CUDC is an orally bioavailable small molecule PI3K and HDAC dual inhibitor that acts on PI3K α And HDAC1 / 2 / 3 / 10 with IC50 of 19 nm and 1.7 nm / 5 nm / 1.8 nm / 2.8 nm [1].
The antitumor activity of the dual function HDAC and PI3K inhibitor CUDC-907 in WSU DLCL2 cells were evaluated. It was observed that CUDC-907 inhibits cell growth and induces apoptosis with nanomolar potency. The cell cycle arrest at G2/M phase, while the expression of cyclin dependent kinase inhibitor 1 was enhanced and the expression of cyclin B was decreased when the cells treated with CUDC-907. CUDC-907 can not only inhibit the phosphorylation of Akt and mTOR and promote the acetylation of histone H3, but also significantly inhibit the phosphorylation levels of Smad2 / 3 and ERK. CUDC-907 may be a candidate drug for the treatment of systemic keloid [2]. CUDC-907 treatment downregulated MYC paralogs and FoxM1, induced G1 cell cycle arrest, and impaired the DNA double strand break (DSB) repair ability of SCLC cells, resulting in an effective antiproliferative effect. In addition, It was found that CUDC-907 treatment enhanced the therapeutic effect of the PARP inhibitor olaparib in SCLC cell models and PDX models. Mechanistic studies showed that cudc-907 synergized with olaparib by blocking the DSB repair pathway and downregulating myc paralogs and FoxM1 [3].
Human pancreatic xenograft model was established by subcutaneous injection of human pancreatic cancer Aspc-1 cells into nude mice. After 19 days of gavage, the tumor growth of Aspc-1 xenograft mice treated with 300 mg / kg cudc-907 once a day was significantly reduced compared with the vehicle group, with a T / C (%) of 43.9% (P ? < 0.01). Importantly, there was no weight loss [4]. It was evaluated that the in vivo role of clinical grade cudc-907 in a mouse model of fibrosis that recapitulates the clinical behavior of idiopathic pulmonary fibrosis. After intratracheal injection of bleomycin, mice were treated with 35% captisol (control) or 1 mg / kg CUDC-907 dissolved in 35% captisol. We found that cudc-907 treatment inhibited collagen accumulation. On day 18, these mice exhibited a significant attenuation of bleomycin induced total lung collagen deposition. In addition, immunohistochemical staining of left lung sections showed that cudc-907 treatment inhibited bleomycin induced total col1, col3 and α- SMA [5].
参考文献:
[1] Whitfield J R, Beaulieu M E, Soucek L. Strategies to inhibit Myc and their clinical applicability[J]. Frontiers in cell and developmental biology, 2017, 5: 10.
[2] Tu T, Huang J, Lin M, et al. CUDC_x001E_907 reverses pathological phenotype of keloid fibroblasts in vitro and in vivo via dual inhibition of PI3K/Akt/mTOR signaling and HDAC2[J]. International journal of molecular medicine, 2019, 44(5): 1789-1800.
[3] Ma L, Bian X, Lin W. The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer[J]. Journal of Experimental & Clinical Cancer Research, 2020, 39(1): 1-14.
[4] Fu X, Zhang X, Yang H, et al. CUDC-907 displays potent antitumor activity against human pancreatic adenocarcinoma in vitro and in vivo through inhibition of HDAC6 to downregulate c-Myc expression[J]. Acta Pharmacologica Sinica, 2019, 40(5): 677-688.
[5] Zhang W, Zhang Y, Tu T, et al. Dual inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 attenuates TGFβ1 induced lung and tumor fibrosis[J]. Cell death & disease, 2020, 11(9): 1-13.
CUDC 是一种口服生物可利用的小分子 PI3K 和 HDAC 双重抑制剂，作用于 PI3K α 和 HDAC1 / 2 / 3 / 10，IC50 分别为 19 nm 和 1.7 nm / 5 nm / 1.8 nm / 2.8 nm [1 ].
在 WSU DLCL2 细胞中评估了双功能 HDAC 和 PI3K 抑制剂 CUDC-907 的抗肿瘤活性。据观察，CUDC-907 以纳摩尔效力抑制细胞生长并诱导细胞凋亡。 CUDC-907处理后细胞周期停滞在G2/M期，细胞周期蛋白依赖性激酶抑制剂1表达增强，细胞周期蛋白B表达降低。 CUDC-907 不仅可以抑制 Akt 和 mTOR 的磷酸化，促进组蛋白 H3 的乙酰化，还可以显着抑制 Smad2/3 和 ERK 的磷酸化水平。 CUDC-907可能是治疗系统性瘢痕疙瘩的候选药物[2]。 CUDC-907 治疗下调 MYC 旁系同源物和 FoxM1，诱导 G1 细胞周期停滞，并损害 SCLC 细胞的 DNA 双链断裂 (DSB) 修复能力，从而产生有效的抗增殖作用。此外，还发现CUDC-907治疗增强了PARP抑制剂奥拉帕尼在SCLC细胞模型和PDX模型中的治疗效果。机制研究表明，cudc-907 通过阻断 DSB 修复途径并下调 myc paralogs 和 FoxM1 [3] 与奥拉帕尼协同作用。
通过将人胰腺癌Aspc-1细胞皮下注射到裸鼠体内，建立人胰腺异种移植模型。灌胃 19 天后，每天一次 300 mg/kg cudc-907 处理的 Aspc-1 异种移植小鼠的肿瘤生长与载体组相比显着降低，T/C (%) 为 43.9% (P ? < ；0.01）。重要的是，体重没有减轻[4]。评估了临床级 cudc-907 在纤维化小鼠模型中的体内作用，该模型概括了特发性肺纤维化的临床行为。气管内注射博来霉素后，用 35% captisol（对照）或溶解在 35% captisol 中的 1 mg/kg CUDC-907 处理小鼠。我们发现 cudc-907 处理抑制了胶原蛋白的积累。在第 18 天，这些小鼠表现出博来霉素诱导的总肺胶原沉积的显着减弱。此外，左肺切片的免疫组织化学染色显示，cudc-907 处理可抑制博来霉素诱导的总 col1、col3 和 α-SMA [5]。
| Cell experiment [1]: | |
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Cell lines |
keloid fibroblasts (KFs) |
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Preparation Method |
The KFs from the secondary culture were seeded onto 96-well plates at a density of 1000 cells/well. Starved cells were treated with medium containing the CUDC-907, GDC-0941 and trichostatin A. Cell proliferation was examined using Cell Counting Kit-8 according to the manufacturer's protocol. |
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Reaction Conditions |
0.32nM 3.2nM 32nM 1、3 、5 、7days |
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Applications |
CUDC-907 significantly decreased the proliferation of KFs in a dose-dependent manner. In addition, the dual inhibitor CUDC-907 was markedly more potent compared with GDC-0941, a PI3K/Akt/mTOR inhibitor, and trichostatin A, a HDAC inhibitor, following drug treatment for 7 days. |
| Animal experiment [2]: | |
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Animal models |
C57BL mice |
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Preparation Method |
When the tumor volume reached about 100mm3 in about 2 to 3 weeks, the mice were randomized into four groups and treated with DMSO control, CUDC-907, olaparib, and CUDC-907/olaparib combination for 15?days. For drug treatment, CUDC-907 was administrated to mice by oral gavage at a dose of 75?mg/kg/day. Olaparib was administrated to mice by intraperitoneal administration at a dose of 55?mg/kg/day. The tumor volume and weight of mice were measured every 3 days. Tumor sizes were measured using a caliper. Tumor weights were measured after 15?days of drug treatment. |
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Dosage form |
75?mg/kg/day |
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Applications |
No significant difference in body weight between control and treated mice was observed, indicating that CUDC-907 monotherapy or in combination with olaparib is well tolerated. While olaparib as monotherapy showed limited efficacy, CUDC-907-treated mice exhibited more potent tumor growth inhibition than vehicle-treated mice. Remarkably, the combination of CUDC-907 and olaparib resulted in a more robust antitumor efficacy in tumor-bearing mice than either single-agent treatment group. |
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参考文献: [1]. Tu T, Huang J, Lin M, et al. CUDC?907 reverses pathological phenotype of keloid fibroblasts in vitro and in vivo via dual inhibition of PI3K/Akt/mTOR signaling and HDAC2[J]. International journal of molecular medicine, 2019, 44(5): 1789-1800. [2]. Ma L, Bian X, Lin W. The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer[J]. Journal of Experimental & Clinical Cancer Research, 2020, 39(1): 1-14. |
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