase in the endoplasmic reticulum. However, AGR2 is secreted by cancer cells that overexpress this molecule. Secretion of AGR2 was also found in salamander limb regeneration. Due to its ubiquity, tumor secretion of AGR2 must serve an important role in cancer, yet its molecular function is largely unknown. This study examined the effect of cancer-secreted AGR2 on normal cells. Prostate stromal cells were cultured, and tissue digestion media containing AGR2 prepared from prostate primary cancer 10-076 CP and adenocarcinoma LuCaP 70CR xenograft were added. The control were tissue digestion media containing no AGR2 prepared from benign prostate 10-076 NP and small cell carcinoma LuCaP 145.1 xenograft. In the presence of tumor-secreted AGR2, the stromal cells were found to undergo programmed cell death (PCD) characterized by formation of cellular blebs, cell shrinkage, and DNA fragmentation as seen when the stromal cells were UV irradiated or treated by a pro-apoptotic drug. PCD could be prevented with the addition of the monoclonal AGR2-neutralizing antibody P3A5. DNA microarray analysis of LuCaP 70CR media-treated vs. LuCaP 145.1 media-treated cells showed downregulation of the gene SAT1 as a major change in cells exposed to AGR2. RT-PCR analysis confirmed the array result. SAT1 encodes spermidine/spermine N1-acetyltransferase, which maintains intracellular polyamine levels. Abnormal polyamine metabolism as a result of altered SAT1 activity has an adverse effect on cells through the induction of PCD.

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“…Thus, MMPs production increased a risk for progression of cancer because intravasation is the first step of metastasis. 46 Based on these previous reports, the injection of the RGD-MEND might also promote metastasis from a primary tumor in our strategy. However, Type 4 collagen was not changed after the RGD-MEND treatment (see Supplementary Figure S9).…”

Section: Discussionmentioning

confidence: 77%