Dr Myko San-Health from Mushrooms Co., Miramarska cesta 109, HR-10000 Zagreb, Croatia.
Divison of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, HR-10000 Zagreb, Croatia.
Molecules. 2020 Oct 28;25(21):5005. doi: 10.3390/molecules25215005.
Due to frequent drug resistance and/or unwanted side-effects during conventional and targeted cancer treatments, development of multi-target therapies is an important research field. Medicinal mushrooms' isolated specific compounds and mushroom extracts have been already proven as non-toxic multi-target inhibitors of specific oncogenic pathways, as well as potent immunomodulators. However, research on antitumor effects of multiple-species extract mixtures was limited so far. The aim of this study was therefore, a study of medicinal mushroom preparations AGARIKON.1 and AGARIKON PLUS on colorectal cell lines in vitro and colorectal mice model in vivo. We found a significant antiproliferative and pro-apoptotic effect of tested medicinal mushroom preparations on colorectal (HCT-116, SW620) tumor cell lines, while the effect on human fibroblast cell line (WI-38) was proliferative emphasizing a specificity towards tumor cell lines. We further investigated the effect of the medicinal mushroom preparations AGARIKON.1 and AGARIKON PLUS in various combinations with conventional cytostatic drug 5-fluorouracil in the advanced metastatic colorectal cancer mouse model CT26.WT. AGARIKON.1 and AGARIKON PLUS exhibited immunostimulatory and antiangiogenic properties in vivo which resulted in significantly increased survival and reduction in tumor volume. The antitumor effects of AGARIKON.1 and AGARIKON PLUS, with or without 5-fluorouracil, are based on M1 macrophage polarization enhancement, inhibition of M2 and tumor-associated macrophage (TAM) polarization, effects on T helper cell Th1/Th2/Th17 cytokine profiles, direct inhibition of CT26.WT tumor growth, inhibition of vascular endothelial growth factors (VEGF) and metalloproteinases 2 and 9 (MMP-2 and MMP-9) modulation. The administration of AGARIKON.1 and AGARIKON PLUS did not show genotoxic effect. This data provides good basis for an expanded translational study.
由于传统和靶向癌症治疗过程中经常出现耐药性和/或不良反应，因此开发多靶点治疗方法是一个重要的研究领域。药用蘑菇分离的特定化合物和蘑菇提取物已被证明是无毒的、针对特定致癌途径的多靶点抑制剂，也是有效的免疫调节剂。然而，迄今为止，关于多种物种提取物混合物的抗肿瘤作用的研究有限。因此，本研究的目的是研究药用蘑菇制剂 AGARIKON.1 和 AGARIKON PLUS 对体外结直肠细胞系和体内结直肠小鼠模型的作用。我们发现，测试的药用蘑菇制剂对结直肠（HCT-116、SW620）肿瘤细胞系具有显著的抗增殖和促凋亡作用，而对人成纤维细胞系（WI-38）的作用则是增殖的，这强调了其对肿瘤细胞系的特异性。我们进一步研究了药用蘑菇制剂 AGARIKON.1 和 AGARIKON PLUS 与传统细胞毒药物 5-氟尿嘧啶联合应用于晚期转移性结直肠癌 CT26.WT 小鼠模型的效果。AGARIKON.1 和 AGARIKON PLUS 在体内具有免疫刺激和抗血管生成特性，导致生存时间显著延长，肿瘤体积减小。AGARIKON.1 和 AGARIKON PLUS 与 5-氟尿嘧啶联合或不联合使用的抗肿瘤作用基于 M1 巨噬细胞极化增强、M2 和肿瘤相关巨噬细胞（TAM）极化抑制、对 Th1/Th2/Th17 辅助性 T 细胞细胞因子谱的影响、对 CT26.WT 肿瘤生长的直接抑制、对血管内皮生长因子（VEGF）和金属蛋白酶 2 和 9（MMP-2 和 MMP-9）的抑制。AGARIKON.1 和 AGARIKON PLUS 的给药未显示出遗传毒性作用。这些数据为扩大转化研究提供了良好的基础。
