Dai Jian, Miller Matthew A, Everetts Nicholas J, Wang Xia, Li Peng, Li Ye, Xu Jian-Hua, Yao Guang
Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, USA.
Jiangsu Academy of Agricultural sciences, Nanjing, Jiangsu, China.
Oncotarget. 2017 Feb 21;8(8):13770-13781. doi: 10.18632/oncotarget.14634.
The medical mushroom Ganoderma lucidum has long been used in traditional Chinese medicine and shown effective in the treatment of many diseases including cancer. Here we studied the cytotoxic effects of two natural compounds purified from Ganoderma lucidum, ergosterol peroxide and ganodermanondiol. We found that these two compounds exhibited cytotoxicity not only against fast proliferating cells, but on quiescent, slow-cycling cells. Using a fibroblast cell-quiescence model, we found that the cytotoxicity on quiescent cells was due to induced apoptosis, and was associated with a shallower quiescent state in compound-treated cells, resultant from the increased basal activity of an Rb-E2F bistable switch that controls quiescence exit. Accordingly, we showed that quiescent breast cancer cells (MCF7), compared to its non-transformed counterpart (MCF10A), were preferentially killed by ergosterol peroxide and ganodermanondiol treatment presumably due to their already less stable quiescent state. The cytotoxic effect of natural Ganoderma lucidum compounds against quiescent cells, preferentially on quiescent cancer cells vs. non-cancer cells, may help future antitumor development against the slow-cycling cancer cell subpopulations including cancer stem and progenitor cells.
药用真菌灵芝长期以来一直用于传统中药，并已证明对包括癌症在内的多种疾病具有治疗效果。在此，我们研究了从灵芝中纯化得到的两种天然化合物——过氧化麦角甾醇和灵芝二醇的细胞毒性作用。我们发现这两种化合物不仅对快速增殖细胞具有细胞毒性，对静止、慢循环细胞也有作用。利用成纤维细胞静止模型，我们发现对静止细胞的细胞毒性是由诱导凋亡所致，并且与化合物处理细胞中较浅的静止状态相关，这是由于控制静止退出的Rb-E2F双稳态开关的基础活性增加所致。因此，我们表明，与未转化的对应细胞（MCF10A）相比，静止的乳腺癌细胞（MCF7）经过氧化麦角甾醇和灵芝二醇处理后优先被杀死，这可能是因为它们的静止状态已经不太稳定。天然灵芝化合物对静止细胞的细胞毒性作用，优先针对静止癌细胞而非非癌细胞，这可能有助于未来针对包括癌症干细胞和祖细胞在内的慢循环癌细胞亚群的抗肿瘤开发。
