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Zardaverine is a novel and selective PDE (Phosphodiesterase) 3/4 inhibitor with IC50 values of 0.5 uM and 0.8 uM respectively. Zardaverine exhibits potent and selective antitumor activity against hepatocellular carcinoma both in vitro and in vivo independently of phosphodiesterase inhibition. Zardaverine may be also useful for both, bronchorelaxation and reduction of inflammation in asthma therapy.
| ln Vitro |
Human HCC cell proliferation is specifically inhibited in vitro by zardaverine (0-30 µM; 72 hours) [1]. While not connected to PDE3/4 inhibition, zardaverine exhibits specific anti-tumor activity that is intimately linked to the control of cell cycle-related proteins [1]. In HCC cells, zardaverine (0.1 µM; 24 hours) specifically induces G0/G1 phase arrest and dysregulates proteins linked to the cell cycle [1]. In Bel-7402 and SMMC-7721 cells, zardaverine (0.01, 0.03, 0.1, 0.3 1 µM/48h; 0.3 1 µM/24, 36, 48, 60, 72 h) causes apoptosis in a time- and concentration-dependent manner [1].
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| ln Vivo |
Mice bearing human Bel-7402 xenografts are unable to grow without the oral drug zardaverine (60, 200 mg/kg; once daily for 14 days) [1]. A rat model of airway inflammation and hyperresponsiveness shows 100% blocking of LPS-induced increases in responsiveness when treated with zardaverine (8046.6 µg/kg; i.p.; single dosage) [2].
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: Bel-7402, Bel-7404, QGY-7701 and SMMC-7721 Tested Concentrations: 0-30 µM Incubation Duration: 72 hrs (hours) Experimental Results: Selective inhibition of SMMC-7721, QGY-7701, Bel- For the growth of 7402 and Bel-7404, the IC50 were 36.6, 51.0, 137.7 and 288.0 respectively. Cell cycle analysis[1] Cell Types: Bel-7402, Bel-7404, QGY-7701 and SMMC-7721 Tested Concentrations: 0.1 µM Incubation Duration: 24 hrs (hours) Experimental Results: Induction of Bel-7402, Bel-7404, QGY-7701 and SMMC- Accumulation of 7721 SMMC-7721 cells are in G0/G1 phase. Western Blot Analysis[1] Cell Types: Bel-7402, SMMC-7721 Tested Concentrations: 0.01, 0.03, 0.1, 0.3 1 µM; 0.3 1 µM Incubation Duration: 48 hrs (hours); 24, 36, 48, 60, 72 hrs (hours) Experimental Results: Induction Concentration- and time-dependent increase in cleavage of PARP and caspase-3, -8, and -9 (apoptotic markers). |
| Animal Protocol |
Animal/Disease Models: Female Balb/cA nude mice (5 to 6 weeks old; human Bel-7402 xenograft model) [1].
Doses: 60, 200 mg/kg Route of Administration: Oral; one time/day for 14 days Experimental Results: The 60 mg/kg dose inhibited the growth of Bel-7402 xenografts for 14 days, and the 200 mg/kg dose caused tumor regression. Animal/Disease Models: Inbred male Fisher 344 (F344) rat (250-350 g; 3 to 4 months old; airway inflammation and hyperresponsiveness model) [2]. Doses: 8046.6 µg/kg (30 µmol/Kg) Route of Administration: intraperitoneal (ip) injection; single Experimental Results:complete blocking of LPS-induced hyperresponsiveness and airway inflammation. |
| References |
[1]. Sun L, et al. Phosphodiesterase 3/4 inhibitor zardaverine exhibits potent and selective antitumor activity against hepatocellular carcinoma both in vitro and in vivo independently of phosphodiesterase inhibition. PLoS One. 2014 Mar 5;9(3):e90627.
[2]. Kips JC, et al. The effect of zardaverine, an inhibitor of phosphodiesterase isoenzymes III and IV, on endotoxin-induced airway changes in rats. Clin Exp Allergy. 1993 Jun;23(6):518-23. [3]. Schudt C, et al. Zardaverine: a cyclic AMP specific PDE III/IV inhibitor. Agents Actions Suppl. 1991;34:379-402. |
| Molecular Formula |
C12H10N2O3F2
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|---|---|
| Molecular Weight |
268.2162
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| CAS # |
101975-10-4
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| SMILES |
O=C1C=CC(C2=CC=C(OC(F)F)C(OC)=C2)=NN1
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~25 mg/mL (~93.21 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (7.75 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (7.75 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.7283 mL | 18.6414 mL | 37.2828 mL | |
| 5 mM | 0.7457 mL | 3.7283 mL | 7.4566 mL | |
| 10 mM | 0.3728 mL | 1.8641 mL | 3.7283 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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