| 生物活性 |
SU212 is a podophyllotoxin-derived ENO1 inhibitor and AMPK activator. SU212 can selectively induce oxidative phosphorylation, reduce glycolysis activity and glucose uptake in tumor cells, and directly bind to ENO1 without affecting these pathways in normal cells. SU212 induces apoptosis and promotes ENO1 degradation via proteasomal and autophagic pathways without inhibiting the catalytic activity. SU212 leads to mitotic arrest and apoptosis in TNBC (triple-negative breast cancer) cells by activating AMPK, demonstrating potent anti-tumor activity in vitro. SU212 inhibits tumor growth and metastasis in syngeneic, xenograft, and diabetic mouse models, exhibiting an excellent safety profile. SU212 can be used in research on t TNBC, diabetes, and fatty liver disease[1][2].
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体外研究
(In Vitro) |
SU212 (0.01-850 μM, 48 小时) 对三阴性乳腺癌细胞 (MDA-MB-231) 表现出比 Etoposide 更低的毒性和更高的效力，其 IC50 为 0.26 μM；其在人源 TNBC 细胞中的 IC50 值分别为：MDA-MB-468 0.1 μM、SUM159 0.24 μM、BT549 0.037 μM；在小鼠 TNBC 细胞系中的 IC50 值分别为：4T1 0.85 μM、EMT6 0.18 μM、E0771 0.039 μM、PY8119 0.31 μM[1][2]。
SU212 (0.5 μM, 6 小时) 在 MDA-MB-231 细胞中的作用靶点与 Etoposide 不同，并通过蛋白酶体和自噬途径促进 ENO1 降解，此作用可被 MG132 或3 MA 共处理部分阻断[1]。
SU212 (0.1-10 μM, 3 分钟-6 小时) 能提高 ENO1 和 ENO3 的热稳定性，且与 ENO1 的相互作用更强，并在多种 TNBC 细胞系 (MDA-MB-231, MDA-MB-468 和 EMT6) 中表现出剂量依赖性效应[1]。
SU212 (0.25 或 0.5 μM, 1.5 小时) 抑制了 MDA-MB-231、MCF12A 和 HEK293 细胞的总体氧消耗率、细胞外酸化率及糖酵解率但不影响正常细胞的糖酵解率和活力[1]。
SU212 (0.1-0.5 μM, 6-10 天) 可抑制 TNBC 细胞的肿瘤再生和复发[1]。
SU212 (0.1-0.5 μM，6 或 12 小时) 在 MDA-MB-468 和 MDA-MB-231 细胞中诱导 G2/M 期阻滞[2]。
SU212 (0.5 μM，12 小时) 降低正常乳腺细胞 MCF10A、MCF12A 或 TNBC 细胞 MDA-MB-231 和 MDA-MB-468 中不同形式微管蛋白的丰度[2]。
SU212 (0.25 或 0.5 μM，12-48 小时) 在 MDA-MB-468 和 MDA-MB-231 细胞中诱导 12-60% 的凋亡性细胞死亡而非自噬性细胞死亡[2]。
SU212 (0.25 或 0.5 μM, 1-6 小时) 在 MDA-MB-231 细胞中通过磷酸化 AMPKα 的 Thr172 位点激活 AMPK，并在 MDA-MB-468 和 MDA-MB-231 细胞中诱导 AMPKα 的显著激活[2]。
SU212 (0.25 μM-0.5 μM，30 分钟至 6 小时) 抑制 MDA-MB-468 和 MDA-MB-231 细胞的乳酸生成且不影响 MDA-MB-231 细胞中 D-葡萄糖、葡萄糖-6-磷酸/果糖-6-磷酸、ATP、柠檬酸、耗氧率 (OCR)、细胞外酸化率 (ECAR) 以及 α-酮戊二酸的细胞水平[2]。
SU212 (0.25 或 0.5 μM，6 小时) 使 MDA-MB-468 和 MDA-MB-231 细胞的细胞脂质含量降低 24-70%[2]。
SU212 (0.5 μM，12 小时) 显著增加 MDA-MB-231 和 MDA-MB-468 细胞系中与氧化磷酸化相关的蛋白质水平，并降低与糖酵解及磷酸戊糖途径相关的蛋白质水平，但在正常乳腺细胞系中无此效应[2]。
SU212 (0.1-0.5 μM，6 或 72 小时) 在 MDA-MB-468 和 MDA-MB-231 细胞中具有依赖 AMPK 激活的细胞毒性效应[2]。
SU212 (0.2-0.6 μM，48 小时) 不依赖于能量应激激活 TNBC 细胞系中的 AMPK[2]。
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Western Blot Analysis[1]
| Cell Line: |
MDA-MB-231 and EMT6 |
| Concentration: |
0.1 μM |
| Incubation Time: |
6 h |
| Result: |
Significantly altered the subcellular localization of eno1, most substantially limiting the membrane-bound pool, while exerting more limited effects on its nuclear and mitochondrial pools.
Induced inhibition of eno1 localization to the cell membrane was partially reversed by co-treatment with MG132 and 3MA.
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Western Blot Analysis[1]
| Cell Line: |
MDA-MB-231 cells |
| Concentration: |
0.5 μM |
| Incubation Time: |
6 h |
| Result: |
Did not stabilizes TOP2A.
Induced ENO1 degradation, and this effect was partially rescued by co-treatment with either MG132 or 3MA.
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Western Blot Analysis[1]
| Cell Line: |
MDA MB-231, MDA-MB-468, and EMT6 |
| Concentration: |
6 h |
| Incubation Time: |
6 or 12 h |
| Result: |
Strongly inhibited ENO1 protein expression, does not change ENO3 protein expression.
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Cell Proliferation Assay[1]
| Cell Line: |
MDA-MB-231, MDA-MB-468, SUM159 and BT549, 4T1, EMT6, E0771 and PY8119 |
| Concentration: |
0.1, 0.25 and 0.5 μM |
| Incubation Time: |
6-10 days |
| Result: |
Significantly inhibited TNBC cells’ clono genic potential and eight other cancer types.
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Cell Cycle Analysis[2]
| Cell Line: |
MDA-MB-468 and MDA-MB-231 |
| Concentration: |
0.1, 0.25 and 0.5 μM |
| Incubation Time: |
6 or 12 h |
| Result: |
Increased the sub-g1 phase (20-35%) with 6 h.
Induced mitotic phase arrest (20-31%) with 6 h.
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Western Blot Analysis[2]
| Cell Line: |
MDA-MB-468 and MDA-MB-231 |
| Concentration: |
0.5 μM |
| Incubation Time: |
6 h |
| Result: |
Resulted in the downregulation of cyclin B1 and CDK1 expression, and an increase in the expression of phospho-histone H3.
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Western Blot Analysis[2]
| Cell Line: |
MDA-MB-468 and MDA-MB-231 |
| Concentration: |
0.5 μM |
| Incubation Time: |
12 h |
| Result: |
Cleaved PARP, Bax, Bcl-2 and CC.
Induced pro-apoptotic Bax expression and inhibited Bcl-2 expres sion, leading to a significant increase in Bax/Bcl-2 ratio.
Induced the cleavage of PARP and caspase 3.
Inhibited Beclin-1 but did not affect LC3 A/B.
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Western Blot Analysis[2]
| Cell Line: |
MDA-MB-468, MDA-MB-231 |
| Concentration: |
0.5 μM |
| Incubation Time: |
6 h |
| Result: |
Downregulated of mtor and acetyl-coa carboxylase (ACC) inhibition.
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Western Blot Analysis[2]
| Cell Line: |
Dorsomorphin (HY-13418A) pretreated MDA-MB-468 and MDA-MB-231. |
| Concentration: |
0.5 μM |
| Incubation Time: |
6 h |
| Result: |
Did not induce AMPK
Were healthier and had a morphology similar.
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Cell Viability Assay[2]
| Cell Line: |
Dorsomorphin pretreated MDA-MB-468 and MDA-MB-231 |
| Concentration: |
0.5 μM |
| Incubation Time: |
72 h |
| Result: |
Reverted cytotoxic effect by Dorsomorphin from 73% to 86%.
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Cell Viability Assay[2]
| Cell Line: |
MDA-MB-468 |
| Concentration: |
0.2, 0.4 and 0.6μM |
| Incubation Time: |
48 h |
| Result: |
Produced an additive inhibitory effect in hypoglycaemic conditions, resulting in about 20–30% enhanced inhibition (P < 0.05) relative to hyperglycaemic conditions.
Did not affect the cytotoxicity of MDA-MB-468 cells by insulin.
Maintained consistent cytotoxicity across physiological and high insulin levels (1–100 ng/ml) but modestly reduced (by 17%) at a supra-pharmacological concentration (10,000 ng/ml).
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药代动力学
(Parmacokinetics) |
| Species |
Dose |
Route |
Indicator |
value |
|
Mice[1]
|
50 mg/kg
|
i.p.
|
T1/2
|
5.2 h
|
|
Rat[1]
|
50 mg/kg
|
i.p.
|
T1/2
|
8.61 h
|
|
Mice[1]
|
50 mg/kg
|
i.p.
|
Cmax
|
1043 ng/mL
|
|
Rat[1]
|
50 mg/kg
|
i.p.
|
Cmax
|
915 ng/mL
|
|
Mice[1]
|
50 mg/kg
|
i.p.
|
Tmax
|
1.00 h
|
|
Rat[1]
|
50 mg/kg
|
i.p.
|
Tmax
|
0.25 h
|
|
Mice[1]
|
50 mg/kg
|
i.p.
|
AUC0-t
|
2495 ng·h/mL
|
|
Rat[1]
|
50 mg/kg
|
i.p.
|
AUC0-t
|
2781 ng·h/mL
|
|
Mice[1]
|
50 mg/kg
|
i.p.
|
AUC0-∞
|
2541 ng·h/mL
|
|
Rat[1]
|
50 mg/kg
|
i.p.
|
AUC0-∞
|
3381 ng·h/mL
|
|
体内研究
(In Vivo) |
SU212 (30 mg/kg，腹腔注射，每日一次，连续 3 天) 在 MDA-MB-231 细胞诱导的雌性 NSG 小鼠模型中，降低了细胞糖酵解速率，从而减少了肿瘤细胞的整体葡萄糖需求[1]。
SU212 (100-400 mg/kg，腹腔注射，单次给药) 在雌性 C57BL/6 小鼠和 SD 大鼠中表现出良好的耐受性[1]。
SU212 (30 mg/kg，腹腔注射，每周 5 天，持续 21 天或 24 天) 在同系原位 TNBC 模型中未诱发肝或肾毒性[1]。
SU212 (20 mg/kg，腹腔注射，每周 5 天) 在杂合 MMTV-PyMT 转基因雌性小鼠模型中对肿瘤的发生和发展具有积极作用[1]。
SU212 (30 mg/kg，腹腔注射，每周 5 天，持续 21 天) 在 TNBC 的原位 EMT6 小鼠模型中，通过诱导ENO1降解导致其亚细胞定位改变并削弱了其兼职功能[1]。
SU212 (10 mg/kg，腹腔注射，每周 5 天，持续 32 天) 在高血糖和高胰岛素血症条件下能抑制肿瘤生长，并可能有助于改善 Leprdb (Db/Db) 小鼠模型的糖尿病和脂肪肝状况[1]。
SU212 (15 或 30 mg/kg，腹腔注射，21 天) 在荧光素酶标记的 MDA-MB-231 异种移植小鼠模型中抑制肿瘤进展[2]。
SU212 (30 mg/kg，腹腔注射，30 天) 在尾静脉肺转移小鼠模型中抑制肺转移[2]。
SU212 (30 mg/kg，腹腔注射，21 天) 在 4T1 同系移植小鼠模型中通过激活 AMPK 通路展现出强效的抗肿瘤生长和抗转移活性，且无显著体重减轻或肝肾毒性并能改善脂质代谢[2]。
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
| Animal Model: |
MDA-MB-231 cells induced- female NSG mice (8-9 weeks)[1] |
| Dosage: |
30 mg/kg |
| Administration: |
i.p., once daily for 3 days |
| Result: |
Did not significantly reduce tumor size compared to the control.
Significantly reduced fdg uptake by tumor cells.
|
| Animal Model: |
Female C57BL/6 mice and SD rats[1] |
| Dosage: |
100, 200, and 400 mg/kg |
| Administration: |
i.p., once |
| Result: |
Observed no signs of stress (behavioral, neurological, and auto nomic stresses.
Did not observe any significant weight loss or mortality.
|
| Animal Model: |
EMT6 cells (1x105) induced-Balb/c mice and PY8119 induced-C57BL/6mice [1] |
| Dosage: |
30 mg/kg |
| Administration: |
i.p. 5 days a week for 21 days (EMT6 induced-Balb/c mice) or 24 days (PY8119 induced-C57BL/6mice) |
| Result: |
Significantly delayed tumor growth in both TNBC models, resulting in significantly lower tumor weight at experiment end.
Did not caused any significant changes in these markers of liver or nephrotoxicity in C57BL/6 mice bearing PY8119 tumors.
|
| Animal Model: |
EMT6 cells (1x105) induced-female NSG mice[1] |
| Dosage: |
30 mg/kg |
| Administration: |
i.p., 5 days/week for 21 days |
| Result: |
Reduced 66% lung metastasis.
|
| Animal Model: |
Female FVB/N-Tg (MMTV-PyVT) 634 Mul/Jmice (5-6 weeks)[1] |
| Dosage: |
20 mg/kg |
| Administration: |
i.p., five days a week |
| Result: |
Improved overall survival and reduced tumor burden and incidence.
|
| Animal Model: |
PY8119 cells (1x105)induced-female Db/Db mice(10 weeks old)[2] |
| Dosage: |
10 mg/kg |
| Administration: |
i.p., 5 days/week for 32 days |
| Result: |
Reduced tumor growth.
Reduced overall tumor burden.
Inhibits eno1 expression.
Did not significantly affect overall mouse body weight.
Did cause a significant drop in blood glucose level.
Significantly reduces the level of AST , ALT, alkaline phosphatase and glutamate dehydroge nase (GLDH).
Significantly reduced liver weight.
Reduced fat-associated space by 80%-90%.
Resulted in a distinct mrna profile, characterized by the downregulation of pi3k pathway genes and the upregulation of mitochondrial respiration pathway genes.
|
| Animal Model: |
MDA-MB-231 cells (2× 106) induced-female NOD/SCID mice (7-8 weeks)[2] |
| Dosage: |
15 and 30 mg/kg |
| Administration: |
i.p., 21 days |
| Result: |
Inhibited TNBC tumour growth by 46 and 71%, respectively.
Did not show significant body-weight changes and no stress or pain behaviour.
Had 42 and 81% less tumour weight at 15mg/kg and 30mg/kg doses respectively.
|
| Animal Model: |
MDA-MB-231 cells (1× 106) induced-female NOD/SCID mice (6-7 weeks)[2] |
| Dosage: |
30 mg/kg |
| Administration: |
i.p., every day for 4 weeks |
| Result: |
Reduced the number of metastatic foci in the lung by 69%.
|
| Animal Model: |
4T1 cells (5×105) induced-female Balb/c mice (7-8 weeks)[2] |
| Dosage: |
30 mg/kg |
| Administration: |
i.p., 30 days |
| Result: |
Inhibited tumour growth by 40% without significant body-weight loss.
Reduced tumour weight by 46%.
Reduced the number of metastatic foci in the lung.
Inhibited the expression of Ki-67 and LDHA Bax and c-Caspase 3.
Causes an inhibition of tumour progression via the AMPK pathway.
Induced the expression of Bax and cleaved caspase 3, consistent with western blot and apoptosis assays.
Did not affect blood glucose, cholesterol, creatinine and BUN, whereas levels of triglycerides and ALP decreased signifi cantly.
Reduced tumour weight by 46%..
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| 分子量 |
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| Formula |
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| CAS 号 |
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| 运输条件 |
Room temperature in continental US; may vary elsewhere.
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| 储存方式 |
Please store the product under the recommended conditions in the Certificate of Analysis.
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| 纯度 & 产品资料 |
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| 参考文献 |
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