The Graduate School, University of Santo Tomas, 1015, Manila, Philippines.
Pharmaceutical Sciences Division, National Research Council of the Philippines, 1630, Taguig, Philippines.
Daru. 2022 Dec;30(2):273-288. doi: 10.1007/s40199-022-00445-9. Epub 2022 Aug 4.
Breast cancer is currently the world's most predominant malignancy. In cancer progression, angiogenesis is a requirement for tumor growth and metastasis.Alpinumisoflavone (AIF), a bioactive isoflavonoid, exhibited good binding affinity with the angiogenesis pathway's druggable target through molecular docking.
To confirm AIF's angiogenesis inhibitory activity, cytotoxic potential toward breast cancer cells, and druggability.
Antiangiogenic activity was evaluated in six pro-angiogenic proteins in vitro, duck chorioallantoic membrane (CAM) in ovo, molecular docking and druggability in silico.
Findings showed that AIF significantly inhibited (p = < 0.001) the HER2(IC = 2.96 µM), VEGFR-2(IC = 4.80 µM), MMP-9(IC = 23.00 µM), FGFR4(IC = 57.65 µM), EGFR(IC = 92.06 µM) and RET(IC = > 200 µM) activity in vitro.AIF at 25 µM-200 µM significantly inhibited (p = < 0.001) the total number of branch points (IC = 14.25 μM) and mean length of tubule complexes (IC = 3.52 μM) of duck CAM comparable (p = > 0.001) with the positive control 200 µM celecoxib on both parameters.AIF inhibited the growth of the estrogen-receptor-positive (ER +) human breast cancer cells (MCF-7) by 44.92 ± 1.79% at 100 µM while presenting less toxicity to human dermal fibroblast neonatal (HDFn) normal cells.The positive control 100 µM doxorubicin showed 86.66 ± 0.93% and 92.97 ± 1.27% inhibition with MCF-7 (IC = 3.62 μM) and HDFn, (IC = 27.16 μM) respectively.In docking, AIF has the greatest in silico binding affinity on HER2 (-10.9 kcal/mol) among the key angiogenic molecules tested. In silico rat oral LD calculation indicates that AIF is moderate to slightly toxic at 146.4 mg/kg with 1.1 g/kg and 20.1 mg/kg upper and lower 95% confidence limits. Lastly, it sufficiently complies with Lipinski's, Veber's, Egan's, Ghose's, and Muegge's Rule, supporting its oral drug-like property.
This study revealed that AIF possesses characteristics of a phytoestrogen compound with significant binding affinity, inhibitory activity against pro-angiogenic proteins, and cytotoxic potential against ER + breast cancer cells.The acceptable and considerable safety and drug-likeness profiles of AIF are worthy of further confirmation in vivo and advanced pre-clinical studies so that AIF can be elevated as a promising molecule for breast cancer therapy.
乳腺癌是目前全球最常见的恶性肿瘤。在癌症进展过程中，血管生成是肿瘤生长和转移的必需条件。白杨素（AIF）是一种生物活性异黄酮，通过分子对接显示出与血管生成途径的可成药性靶标良好的结合亲和力。
证实 AIF 的血管生成抑制活性、对乳腺癌细胞的细胞毒性潜力和可成药性。
在体外评估了六种促血管生成蛋白、鸡胚绒毛尿囊膜（CAM）体内、分子对接和计算机模拟中的药物性质。
研究结果表明，AIF 显著抑制了 HER2（IC=2.96µM）、VEGFR-2（IC=4.80µM）、MMP-9（IC=23.00µM）、FGFR4（IC=57.65µM）、EGFR（IC=92.06µM）和 RET（IC=>200µM）的活性（p<0.001）。AIF 在 25µM-200µM 浓度下显著抑制了鸭 CAM 的总分支点数量（IC=14.25µM）和管状复合物的平均长度（IC=3.52µM）（p<0.001），与阳性对照物 200µM 塞来昔布在这两个参数上相当。AIF 在 100µM 时对雌激素受体阳性（ER+）人乳腺癌细胞（MCF-7）的生长抑制率为 44.92±1.79%，而对人真皮成纤维细胞新生儿（HDFn）正常细胞的毒性较小。阳性对照物 100µM 阿霉素对 MCF-7（IC=3.62µM）和 HDFn（IC=27.16µM）的抑制率分别为 86.66±0.93%和 92.97±1.27%。在对接中，AIF 在测试的关键血管生成分子中对 HER2 具有最大的计算亲和力（-10.9kcal/mol）。大鼠口服 LD 的计算表明，AIF 在 146.4mg/kg 时具有中等至轻度毒性，上下置信限的 95%置信区间为 1.1g/kg 和 20.1mg/kg。最后，它充分符合 Lipinski、Veber、Egan、Ghose 和 Muegge 的规则，支持其口服药物特性。
本研究表明，AIF 具有植物雌激素化合物的特征，具有显著的结合亲和力、对促血管生成蛋白的抑制活性和对 ER+乳腺癌细胞的细胞毒性潜力。AIF 的可接受性和相当大的安全性和药物样特性值得进一步在体内和先进的临床前研究中证实，以便将 AIF 提升为一种有前途的乳腺癌治疗分子。
