Cell lines

keloid fibroblasts (KFs)

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.

Reaction Conditions

0.32nM 3.2nM 32nM 1、3 、5 、7days

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 models

C57BL mice

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.

Dosage form

75 mg/kg/day

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.

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].

References:
[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. CUDC907 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.