Cancer Institute, The Second Affiliated Hospital, ZJU-UCLA Joint Center for Medical Education and Research, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China.
Biomed Pharmacother. 2021 Jun;138:111501. doi: 10.1016/j.biopha.2021.111501. Epub 2021 Mar 23.
Martynoside (MAR) is a bioactive glycoside of Rehmannia glutinosa, a traditional Chinese herb frequently prescribed for treating chemotherapy-induced pancytopenia. Despite its clinical usage in China for thousands of years, the mechanism of MAR's hematopoietic activity and its impact on chemotherapy-induced antitumor activity are still unclear. Here, we showed that MAR protected ex vivo bone marrow cells from 5-fluorouracil (5-FU)-induced cell death and inflammation response by down-regulating the TNF signaling pathway, in which II1b was the most regulatory gene. Besides, using mouse models with melanoma and colon cancer, we further demonstrated that MAR had protective effects against 5-FU-induced myelosuppression in mice without compromising its antitumor activity. Our results showed that MAR increased the number of bone marrow nucleated cells (BMNCs) and the percentage of leukocyte and granulocytic populations in 5-FU-induced myelosuppressive mice, accompanied by an increase in numbers of circulating white blood cells and platelets. The transcriptome profile of BMNCs further showed that the mode of action of MAR might be associated with the increased survival of BMNCs and the improvement of the bone marrow microenvironment. In summary, we revealed the potential molecular mechanism of MAR to counteract 5-FU-induced bone marrow cytotoxicity both ex vivo and in vivo, and highlighted its potential clinical usage in cancer patients experiencing chemotherapy-induced multi-lineage myelosuppression.
马丁苷（MAR）是一种来源于地黄的生物活性糖苷，地黄是一种传统的中药，常用于治疗化疗引起的全血细胞减少症。尽管在中国临床应用已有数千年，但 MAR 的造血活性机制及其对化疗诱导的抗肿瘤活性的影响仍不清楚。在这里，我们表明 MAR 通过下调 TNF 信号通路，保护体外骨髓细胞免受 5-氟尿嘧啶（5-FU）诱导的细胞死亡和炎症反应，其中 II1b 是最具调节作用的基因。此外，使用黑色素瘤和结肠癌的小鼠模型，我们进一步证明 MAR 对 5-FU 诱导的骨髓抑制具有保护作用，而不影响其抗肿瘤活性。我们的结果表明，MAR 增加了骨髓有核细胞（BMNCs）的数量和白细胞及粒细胞群体的百分比，在 5-FU 诱导的骨髓抑制小鼠中，循环白细胞和血小板的数量也增加了。BMNCs 的转录组谱进一步表明，MAR 的作用模式可能与 BMNCs 的存活增加和骨髓微环境的改善有关。总之，我们揭示了 MAR 对抗 5-FU 诱导的骨髓细胞毒性的潜在分子机制，无论是在体外还是体内，并强调了其在癌症患者化疗引起的多谱系骨髓抑制中的潜在临床应用。
