BMH-21 binds ribosomal DNA and inhibits RNA polymerase I (Pol I) transcription. Despite DNA intercalation, BMH-21 does not cause phosphorylation of H2AX, a key biomarker activated in DNA damage stress.BMH-21 inhibits RNA polymerase I (Pol I) transcription, causes the degradation of Pol I catalytic subunit RPA194, and has potent anticancer activity. BMH-21 has wide and potent antitumorigenic activity across NCI60 cancer cell lines and represses tumor growth in vivo. BMH-21 binds GC-rich sequences, which are present at a high frequency in ribosomal DNA genes, and potently and rapidly represses RNA polymerase I (Pol I) transcription. BMH-21 causes proteasome-dependent destruction of RPA194, the large catalytic subunit protein of Pol I holocomplex, and this correlates with cancer cell killing.
|Cell lines||U2OS osteosarcoma cells|
|Preparation method||Maintaining the cells at 37 °C in a humidified atmosphere containing 5% CO2. Culturing U2OS osteosarcoma cells in DMEM supplemented with 15% fetal bovine serum. Plating cells in 96-well plates at a density of 10000 cells/well in triplicate and incubated for 48 h with the compounds. Using WST-1 cell proliferation reagent to determine viability .|
|Incubation time||48 hours|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Oncol Rep (2017). Figure 2. BMH-21|
|Cell Lines||SKOV3 cells|
|Concentrations||1, 2 and 4 μM|
|Incubation Time||24 h|
|Results||The results showed that the levels of BAX and cleaved caspase-3 increased in BMH-21 treated cells, compared with the control group|
Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress.
Peltonen K, et al. Mol Cancer Ther. 2014 Nov;13(11):2537-46. PMID: 25277384.
DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response.
Colis L, et al. Oncotarget. 2014 Jun 30;5(12):4361-9. PMID: 24952786.
A targeting modality for destruction of RNA polymerase I that possesses anticancer activity.
Peltonen K, et al. Cancer Cell. 2014 Jan 13;25(1):77-90. PMID: 24434211.
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