体外研究
(In Vitro) | CA224 (Compound 1) (48 h) shows antiproliferation activity against human cancer cell lines[1].
CA224 (18-48 h) blocks the growth of cancer cells at G0/G1 and G2/M phase of the cell cycle, and selectively kills SV40 large T-antigen transformed normal mouse embryonic liver cells (BNL SV A.8)[1][2].
CA224 (0-4 μM, 30 min) inhibits tubulin polymerization and enhances the depolymerization of stabilized tubulin protein[1].
CA224 (0-72 h) induces cell apoptosis in cancer cells[1].
CA224 (10 μM) shows 50%, 14%, 51% and 19% inhibition of CYP3A4, CYP2D6, CYP2C9, and CYP2C19, respectively[1].
Cell Proliferation Assay[1] | Cell Line: | LS174T, PC-3, MiaPaCa, A549, Calu-1, NCI-H460, NCI-H1299, NCI-H358, BNL CL2 and BNL SV A.8 | | Concentration: | | | Incubation Time: | 48 h | | Result: | Showed antiproliferation activity with IC50values of 3.5, 6.2, 4.0, 3.5, 11.5, 2.0, 2.5, 2.2, 2.6 and 3.8 uM against LS174T, PC-3, MiaPaCa, A549, Calu-1, NCI-H460, NCI-H1299, NCI-H358, BNL CL2 and BNL SV A.8, respectively. |
Cell Cycle Analysis[1][2] | Cell Line: | A549, NCI-H1299, NCI-H358, BNL CL2, BNL SV A.8 and Calu-1 | | Concentration: | IC50concentration (IC70for Calu-1) | | Incubation Time: | 24 h for A549, NCI-H1299 and Calu-1, 18 h for NCI-H358, 48 h for BNL CL2 and BNL SV A.8 | | Result: | Induced a profound block at G2/M in A549 and NCI-H1299 cells. Maintained nocodazole- and paclitaxel-induced G2/M block in NCI-H358 cells. Exhibited prominent G2/M arrest in BNL CL2 cells. 31% of cells were detected in sub-G1 phase (control: 0%) in BNL SV A.8 cells. Retained the G0/G1 block in serum-starved p53-null Calu-1 cells. |
Western Blot Analysis[1] | Cell Line: | A549 and LS174T | | Concentration: | IC50concentration; 1, 2, 3 and 4 μM for tubulin polymerization | | Incubation Time: | 24 h; 30 min for tubulin polymerization in A549 cells | | Result: | Induced p53, p21, and p27. Downregulated cyclin B1 and Cdk1. Inhibited tubulin polymerization in a dose-dependent manner and resulted in accumulation of unassembled tubulin in the supernatant. |
Apoptosis Analysis[1] | Cell Line: | A549, NCI-H460, NCI-H358, and NCI-H1299 | | Concentration: | IC50and IC70concentration | | Incubation Time: | 24, 48 and 72 h | | Result: | Induces apoptotic cell death in a dose- and time-dependent manner. |
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体内研究
(In Vivo) | CA224 (Compound 1) (100 mg/kg; i.p.; once a day for 9 days) shows significant tumor growth inhibition without obvious toxicity[1].
| Animal Model: | The severe combined immunodeficient (SCID) mouse, lacking both T and B immune cells. Male mice weighing 18–25 g, 6–8 weeks of age for subcutaneous injection of HCT-116, female mice weighing 15–24 g, 6–8 weeks of age for subcutaneous injection of NCI-H460[1] | | Dosage: | 100 mg/kg | | Administration: | Intraperitoneal injection, once a day for 9 consecutive days | | Result: | Showed significant tumor growth inhibition in both HCT-116 and NCI-H460 tumor models without significant bodyweight loss. |
| Animal Model: | BALB/c mice[1] | | Dosage: | 10 mg/kg (oral administration) or 1.0 mg/kg (intravenous injection) | | Administration: | Oral or intravenous injection (Pharmacokinetics Analysis) | | Result: | Pharmacokinetics parameters determined for CA224 after IV and PO administration[1].
| Parameter | IV (1 mg/kg) | Oral (10 mg/kg) | | t1/2,β(h) | 0.33 | 1.16 | | AUC0-t(ng·h/mL) | 187 | 172 | | AUC0-∞(ng·h/mL) | 189 | 182 | | Cmax (ng/mL) | 371 | 190 | | Vd(L/Kg) | 2.52 | nd | | Vdss(L/Kg) | 1.76 | nd | | CL (mL/min/kg) | 88.3 | nd | | Bioavailability | - | 9.6% | Time points considered
for t1/2,βcalculation | 0.5-2 h | 1-4 h |
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