Herbacetin

Herbacetin, a natural compound found in flax and other plants, is an effective and nontoxic allosteric inhibitor of Ornithine decarboxylase (ODC). ODC is a rate-limiting enzyme in the first step of polyamine biosynthesis that is associated with cell growth and tumor formation. Herbacetin exhibits potent anticancer activity in colon cancer cell lines with high ODC expression by binding to aspartate 44 in ODC^[1]. Herbacetin also exerts potent anti-inflammatory effects by inhibiting the release of pro-inflammatory cytokines such as TNF-α and IL-1β and reducing cellular nitric oxide (NO) production, while also exhibiting antihyperglycemic and antihyperlipidemic properties^[2][3]. Herbacetin is also a potent cytochrome P450 (CYP) inhibitor that inhibits CYP3A4, CYP2B6, CYP2C9, and CYP2E1 in a mixed manner and non-competitively blocks CYP2D6, with IC₅₀ values below 10μM for each tested isoenzyme^[4].

In vitro, Herbacetin (5-30μM; 48h) inhibited the proliferation and increased the doubling time of colon cancer cells (HCT116, DLD1 and HT29) in a dose-dependent manner, particularly HCT116 cells expressing high levels of ODC^[1]. Herbacetin (5-30μM; 48h) dose-dependently inhibited ODC activity in the HCT116 cell line, thereby suppressing the reporter activity of the MAP kinase transcription factor activator protein-1 (AP-1)^[1].

In vivo, treatment with Herbacetin (0.4 and 2mg/kg; i.p.; 3 times per week for 8 weeks) significantly suppressed polyp number, size, ODC activity, and markedly decreased putrescine and spermidine levels in APC^Min/+ mice, in which ODC expression is upregulated in intestinal tissue, without overt signs of toxicity or significant body weight loss^[1]. Treatment with Herbacetin (0.4 and 2mg/kg; i.p.; 3 times per week for 2 weeks) strongly suppressed tumor growth by more than 70% and markedly decreased the expression of phosphorylated ERKs and RSK in HCT116 colon cancer xenograft mice^[1]. Herbacetin (100mg/kg; p.o.; 5 times per week for 18 days) significantly suppressed tumor growth and phosphorylated ERKs and RSK in HCT116 colon cancer xenograft mice^[1].

References:
[1] Kim DJ, Roh E, Lee MH, et al. Herbacetin Is a Novel Allosteric Inhibitor of Ornithine Decarboxylase with Antitumor Activity. Cancer Res. 2016;76(5):1146-1157.
[2] Li, Liang et al. “Herbacetin inhibits RANKL-mediated osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo.” European journal of pharmacology vol. 777 (2016): 17-25.
[3] Veeramani, Chinnadurai et al. “Herbacetin, a flaxseed flavonoid, ameliorates high percent dietary fat induced insulin resistance and lipid accumulation through the regulation of hepatic lipid metabolizing and lipid-regulating enzymes.” Chemico-biological interactions vol. 288 (2018): 49-56.
[4] Qian, Jianchang et al. “Herbacetin Broadly Blocks the Activities of CYP450s by Different Inhibitory Mechanisms.” Planta medica vol. 88,7 (2022): 507-517.

Herbacetin是一种存在于亚麻和其他植物中的天然化合物，是鸟氨酸脱羧酶（ODC）的有效且无毒的变构抑制剂。ODC是多胺生物合成第一步的限速酶，与细胞生长和肿瘤形成有关。Herbacetin通过与ODC中的天冬氨酸44结合，在ODC高表达的结肠癌细胞系中显示出强大的抗癌活性^[1]。Herbacetin还通过抑制促炎细胞因子如TNF-α和IL-1β的释放和减少细胞一氧化氮（NO）的产生而发挥有效的抗炎作用，同时还具有抗高血糖和抗高血脂的特性^[2][3]。Herbacetin也是一种有效的细胞色素P450（CYP）抑制剂，以混合方式抑制CYP3A4， CYP2B6， CYP2C9和CYP2E1，并且非竞争性地阻断CYP2D6，其对每种同工酶的IC₅₀值均低于10μM^[4]。

体外实验中，Herbacetin（5-30μM；48h）以剂量依赖的方式抑制结肠癌细胞系的增殖和增加细胞倍增时间，特别是在高表达鸟氨酸脱羧酶的HCT116中^[1]。Herbacetin（5-30μM；48h）剂量依赖性地抑制HCT116细胞系中ODC的活性，进而抑制MAP激酶转录因子激活蛋白-1（AP-1）的报告活性^[1]。

体内实验中，Herbacetin（0.4和2mg/kg；腹腔注射；每周3次，连续8周）在肠道组织ODC表达上调的APC^Min/+小鼠中，显著抑制了息肉数量、大小及ODC活性，并明显降低了腐胺和亚精胺水平，且未出现明显毒性或显著体重下降^[1]。Herbacetin（0.4和2mg/kg；腹腔注射；每周3次，连续2周）在HCT116结肠癌异种移植小鼠模型中，可显著抑制肿瘤生长超过70%，并明显降低磷酸化ERKs和RSK的表达水平^[1]。Herbacetin（100mg/kg；口服；每周5次，连续18天）显著抑制HCT116结肠癌异种移植小鼠的肿瘤生长和磷酸化ERKs和RSK^[1]。