Method of treating BCL-2 over-expressing disorders using arts containing a BH3-like domain

A method for treating a B-cell lymphoma 2 (Bcl-2) over-expressing pathological disorder in a subject in need thereof, said method comprising the steps of:

• (a) determining the level of expression of said Bcl-2 protein in at least one biological sample of a potential subject to obtain an expression value;
• (b) determining if the expression value obtained in step (a) is any one of positive or negative with respect to a predetermined standard expression value or to an expression value of said Bcl-2 in a control sample;
• (c) identifying the potential subject as a subject in need of treatment for a Bcl-2 over-expressing pathological disorder, if the determination of step (b) is that the expression value obtained in step (a) is positive, and
• (d) administering to said subject identified in step (c) a therapeutically effective amount of at least one antagonist of said Bcl-2 protein comprising a peptide of ARTS or any composition comprising the same, wherein said peptide of ARTS comprises a BH3-like domain and consists of residues 1-128, 1-148, 106-148, 106-128, 106-133, 112-148, 112-128, 112-133, 106-140 or 112-126 of ARTS (SEQ ID NO. 9).

A method for treating a Bcl-2 over-expressing pathological disorder in a subject in need thereof comprising inhibiting Bcl-2 over-expression or inducing apoptosis in said subject, said method comprising the steps of:

• (a) determining the level of expression of ARTS in at least one biological sample of a potential subject, to obtain an expression value;
• (b) determining if the expression value obtained in step (a) is any one of positive or negative with respect to a predetermined standard expression value or to an expression value of ARTS in a control sample;
• (c) identifying the potential subject as a subject if the determination of step (b) is that the expression value obtained in step (a) is negative;
• and
• (d) administering to said subject identified in step (c) at least one BH3-like antagonist comprising ARTS or any peptide thereof comprising the BH3-like domain, or any composition comprising the same, and at least one BH3 mimetics compound;
• wherein the combination of said antagonist with said BH3 mimetics results in a synergistic effect on induction of apoptosis in said subject, wherein said ARTS peptide consists of residues 1-128, 1-148, 106-148, 106-128, 106-133, 112-148, 112-128, 112-133, 106-140 or 112-126 of ARTS (SEQ ID NO:
• 9), and wherein BH3 mimetics compound is selected from the group consisting of 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[ [4-[ [(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl] amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (ABT-263), (R)-4-(4-((4′-chloro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide (ABT-737), 1,1′,6,6′,7,7′-hexahydroxy-5,5′-diisopropyl-3,3′-dimethyl-[2,2′-binaphthalene]-8,8′-dicarbaldehyde (AT-101), (Z)-2-(2-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-3-methoxy-2H-pyrrol-5-yl)-1H-indole methanesulfonate (GX15-070), and DNA, d(P-thio)(T-C-T-C-C-C-A-G-C-G-T-G-C-G-C-C-A-T (SEQ ID NO. 7)) (oblimersen sodium).

A method for treating a Bcl-2 over-expressing pathological disorder in a subject, said method comprising the step of administering to said subject a therapeutically effective amount of at least one antagonist of Bcl-2 protein comprising ARTS or any peptide thereof, or any composition comprising the same, simultaneously with at least one BH3-mimetics compound, wherein the combination of said antagonist with said BH3 mimetics compound results in a synergistic effect on induction of apoptosis in said subject, wherein said peptide of ARTS comprises a BH3-like domain and consists of residues 1-128, 1-148, 106-148, 106-128, 106-133, 112-148, 112-128, 112-133, 106-140 or 112-126 of ARTS (SEQ ID NO:9), and wherein said BH3 mimetics compound is selected from the group consisting of 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (ABT-263), (R)-4-(4-((4′-chloro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide (ABT-737), 1,1′,6,6′,7,7′-hexahydroxy-5,5′-diisopropyl-3,3′-dimethyl-[2,2′-binaphthalene]-8,8′-dicarbaldehyde (AT-101), (Z)-2-(2-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)-3-methoxy-2H-pyrrol-5-yl)-1H-indole methanesulfonate (GX15-070), and DNA, d(P-thio)(T-C-T-C-C-C-A-G-C-G-T-G-C-G-C-C-A-T (SEQ ID NO. 7)) (oblimersen sodium).