Inhibitors of Bcl-2
A protease resistant polypeptide includes an amino acid sequence that has a sequence identity at least 80% homologous to about 10 to 80 consecutive amino acids of SEQ ID NO:1.
1. A method of inducing apoptosis in a lymphoma, leukemia, or a multiple myeloma cell expressing Bcl-2 and IP 3 R, comprising:
administering to the lymphoma, leukemia, or multiple myeloma cell, wherein the cell overexpresses Bcl-2, a therapeutically effective amount of a polypeptide that inhibits binding of Bcl-2 to IP 3 receptors (IP 3 R) of cells that express IP 3 R and Bcl-2, the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, and 7, and a transport moiety that facilitates transport of the purified peptide across a biological membrane.
2. The method of claim 1 , the polypeptide reversing the interaction of Bcl-2 with IP 3 R of cells that express IP 3 R and Bcl-2.
3. The method of claim 1 , further comprising administering a second agent to the cells that inhibits binding of Bcl-2 to BH3 pro-apoptotic proteins.
4. The method of claim 3 , the second agent comprising N-(4-(4-(4′-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl)-bezoyl)-4-(3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-3-nitro-benzenesulfonamide ABT-737.
5. A method of treating a neoplastic disorder in a subject, comprising:
administering to neoplastic cells of the subject expressing IP 3 R and Bcl-2, wherein the neoplastic cells overexpress Bcl-2, a therapeutically effective amount of a polypeptide that inhibits binding of Bcl-2 to IP 3 receptors (IP 3 R) of cells that express IP 3 R and Bcl-2, the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6,and 7, and a transport moiety that facilitates transport of the purified peptide across a biological membrane:
wherein the neoplastic disorder comprises lymphoma, leukemia, or multiple myeloma.
6. The method of claim 5 , the polypeptide reversing the interaction of Bcl-2with IP 3 R of cells that express IP 3 R and Bcl-2.
7. The method of claim 5 , further comprising administering a second agent to the cells that inhibits binding of Bcl-2 to BH3 pro-apoptotic proteins.
8. The method of claim 7 , the second agent comprising N-(4-(4-(4′-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl)-bezoyl)-4-(3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-3-nitro-benzenesulfonamide or ABT-737.
9. The method of claim 5 , wherein the neoplastic disorder comprises chronic lymphocytic leukemia or multiple myeloma.
10. The method of claim 1 , the polypeptide having an amino acid sequence comprising SEQ ID NO: 12.
11. The method of claim 5 , the polypeptide having an amino acid sequence comprising SEQ ID NO: 12.