| In Vitro | In vitro activity: BTSA1 has no ability 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.
Cell Assay: AML cells are seeded in 96-well white plates (2 × 104 cells/well ) 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 hr. |
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| In Vivo | BTSA1 potently suppresses human acute myeloid leukemia (AML) xenografts and increases host survival without toxicity. It is well-tolerated in mice with 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. |
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| Animal model | NOD-SCID IL2Rg null (NSG) mice/ICR (CD-1) male mice, 6-8 weeks old |
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| Formulation & Dosage | Formulated in 1% DMSO, 30% PEG-400, 65% D5W (5% dextrose in water), 4% Tween-80; 10 mg/kg; P.O. and I.V. |
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| References | Cancer Cell. 2017 Oct 9;32(4):490-505.e10. |
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