DMXAA (Vadimezan, AS-1404) is a selective inhibitor of DT-diaphorase with Ki50 and IC50 value of 20 μM and 62.5 μM, respectively [1, 2].
DT-diaphorase (DTD) is an obligate two-electron reductase and it has been reported that the expression of DTD is elevated in a variety of cancers [2].
DMXAA (Vadimezan) a potent DT-diaphorase inhibitor and is also reported as a multi-inhibitor for several kinases. When tested with sections of colon 38 tumors isolated from C57Bl/6 mice at different time, DMXAA (Vadimezan) (25 mg/kg) showed a high induction on endothelium cell apoptosis after 30 min treatment and showed intensely apoptotic vessels and large areas of necrosis of the tumor after 3 h treatment [2]. In NSCLC cell line A549 cells, DMXAA (Vadimezan) treatment arrested cell in G1 phase and induced cell apoptosis and autophagy by increasing cytosolic level of cytochrome and activation of caspase3 in a dose dependent manner from 0.1 μM to 10 μM [3].
In C57Bl/6 mice model with luciferase-expressing murine GL261 glioma cells subcutaneous xenograft, administration of DMXAA (Vadimezan) (25 mg/kg) resulted in widespread necrosis at 24 h, a 9-day growth delay and complete regressions in 50 % mice. Furthermore, co-administration of lenalidomide (100 mg/kg) significantly increased the growth delay to 20 days and the percentage of cures to 83 % [4].
It is reported that DMXAA (Vadimezan) is a multi-inhibitor to several kinases, with most potent effects being on members of the VEGFR (vascular endothelial growth factor receptor) tyrosine kinase family. In zebrafish embryos and HUVECs (human umbilical vein endothelial cells), DMXAA (Vadimezan) blocked the angiogenesis and VEGFR2 signalling [5].
参考文献:
[1].? Phillips, R.M., Inhibition of DT-diaphorase (NAD(P)H:quinone oxidoreductase, EC 1.6.99.2) by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA): implications for bioreductive drug development. Biochem Pharmacol, 1999. 58(2): p. 303-10.
[2].? Ching, L.M., et al., Induction of endothelial cell apoptosis by the antivascular agent 5,6-Dimethylxanthenone-4-acetic acid. Br J Cancer, 2002. 86(12): p. 1937-42.
[3].? Pan, S.T., et al., Proteomic response to 5,6-dimethylxanthenone 4-acetic acid (DMXAA, vadimezan) in human non-small cell lung cancer A549 cells determined by the stable-isotope labeling by amino acids in cell culture (SILAC) approach. Drug Des Devel Ther, 2015. 9: p. 937-68.
[4].? Yung, R., et al., Efficacy against subcutaneous or intracranial murine GL261 gliomas in relation to the concentration of the vascular-disrupting agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), in the brain and plasma. Cancer Chemother Pharmacol, 2014. 73(3): p. 639-49.
[5].?? Buchanan, C.M., et al., DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGFR2 in particular. Clin Sci (Lond), 2012. 122(10): p. 449-57.
| Cell experiment: [1] | |
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Cell lines |
HECPP cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Reaction Conditions |
IC50: 500 μg/mL, 24 hours |
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Applications |
DMXAA did not induce mRNA for TNF or interferons in the HECPP cells. The mRNA of IP-10 was up-regulated following 2 h incubation with DMXAA at 400 μg/mL. Apoptotic cells were seen after 6 h incubation with DMXAA at this concentration. And the numbers increased with prolonged exposure. Apoptotic cell numbers at 24 h increased linearly with increasing dose of DMXAA above 100 μg/mL. The DMXAA concentration that induced 50% apoptosis after incubation for 24 h was 500 μg/mL. |
| Animal experiment: [2] | |
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Animal models |
Male 129/Sv mice injected with 344SQ-ELuc cells |
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Dosage form |
Intraperitoneal injection, 25 mg/kg |
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Applications |
Once tumors were established (day 7 or day 14 for subcutaneous tumors), mice were given 25 mg/kg of DMXAA by i.p. injection. BLI was carried out at 6 and 24 hours. 344SQ-ELuc NSCLC subcutaneous tumors respond dramatically to DMXAA, with a marked (~2-logs) decrease in bioluminescence (BLI) signals post-drug injection. The drop in BLI following DMXAA treatment was not due to direct tumor cell toxicity since DMXAA had no detrimental effect on 344SQ-ELuc cell viability. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1] Ching L M, Cao Z, Kieda C, et al. Induction of endothelial cell apoptosis by the antivascular agent 5, 6-dimethylxanthenone-4-acetic acid. British journal of cancer, 2002, 86(12): 1937-1942. [2] Downey C M, Aghaei M, Schwendener R A, et al. DMXAA Causes Tumor Site-Specific Vascular Disruption in Murine Non-Small Cell Lung Cancer, and like the Endogenous Non-Canonical Cyclic Dinucleotide STING Agonist, 2′ 3′-cGAMP, Induces M2 Macrophage Repolarization. PloS one, 2014, 9(6): e99988. |
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