In vitro: BTSA1 has no capacity to directly activate the pro-apoptotic homolog BAK. BTSA1 treatment potently and dose-responsively induces membrane translocation of recombinant soluble BAX to mitochondrial membrane, which is followed by induction of BAX oligomerization. BTSA1-induced BAX activation promotes apoptosis in cancer cells. BTSA1 reduces viability of all AML cell lines in a dose-dependent manner with IC50 values ranged between 1 and 4 μM, which leads to complete effect within 24 hr treatment. It induces dose-dependent caspase-3/7 activation in all five AML cell lines.
In vivo: BTSA1 potently suppresses human acute myeloid leukemia (AML) xenografts and increases host survival without toxicity. It is well-tolerated in mice. BTSA1 has no toxic effects on healthy hematopoiesis, including healthy stem cellenriched (LSK) cells, common myeloid progenitors, granulocyte-monocyte progenitors, and megakaryocyte-erythrocyte progenitors. BTSA1 has substantial half-life in mouse plasma (T1/2 = 15 hr) and oral bioavailability (%F = 51), while a 10 mg/kg dose reaches sufficient levels (~15 μM) of BTSA1 to induce BAX activation and apoptosis in leukemia cells. Thus, BTSA1 is orally bioavailable with excellent pharmacokinetics, has significant anti-tumor activity in leukemia xenografts by promoting apoptosis, and at therapeutically effective doses it does not show any detectable toxicity in the hematopoietic system or other tissues.
|Cell lines||AML cells|
|Preparation method||AML cells (2 × 10^4 cells/well) are seeded in 96-well white plates and incubated with serial dilutions of BTSA1 or BTSA2 or vehicle (0.15% DMSO) in no FBS media for 2.5 hr, followed by 10% FBS replacement to a final volume of 100 μl. Cell viability is assayed at 24 h|
|Incubation time||2.5 h|
|Animal models||6-8 weeks old NOD-SCID IL2Rg null (NSG) mice/6-8 weeks old ICR (CD-1) male mice|
|Formulation||1% DMSO, 30% PEG-400, 65% D5W (5% dextrose in water), 4% Tween-80|
|Administration||oral gavage or intravenous injection|
|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.
|Solubility||81 mg/mL in DMSO|
Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia.
Reyna DE, et al. Cancer Cell. 2017 Oct 9;32(4):490-505. PMID: 29017059.
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