Bardoxolone

Biological Activity

In vitro: Bardoxolone exhibits potent inhibitory activities against production of nitric oxide induced by interferon-Ƴ in mouse macrophages with IC50 of 0.1 nM. Bardoxolone Methyl decreases the viability of leukemic HL-60, KG-1, and NB4 cells with IC50 of 0.4, 0.4, and 0.27 μM, respectively. CDDO-Me induces pro-apoptotic Bax protein, inhibits the activation of ERK1/2, and it blocks Bcl-2 phosphorylation, which contributes to the induction of apoptosis. Bardoxolone Methyl potently inhibits both constitutive and inducible NF-kappaB activated by TNF, interleukin (IL)-1beta, phorbol ester, okadaic acid, hydrogen peroxide, lipopolysaccharide, and cigarette smoke.

In vivo: Bardoxolone (60 mg/kg) reduces the number, size, and severity of lung tumors in vivo. Bardoxolone Methyl significantly reduces the in vivo inflammatory cytokine response following LPS challenge, induces HO-1 protein expression in the spleen, and protects mice against lethal-dose LPS.

Protocol

Cell Experiment
Cell lines	HL-60, KG-1, and NB4 cells
Preparation method	Leukemic cell lines are cultured at a density of 3.0 × 10^5 cells/mL, and AML mononuclear cells are cultured at 5 × 10^5 cells/mL in the presence or absence of indicated concentrations of CDDO-Me. Appropriate amounts of DMSO (final concentration less than 0.05%) are included as control. For cytotoxicity studies, 1 μM ara-C is added to the cultures. After 24 to 72 hours, viable cells are counted with the trypan blue dye exclusion method using a hematocytometer.
Concentrations	~5 μM
Incubation time	72 hours

Animal Experiment
Animal models	Female A/J mice are injected i.p. with vinyl carbamate.
Formulation	DMSO
Dosages	~60 mg/kg
Administration	Oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

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 K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

References

Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl.
Chin MP, et al. J Card Fail. 2014 Dec;20(12):953-8. PMID: 25307295.

Mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl.
Chin MP, et al. Am J Nephrol. 2014;39(6):499-508. PMID: 24903467.

Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.
de Zeeuw D, et al. N Engl J Med. 2013 Dec 26;369(26):2492-503. PMID: 24206459.