PO.TB04.08 · 肿瘤生物学
妇科肿瘤中植物化学物质的离体药物敏感性与计算机模拟评估
Ex vivo drug sensitivity and in silico evaluation of phytochemicals in gynaecological cancers
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：妇科肿瘤——包括宫颈癌、卵巢癌、子宫内膜癌和外阴癌——由于确诊晚、治疗耐药以及癌症干细胞的存在，构成了重大的治疗挑战。膳食植物化学物质正逐渐成为癌症相关通路的潜在调节剂，但其临床应用往往受限于不良的药代动力学特性。将计算机模拟（in silico）ADMET（吸收、分布、代谢、排泄和毒性）分析、分子对接以及离体药物敏感性筛查相结合，可能有助于识别有效的治疗方案。
方法：从22例（年龄范围29-83岁）接受手术的患者中分离原代肿瘤细胞，包括宫颈癌（n=13）、卵巢癌（n=2）、子宫内膜/子宫癌（n=4）和外阴癌（n=3）。细胞产量范围为15.9×10⁶至3.05×10⁹，活力介于14-99%之间。细胞经冷冻保存以用于下游检测。使用SwissADME和pkCSM对六种膳食植物化学物质（槲皮素、姜黄素、白藜芦醇、EGCG、染料木黄酮、熊果酸）进行评估，以预测其药代动力学和毒性特征。采用Boiled-egg图评估胃肠道吸收和血脑屏障通透性。使用AutoDock Vina针对妇科肿瘤通路相关的关键酶（EGFR、VEGFR-2、PI3K、TOP2A）进行分子对接。离体药物敏感性筛查将FDA批准的化疗药物与所选植物化学物质进行比较，以识别具有更高细胞毒性潜力的化合物。
结果：ADMET分析显示槲皮素、姜黄素、白藜芦醇和染料木黄酮具有高胃肠道吸收（HIA 77-93%），除白藜芦醇外血脑屏障穿透性有限。熊果酸和EGCG表现出较差的吸收。大多数化合物的P-糖蛋白外排和CYP抑制作用极小，但EGCG表现出hERG II抑制，熊果酸则存在肝毒性风险。分子对接显示EGCG与EGFR（-9.3 kcal/mol）、姜黄素与VEGFR-2（-9.4 kcal/mol）以及熊果酸与TOP2A（-9.1 kcal/mol）具有良好的结合，与FDA批准的抑制剂相当。初步离体药物筛查表明，与膳食植物化学物质相比，FDA批准的化疗药物在患者来源细胞中表现出更高的细胞毒性。
结论与未来方向：我们的整合方法表明，离体药物敏感性筛查与计算机模拟ADMET和分子对接相互补充，为优先筛选治疗候选药物提供了平台。初步数据提示，在患者来源模型中，FDA批准的化疗药物优于膳食植物化学物质。未来工作将纳入生物统计和基因组分析，以预测个体化治疗的最佳药物组合，从而可能为妇科肿瘤实现精准肿瘤学策略。
查看英文原文 English abstract
Background: Gynaecological cancers-including cervical, ovarian, endometrial, and vulvar cancers-pose significant therapeutic challenges due to late-stage diagnosis, therapeutic resistance, and the presence of cancer stem cells. Dietary phytochemicals are emerging as potential modulators of cancer-related pathways, but their clinical utility is often limited by poor pharmacokinetics. Integrating in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling, molecular docking, and ex vivo drug sensitivity screening may facilitate the identification of effective therapies.
Methods: Primary tumor cells were isolated from 22 patients (age range 29-83 years) undergoing surgery for cervical (n=13), ovarian (n=2), endometrial/uterine (n=4), and vulvar (n=3) cancers. Cell yields ranged from 15.9 ×10⁶ to 3.05 ×10⁹ with viability between 14-99%. Cells were cryopreserved for downstream assays. Six dietary phytochemicals (quercetin, curcumin, resveratrol, EGCG, genistein, ursolic acid) were evaluated using SwissADME and pkCSM to predict pharmacokinetic and toxicity profiles. Boiled-egg plots assessed gastrointestinal absorption and blood-brain barrier permeability. Molecular docking was performed against key enzymes implicated in gynecological cancer pathways (EGFR, VEGFR-2, PI3K, TOP2A) using AutoDock Vina. Ex vivo drug sensitivity screening compared FDA-approved chemotherapeutics with the selected phytochemicals to identify compounds with higher cytotoxic potential.
Results: ADMET profiling revealed high gastrointestinal absorption for quercetin, curcumin, resveratrol, and genistein (HIA 77-93%), with limited BBB penetration except for resveratrol. Ursolic acid and EGCG demonstrated poor absorption. P-glycoprotein efflux and CYP inhibition were minimal for most compounds, though EGCG showed hERG II inhibition, and ursolic acid presented hepatotoxicity risk. Molecular docking showed favorable binding of EGCG to EGFR (-9.3 kcal/mol), curcumin to VEGFR-2 (-9.4 kcal/mol), and ursolic acid to TOP2A (-9.1 kcal/mol), comparable to FDA-approved inhibitors. Preliminary ex vivo drug screening indicated that FDA-approved chemotherapeutics exhibited higher cytotoxicity across patient-derived cells compared to the dietary phytochemicals.
Conclusions and Future Directions: Our integrated approach demonstrates that ex vivo drug sensitivity screening complements in silico ADMET and molecular docking, providing a platform to prioritize therapeutic candidates. Preliminary data suggest FDA-approved chemotherapeutics outperform dietary phytochemicals in patient-derived models. Future work will incorporate biostatistical and genomic analyses to predict optimal drug combinations for individualized therapy, potentially enabling precision oncology strategies for gynecological cancers.
利益披露 Disclosure
M. N. Sikhakhane, None..
X. Siwe Noundou, None.