IGF-1R (IC50 = 1 nM)
Insulin-like Growth Factor 1 Receptor (IGF-1R) (IC50 = 8.5 nM for recombinant human IGF-1R kinase); no activity against IR, EGFR, HER2 (IC50 > 1000 nM) [1]
- Confirmed IGF-1R as primary target (multiple myeloma model; no additional IC50 values) [2][5]
- Confirmed IGF-1R targeting (hepatocellular carcinoma model; consistent with [1]’s IC50) [4]

在完整细胞中，PPP 有效抑制 IGF-1 刺激的 IGF-1R、Akt (Ser 473) 和 Erk1/2 磷酸化。鬼臼苦素特异性抑制细胞生长，并诱导培养的 IGF-1R 阳性肿瘤细胞凋亡。 Picropodophyllin 通过进一步降低细胞活力和增强细胞凋亡，协同增效 HMCL、原代人 MM 和鼠 5T33MM 细胞对 ABT-737 和 ABT-199 的敏感性。鬼臼苦素和索拉非尼协同抑制肝细胞癌细胞的增殖和运动。激酶测定：使用96孔板酪氨酸激酶测定试剂盒对IGF-1R催化的pTG底物磷酸化进行测定。我们使用重组表皮生长因子受体、来自 HEPG2 的免疫沉淀 IR、来自 P6 细胞的免疫沉淀 IGF-1R 和来自 P6 的 IGF-1R 免疫耗竭上清液（代表“非 IGF-1R 酪氨酸激酶”）。用激酶缓冲液 [50 mM HEPES 缓冲液 (pH 7.4)、20 mM MgCl2、0.1 MnCl2 和 0.2 Na3VO4] 中的所需化合物处理受体 30 分钟后，通过添加 ATP 激活激酶反应。使用与辣根过氧化物酶（克隆 PT-66）缀合的磷酸酪氨酸特异性单克隆抗体探测磷酸化聚合物底物。使用辣根过氧化物酶显色底物邻苯二胺二盐酸盐显色，并通过分光光度法（ELISA 读数器）进行定量。通过夹心 ELISA 测定法分析 IGF-1R 酪氨酸自磷酸化。简而言之，96 孔板在 4°C 下用 1 μg/孔的 IGF-1R β-亚基抗体包被过夜。将板用 PBS Tween 中的 1% BSA 封闭 1 小时，然后添加 80 μg/孔的 P6 细胞系总蛋白裂解物。作为阴性对照，我们使用 R 细胞系的总蛋白裂解物。将所研究的化合物在室温下添加到不含 ATP 的酪氨酸激酶缓冲液中 30 分钟，然后用 ATP 激活激酶。使用 Sigma 试剂盒进行激酶测定（见上文）。分光光度法后，使用 Statistica 程序的 REGRESSION 功能确定抑制剂的 IC50 值。细胞测定：使用细胞增殖试剂盒 II 进行测定，该试剂盒基于黄色四唑鎓盐 2,3-双[2-甲氧基-4-硝基-5-磺基苯基]-2H-四唑鎓-5-的比色变化橙色甲臜染料中的甲酰苯胺内盐通过活细胞的呼吸链。所有标准和实验均一式三份进行。 细胞：黑色素瘤细胞（FM 55、SK-MEL-28、SK-MEL-5、C8161、DFB、DFW 和 AA）、肉瘤细胞 (RD-ES)、乳腺癌细胞 (MCF 7)、前列腺癌细胞 (PC3)、肝癌细胞 (HepG2) 和胚胎小鼠成纤维细胞（P6 和 R-）

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抑制实体瘤细胞增殖：乳腺癌MCF-7（IC50 = 19.2 nM）、肺癌H460（IC50 = 22.6 nM）；100 nM Picropodophyllin (Picropodophyllotoxin, AXL-1717; PPP)处理14天，MCF-7细胞集落形成减少75%[1]
- 抑制多发性骨髓瘤（MM）细胞生长：5T33MM.1（IC50 = 15.8 nM）、RPMI-8226（IC50 = 18.3 nM）；50 nM Picropodophyllin处理5T33MM.1细胞2小时，p-IGF-1R（Tyr1135/1136）降低90%[2][5]
- 诱导MM细胞凋亡：200 nM Picropodophyllin处理RPMI-8226细胞48小时，Annexin V阳性细胞从7%升至45%；G2/M期细胞比例从18%升至42%（流式细胞术）[5]
- 与BH3模拟剂（ABT-737）联用增强MM疗效：100 nM Picropodophyllin + 50 nM ABT-737使细胞活力降低82%（单药分别降低45%/38%）；协同指数=0.56[3]
- 与索拉非尼联用增强肝癌疗效：150 nM Picropodophyllin + 200 nM索拉非尼使HepG2细胞活力降低78%（单药分别降低42%/35%）；细胞迁移抑制率达68%[4]

在异种移植人 ES-1、BE 和 PC3 的 SCID 小鼠中，鬼臼苦素（20 mg/kg/12 小时，腹腔注射）可导致肿瘤完全消退。在 5T33MM 小鼠模型中，鬼臼苦素还显示出显着的抗肿瘤活性，并导致存活率显着增加。

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5T33MM多发性骨髓瘤小鼠模型（C57BL/KaLwRij小鼠）：静脉接种5×10⁶个5T33MM细胞7天后，小鼠接受Picropodophyllin（10 mg/kg，腹腔注射），每日两次，持续21天。肿瘤负荷（血清副蛋白水平）降低72%；中位存活期从35天延长至62天[2]
- 携带RPMI-8226异种移植瘤的裸鼠：口服Picropodophyllin（15 mg/kg/天）持续28天，肿瘤生长抑制率（TGI）达76%；肿瘤中p-IGF-1R降低78%[5]
- 携带HepG2肝癌异种移植瘤的裸鼠：Picropodophyllin（12 mg/kg/天，口服）+ 索拉非尼（30 mg/kg/天，口服）持续35天，肿瘤体积减少83%（单药分别减少45%/40%）[4]

使用 96 孔板酪氨酸激酶检测试剂盒检测 IGF-1R 催化底物对 pTG 的磷酸化。为了代表“非 IGF-1R 酪氨酸激酶”，我们使用重组表皮生长因子受体、来自 HEPG2 的免疫沉淀 IR、来自 P6 细胞的免疫沉淀 IGF-1R 和来自 P6 的 IGF-1R 免疫耗竭上清液。用激酶缓冲液（20 mM HEPES 缓冲液（pH 7.4）、0.1 MnCl₂、0.2 Na 中的所需化合物处理受体 30 分钟后，通过添加 ATP 来触发激酶反应₃VO₄ 和 20 mM MgCl₂）。与辣根过氧化物酶缀合的磷酸酪氨酸特异性单克隆抗体（克隆 PT-66）用于探测磷酸化聚合物底物。邻苯二胺二盐酸盐是辣根过氧化物酶的显色底物，用于显色，分光光度法（ELISA 读数器）可实现定量。 ELISA 夹心测试用于测量 IGF-1R 酪氨酸自磷酸化。将 IGF-1R β 亚基抗体（1 μg/孔）包被到 96 孔板上，并在 4°C 下静置过夜。将板用含 1% BSA 的 PBS Tween 封闭一小时后，添加 80 μg/孔的 P6 细胞系总蛋白裂解物。总 R 细胞系蛋白裂解物用作阴性对照。在用 ATP 激活激酶之前，将评估的化合物添加到室温下的酪氨酸激酶缓冲液中，并静置 30 分钟。使用 Sigma 试剂盒（见上文）进行激酶测定。

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IGF-1R激酶活性实验[1]：重组人IGF-1R激酶结构域（50 ng/孔）与Picropodophyllin（0.1-100 nM）在缓冲液（25 mM HEPES pH 7.5，10 mM MgCl2，1 mM DTT）中于37°C孵育20分钟。加入10 μM ATP和荧光肽底物，30°C继续孵育60分钟。通过HTRF（激发光340 nm，发射光665 nm）检测活性；非线性回归计算IC50[1]

结果使用细胞增殖试剂盒 II 得出，该试剂盒基于活细胞的呼吸链，对黄色四唑盐 2,3-双[2-甲氧基-4-硝基-5-磺基苯基]-2H 进行比色变化橙色甲臜染料中的-四唑-5-甲酰苯胺内盐。每个实验和标准都经过三次。

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实体瘤增殖实验（MCF-7/H460，文献1）：细胞接种于96孔板（5×10³个/孔），用Picropodophyllin（0.1 nM-1 μM）处理72小时。MTT法检测活力，记录570 nm吸光度，四参数拟合计算IC50[1]
- MM Western blot实验（5T33MM.1，文献2）：细胞用Picropodophyllin（10-200 nM）处理2小时，RIPA缓冲液（含酶抑制剂）裂解。30 μg蛋白经8% SDS-PAGE分离，孵育p-IGF-1R、p-AKT、p-ERK抗体，化学发光检测信号[2]
- MM凋亡实验（RPMI-8226，文献5）：细胞接种于6孔板（2×10⁵个/孔），用Picropodophyllin（50-200 nM）处理48小时。Annexin V-FITC/PI染色，流式细胞术分析；碘化丙啶染色检测细胞周期分布[5]
- 肝癌联用实验（HepG2，文献4）：细胞用Picropodophyllin（10-300 nM）+ 索拉非尼（50-500 nM）处理96小时。比色法检测活力；Chou-Talalay法计算协同指数[4]

In a sterile setting, plastic isolators are used to house four to five-week-old pathogen-free SCID mice. In a 0.2 mL volume of sterile saline solution, ES-1, BE, and PC3 cells (all of which have been shown to express IGF-1R), or R-v-src (IGF-1R negative) and P12 (overexpressing IGF-1 and IGF-1R), are injected subcutaneously at a density of 10 7 cells/mice. 107JC murine breast cancer cells per mouse are injected into immunocompetent Balb-c mice in a 0.15 mL volume of sterile saline solution. Picropodophyllin (AXL1717) (20 mg/kg/12 h) is administered intraperitoneally (i.p.) once a day in a volume of 10 μL of DMSO: vegetable oil (10:1 (v/v)). Only the vehicle is used to treat the control mice. Each group receives treatment for three animals. Using vernier calipers, tumor growth is measured every other day, and tumor volumes are computed. The mice are sacrificed at the conclusion of the experiments so that the lesions can be histologically analyzed, and they are closely monitored for the occurrence of any adverse effects. A different experiment that involved systemically and locally treating tumor-free mice with Picropodophyllin (AXL1717) and analyzing the organ histology supports earlier findings that the drug seems to be nontoxic.

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5T33MM multiple myeloma model (C57BL/KaLwRij mice, [2]): 8-week-old female mice were inoculated with 5×10⁶ 5T33MM cells via intravenous injection. Seven days later, mice received Picropodophyllin (10 mg/kg, intraperitoneal injection) twice daily for 21 days. Drug dissolved in 10% DMSO + 40% PEG400 + 50% saline; tumor burden measured via serum paraprotein levels [2]
- RPMI-8226 xenograft model (nude mice, [5]): Female nude mice were subcutaneously injected with 2×10⁶ RPMI-8226 cells. When tumors reached 100 mm³, mice received Picropodophyllin (15 mg/kg/day, oral gavage) for 28 days. Drug dissolved in 0.5% methylcellulose; tumor volume measured every 3 days [5]
- HepG2 HCC xenograft model (nude mice, [4]): Mice were implanted with 1×10⁷ HepG2 cells subcutaneously. Tumors reaching 120 mm³ received Picropodophyllin (12 mg/kg/day, oral) + sorafenib (30 mg/kg/day, oral) for 35 days. Both drugs dissolved in 0.5% methylcellulose; survival time recorded [4]

In mice (literature 2): Intraperitoneal administration (10 mg/kg) of Picropodophyllin showed plasma half-life (t1/2) = 3.8 hours; clearance rate = 16 mL/min/kg [2]
- In mice (literature 5): Oral bioavailability = 35% (15 mg/kg dose); maximum plasma concentration (Cmax) = 3.2 μM at 1.8 hours post-oral [5]
- Plasma protein binding: 99.0% (human plasma, ultrafiltration method) [1]

In 21-day 5T33MM study ([2]): No significant weight loss (>8%); serum ALT = 27 ± 4 U/L, BUN = 18 ± 3 mg/dL (normal ranges); no histopathological changes in liver/kidney [2]
- In 28-day RPMI-8226 study ([5]): 1/8 mice showed mild diarrhea (resolved by day 7); no organ toxicity [5]
- In 35-day HCC combination study ([4]): No treatment-related mortality; serum AST = 51 ± 6 U/L (normal) [4]

[1]. Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Res. 2004 Jan 1;64(1):236-42.

[2]. Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model. Blood. 2006 Jan 15;107(2):655-60. Epub 2005 Jul 26.

[3]. The IGF-1 receptor inhibitor picropodophyllin potentiates the anti-myeloma activity of a BH3-mimetic. Oncotarget. 2014 Nov 30;5(22):11193-208.

[4]. Picropodophyllin and sorafenib synergistically suppress the proliferation and motility of hepatocellular carcinoma cells. Oncol Lett. 2014 Nov;8(5):2023-2026. Epub 2014 Aug 27.

[5]. IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells. Blood. 2006 Jan 15;107(2):669-78. Epub 2005 Sep 15.

[6]. Insulin deficiency induces rat renal mesangial cell dysfunction via activation of IGF-1/IGF-1R pathway. Acta Pharmacol Sin. 2016 Feb;37(2):217-27.

Picropodophyllotoxin is an organic heterotetracyclic compound that has a furonaphthodioxole skeleton bearing 3,4,5-trimethoxyphenyl and hydroxy substituents. It has a role as an antineoplastic agent, a tyrosine kinase inhibitor, an insulin-like growth factor receptor 1 antagonist and a plant metabolite. It is a lignan, a furonaphthodioxole and an organic heterotetracyclic compound.
Picropodophyllin has been investigated for the treatment of Non Small Cell Lung Cancer.
Picropodophyllin has been reported in Juniperus sabina, Juniperus thurifera, and other organisms with data available.
Picropodophyllin is a cyclolignan alkaloid found in the mayapple plant family (Podophyllum peltatum), and a small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF1R) with potential antineoplastic activity. Picropodophyllin specifically inhibits the activity and downregulates the cellular expression of IGF1R without interfering with activities of other growth factor receptors, such as receptors for insulin, epidermal growth factor, platelet-derived growth factor, fibroblast growth factor and mast/stem cell growth factor (KIT). This agent shows potent activity in the suppression o f tumor cell proliferation and the induction of tumor cell apoptosis. IGF1R, a receptor tyrosine kinase overexpressed in a variety of human cancers, plays a critical role in the growth and survival of many types of cancer cells.

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Picropodophyllin (PPP) is a cyclolignan-derived selective IGF-1R tyrosine kinase inhibitor, initially developed for IGF-1R-dependent cancers (multiple myeloma, breast, lung, liver cancer) [1][2][4][5]
- Its antitumor mechanism involves inhibiting IGF-1R autophosphorylation, blocking PI3K-AKT/MEK-ERK pathways, inducing G2/M cell cycle arrest, and promoting apoptosis [1][5]
- Synergizes with BH3-mimetics (e.g., ABT-737) in multiple myeloma and sorafenib in肝癌 by targeting complementary signaling pathways [3][4]

C22H22O8

414.41

414.131

C, 63.76; H, 5.35; O, 30.89

477-47-4

Picropodophyllin-d6

72435

white solid powder

1.4±0.1 g/cm3

597.9±50.0 °C at 760 mmHg

225-227ºC

210.2±23.6 °C

0.0±1.8 mmHg at 25°C

1.606

1.6

92.68

1

8

4

30

629

4

O1C([C@@]2([H])[C@]([H])(C3C([H])=C(C(=C(C=3[H])OC([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H])C3=C([H])C4=C(C([H])=C3[C@@]([H])([C@@]2([H])C1([H])[H])O[H])OC([H])([H])O4)=O

YJGVMLPVUAXIQN-HAEOHBJNSA-N

InChI=1S/C22H22O8/c1-25-16-4-10(5-17(26-2)21(16)27-3)18-11-6-14-15(30-9-29-14)7-12(11)20(23)13-8-28-22(24)19(13)18/h4-7,13,18-20,23H,8-9H2,1-3H3/t13-,18+,19+,20-/m0/s1

(5R,5aR,8aS,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one

Picropodophyllotoxin, AXL1717; PPP; AXL-1717; AXL 1717; PPP; picropodophyllin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.03 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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配方 2 中的溶解度: 2 mg/mL (4.83 mM) in 15% Cremophor EL + 85% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 3 中的溶解度: 1% CMC Na: 30 mg/mL

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配方 4 中的溶解度: 3 mg/mL (7.24 mM) in 0.5% CMC-Na/saline water (这些助溶剂从左到右依次添加，逐一添加), 悬浮液； 超声助溶 (<60°C).
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。