Natural Products Institute, The University of West Indies, Mona, Jamaica, West Indies.
Department of Basic Medical Sciences, Faculty of Medical Sciences, University of the West Indies, Mona, Jamaica, Jamaica, West Indies.
Sci Rep. 2021 Mar 25;11(1):6854. doi: 10.1038/s41598-021-86040-5.
Colorectal cancer (CRC) represents the third leading cause of death among cancer patients below the age of 50, necessitating improved treatment and prevention initiatives. A crude methanol extract from the wood pulp of Artocarpus heterophyllus was found to be the most bioactive among multiple others, and an enriched extract containing 84% (w/v) artocarpin (determined by HPLC-MS-DAD) was prepared. The enriched extract irreversibly inhibited the activity of human cytochrome P450 CYP2C9, an enzyme previously shown to be overexpressed in CRC models. In vitro evaluations on heterologously expressed microsomes, revealed irreversible inhibitory kinetics with an IC value of 0.46 µg/mL. Time- and concentration-dependent cytotoxicity was observed on human cancerous HCT116 cells with an IC value of 4.23 mg/L in 72 h. We then employed the azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-induced model in C57BL/6 mice, which revealed that the enriched extract suppressed tumor multiplicity, reduced the protein expression of proliferating cell nuclear antigen, and attenuated the gene expression of proinflammatory cytokines (Il-6 and Ifn-γ) and protumorigenic markers (Pcna, Axin2, Vegf, and Myc). The extract significantly (p = 0.03) attenuated (threefold) the gene expression of murine Cyp2c37, an enzyme homologous to the human CYP2C9 enzyme. These promising chemopreventive, cytotoxic, anticancer and anti-inflammatory responses, combined with an absence of toxicity, validate further evaluation of A. heterophyllus extract as a therapeutic agent.
结直肠癌（CRC）是 50 岁以下癌症患者的第三大死亡原因，需要改进治疗和预防措施。从面包果树（Artocarpus heterophyllus）木浆中提取的粗甲醇提取物在多种提取物中具有最高的生物活性，并且制备了含有 84%（w/v）的角甾素（通过 HPLC-MS-DAD 确定）的富集提取物。该富集提取物不可逆地抑制了人类细胞色素 P450 CYP2C9 的活性，该酶先前已被证明在 CRC 模型中过表达。在异源表达的微粒体中的体外评估显示出不可逆的抑制动力学，IC 值为 0.46µg/mL。在人源性 HCT116 癌细胞中观察到时间和浓度依赖性的细胞毒性，72 小时的 IC 值为 4.23mg/L。然后，我们在 C57BL/6 小鼠中使用了氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）结肠炎诱导模型，结果表明，富集提取物抑制了肿瘤的多发性，降低了增殖细胞核抗原的蛋白表达，并减弱了促炎细胞因子（IL-6 和 IFN-γ）和促肿瘤标志物（Pcna、Axin2、Vegf 和 Myc）的基因表达。该提取物显著（p=0.03）下调了与人类 CYP2C9 酶同源的鼠 Cyp2c37 基因的表达（三倍）。这些有前景的化学预防、细胞毒性、抗癌和抗炎反应，加上无毒性，验证了进一步评估面包果树提取物作为治疗剂的价值。
