Matsushita Shigeto, Tada Ko-Ichi, Kawahara Ko-Ichi, Kawai Kazuhiro, Hashiguchi Teruto, Maruyama Ikuro, Kanekura Takuro
Department of Dermatology, Field of Sensory Organology, and.
Exp Ther Med. 2010 Jul;1(4):569-574. doi: 10.3892/etm_00000089. Epub 2010 Jul 1.
Malignant melanoma (MM) is an aggressive chemoresistant skin cancer characterized by rapid metastasis and a poor prognosis. Therefore, the development of innovative effective therapies is critical. MK615 is an extract from the Japanese apricot Prunus mume Sieb. Et Zucc (Ume). At a neutral pH, it contains natural chemical substances such as triterpenoids that exert anti-neoplastic effects in several types of cancers. We found that in patients with advanced MM, MK615 dramatically suppressed the cutaneous in-transit metastasis of the disease. Pre- and post-treatment comparison of tumors showed that the apoptotic index was significantly increased by MK615. In vitro studies, MTT assay, flow cytometric cell cycle analysis and immunofluorescence microscopy revealed that MK615 inhibited the growth of SK-MEL28 cells in a dose-dependent manner, increased the proportion of cells in sub-G1 phase and induced apoptosis. We further examined the expression of the receptor for advanced glycation end products (RAGE). RAGE is a multi-ligand receptor that binds to a novel cytokine, high mobility group box protein 1 (HMGB1), as well as advanced glycation end products. There is evidence that RAGE/HMGB1 interactions enhance cell invasion in MM. Here, we present Western blotting and immunofluorescence microscopy data indicating that MK615 inhibited the expression of RAGE in SK-MEL28 cells, and suppressed the release of HMGB1 by SK-MEL28 cells. Our findings suggest that MK615 may be a valuable tool for treating MM and other malignant tumors.
恶性黑色素瘤（MM）是一种侵袭性的化疗耐药性皮肤癌，其特征为快速转移且预后不良。因此，开发创新有效的治疗方法至关重要。MK615是从日本杏梅（Prunus mume Sieb. Et Zucc，即乌梅）中提取的提取物。在中性pH值下，它含有三萜类等天然化学物质，这些物质在几种类型的癌症中发挥抗肿瘤作用。我们发现，在晚期MM患者中，MK615显著抑制了该疾病的皮肤移行转移。肿瘤治疗前后的比较显示，MK615显著提高了凋亡指数。在体外研究中，MTT法、流式细胞术细胞周期分析和免疫荧光显微镜检查显示，MK615以剂量依赖性方式抑制SK-MEL28细胞的生长，增加亚G1期细胞的比例并诱导凋亡。我们进一步检测了晚期糖基化终末产物受体（RAGE）的表达。RAGE是一种多配体受体，可与一种新型细胞因子——高迁移率族蛋白B1（HMGB1）以及晚期糖基化终末产物结合。有证据表明，RAGE/HMGB1相互作用增强了MM中的细胞侵袭。在此，我们展示了蛋白质印迹法和免疫荧光显微镜检查数据，表明MK615抑制了SK-MEL28细胞中RAGE的表达，并抑制了SK-MEL28细胞释放HMGB1。我们的研究结果表明，MK615可能是治疗MM和其他恶性肿瘤的一种有价值的工具。
