methimazole and Melanoma

To evaluate whether (a) Wnt5a expression in pancreatic cancer and malignant melanoma cells might be associated with constitutive levels of Toll-like receptor 3 (TLR3) and/or TLR3 signaling; (b) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a and TLR3 levels together with cell growth and migration; and (c) the efficacy of C10 as a potential inhibitor of pancreatic cancer and malignant melanoma cell growth in vivo.. We used a variety of molecular biology techniques including but not limited to PCR, Western blotting, and ELISA to evaluate the presence of constitutively activated TLR3/Wnt5a expression and signaling. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based technology and scratch assays were used to evaluate inhibition of cell growth and migration, respectively. TLR3 regulation of cell growth was confirmed using small interfering RNA technology. Nude and severe combined immunodeficient mice were implanted with human pancreatic cancer and/or melanoma cells and the effects of C10 on tumor growth were evaluated.. We show that constitutive TLR3 expression is associated with constitutive Wnt5a in human pancreatic cancer and malignant melanoma cell lines, that C10 can decrease constitutive TLR3/Wnt5a expression and signaling, suggesting that they are interrelated signal systems, and that C10 inhibits growth and migration in both of these cancer cell lines. We also report that C10 is effective at inhibiting human pancreatic cancer and malignant melanoma tumor growth in vivo in nude or severe combined immunodeficient mice and associate this with inhibition of signal transducers and activators of transcription 3 activation.. C10 may have potential therapeutic applicability in pancreatic cancer and malignant melanoma.

Topics: Animals; Antithyroid Agents; Cell Line, Tumor; Chemokine CXCL10; Gene Knockdown Techniques; Humans; Interferon-beta; Interleukin-6; Melanoma; Methimazole; Mice; Mice, Nude; Mice, SCID; Pancreatic Neoplasms; Proto-Oncogene Proteins; RNA, Small Interfering; Signal Transduction; Skin Neoplasms; STAT3 Transcription Factor; Thiones; Toll-Like Receptor 3; Wnt Proteins; Wnt-5a Protein

Thiocarbamides were converted to their di-N-pentafluorobenzyl (PFB) derivatives and analysed by gas chromatography/negative-ion chemical-ionization mass spectrometry with methane as reagent gas. The PFB derivatives of the 2-thiouracils gave mass spectra in which the ion current was carried largely by an ion arising from [M-PFB]-. The derivative was used in the determination of the uptake and metabolism of thiocarbamides by cultures of melanoma cells.

Topics: Gas Chromatography-Mass Spectrometry; Melanoma; Methimazole; Methylthiouracil; Propylthiouracil; Thiouracil; Tumor Cells, Cultured

Melanotic melanomas show a high rate of melanin synthesis. Foreign substances that are accepted as precursors in the formation of melanin may therefore be useful in the diagnosis and therapy of malignant melanotic melanomas, if labelled with suitable radionuclides. We have earlier reported that 2-thiouracil is incorporated in melanotic melanomas, apparently as a false melanin precursor. In the present study it is shown that methimazole and 5-iodo-2-thiouracil are as well accepted as melanin precursors. 5-Iodo-2-thiouracil is of special interest, since iodine has many clinically useful radioisotopes. The chemical properties that characterize substances which are incorporated as false precursors into melanin are discussed. A free sulfur ligand of the thioamides (2-thiouracil, 5-iodo-2-thiouracil, methimazole and thiourea are all incorporated into melanin) seems to be essential and the link between these substances and the melanin. Uracil (which lacks sulfur) and 2-benzylthiouracil (where the sulfur is blocked with a benzyl group) do not attach to melanin. Our conclusion therefore is that the thioureylene structure is the smallest common molecular fragment of the false melanin precursors.

Topics: Amides; Animals; Autoradiography; Eye; Liver; Melanins; Melanoma; Methimazole; Mice; Mice, Inbred DBA; Neoplasm Transplantation; Neoplasms, Experimental; Thioamides