Tang Da, Zhang Wei, Zou Zhenxing, Wang Yikun, Yan Shichao, Zhang Sha, Cai Wenwu, Li Daming, Li Qiuguo, Li Wenbo
Department of Plastic and Aesthetic (Burn) Surgery, the Second Xiangya Hospital of Central South University, Changsha, China.
Department of General Surgery, the Third Xiangya Hospital of Central South University, Changsha, China.
J Cancer. 2022 Oct 31;13(14):3554-3565. doi: 10.7150/jca.77588. eCollection 2022.
Colorectal cancer (CRC) is one of the major killer diseases worldwide, and more effective therapeutic compounds for CRC treatment are urgently needed. Although bioactive natural products derived from endophytic fungi have been extensively employed as antibiotics and anticancer agents, little is known about the effect of Rhytidhysteron sp. BZM-9 (an endophytic fungus)-derived compounds on CRC. Herein, a natural molecule porric acid E was isolated from Rhytidhysteron sp. BZM-9. Alamar Blue cell viability assay, Western blotting, transmission electron microscopy, flow cytometry analysis, and fluorescence image examination were employed to evaluate the antitumor effects of porric acid E on CRC cell lines. To establish the xenograft tumor model, nude mice received subcutaneous implants consisting of CRC cells on their flanks. Then the mice were treated with porric acid E or vehicle to assess the tumor-killing effects. The results revealed that porric acid E exhibited cytotoxicity by inhibiting proliferation and promoting apoptosis in CRC cells . Additionally, compared with fluorouracil (5-FU), porric acid E exhibited a more potent inhibitory effect on CRC HT29 cells. Importantly, extensive autophagy induced by porric acid E was detected in CRC cells, whereas inhibition of autophagy could significantly ameliorate porric acid E-mediated cytotoxic effect on CRC cells. Moreover, porric acid E treatment could markedly suppress subcutaneous HT29 xenograft tumor growth . Bioinformatics prediction indicated that Beclin-1 might be the potential target of porric acid E. These findings might afford a useful and important method for the treatment of CRC through fungal endophyte-derived natural compounds.
结直肠癌（CRC）是全球主要的致命疾病之一，因此迫切需要更有效的治疗化合物来治疗CRC。尽管源自内生真菌的生物活性天然产物已被广泛用作抗生素和抗癌剂，但关于Rhytidhysteron sp. BZM-9（一种内生真菌）衍生的化合物对CRC的影响却知之甚少。在此，从Rhytidhysteron sp. BZM-9中分离出一种天然分子——麦角甾酸E。采用alamar蓝细胞活力测定、蛋白质免疫印迹法、透射电子显微镜、流式细胞术分析和荧光图像检查来评估麦角甾酸E对CRC细胞系的抗肿瘤作用。为建立异种移植肿瘤模型，将裸鼠两侧腹侧皮下植入CRC细胞。然后用麦角甾酸E或赋形剂处理小鼠，以评估其杀瘤效果。结果显示，麦角甾酸E通过抑制CRC细胞增殖和促进其凋亡而表现出细胞毒性。此外，与氟尿嘧啶（5-FU）相比，麦角甾酸E对CRC HT29细胞表现出更强的抑制作用。重要的是，在CRC细胞中检测到麦角甾酸E诱导了广泛的自噬，而抑制自噬可显著改善麦角甾酸E介导的对CRC细胞的细胞毒性作用。此外，麦角甾酸E处理可显著抑制皮下HT29异种移植肿瘤的生长。生物信息学预测表明，Beclin-1可能是麦角甾酸E的潜在靶点。这些发现可能为通过真菌内生菌衍生的天然化合物治疗CRC提供一种有用且重要的方法。
