Katsuhiko Warita

Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, an antiplatelet agent, is known to inhibit SREBP2 upregulation. We aimed to demonstrate the efficacy of statin–dipyridamole combination treatment in both human and spontaneously occurring canine melanoma cell lines. The half maximal inhibitory concentration (IC50) of atorvastatin showed a 68–92% reduction when combined with dipyridamole, compared with that of atorvastatin alone. In some melanoma cell lines, cell proliferation was suppressed to almost zero by the combination treatment (≥3 μM atorvastatin). Finally, the BRAF inhibitor, vemurafenib, further potentiated the effects of the combined statin–dipyridamole treatment in BRAF V600E mutation-bearing human melanoma cell lines. In conclusion, the inexpensive and frequently prescribed statin–dipyridamole combination therapy may lead to new developments in the treatment of melanoma and may potentiate the effects of vemurafenib for the targeted therapy of BRAF V600E-mutation bearing melanoma patients. The concordance between the data from canine and human melanoma cell lines reinforces this possibility.

Chondroitin sulfate/dermatan sulfate (CS/DS) is a member of glycosaminoglycans (GAGs) found in animal tissues. Major CS/DS subclasses, O, A, C, D, and E units, exist based on the sulfation pattern in d ‐glucuronic acid (GlcA) and N ‐acetyl‐ d ‐galactosamine repeating units. DS is formed when GlcA is epimerized into l ‐iduronic acid. Our study aimed to analyze the CS/DS profile in 3T3‐L1 cells before and after adipogenic induction. CS/DS contents, molecular weight (Mw), and sulfation pattern were analyzed by using high‐performance liquid chromatography. CS/DS synthesis‐ and sulfotransferase‐related genes were analyzed by reverse transcription real‐time PCR. CS/DS amount was significantly decreased in the differentiated (DI) group compared to the non‐differentiated (ND) group, along with a lower expression of CS biosynthesis‐related genes, chondroitin sulfate N ‐acetylgalactosaminyltransferase 1 and 2, as well as chondroitin polymerizing factor. GAGs in the DI group also showed lower Mw than those of ND. Furthermore, the A unit was the major CS/DS in both groups, with a proportionally higher CS‐A in the DI group. This was consistent with the expression of carbohydrate sulfotransferase 12 that encodes chondroitin 4‐ O ‐sulfotransferase, for CS‐A formation. These qualitative and quantitative changes in CS/DS and CS/DS‐synthases before and after adipocyte differentiation reveal valuable insights into adipocyte development.