title: Hematologic malignancies: newer strategies to counter the BCL-2 protein.
abstract: BACKGROUND
  BCL-2 is the founding member of the BCL-2 family of apoptosis regulatory proteins that either induce (pro-apoptotic) or inhibit (anti-apoptotic) apoptosis. The anti-apoptotic BCL-2 is classified as an oncogene, as damage to the BCL-2 gene has been shown to cause a number of cancers, including lymphoma. Ongoing research has demonstrated that disruption of BCL-2 leads to cell death. BCL-2 is also known to be involved in the development of resistance to chemotherapeutic agents, further underscoring the importance of targeting the BCL-2 gene in cancer therapeutics. Thus, numerous approaches have been developed to block or modulate the production of BCL-2 at the RNA level using antisense oligonucleotides or at the protein level with BCL-2 inhibitors, such as the novel ABT737.
  
  
  METHODS
  In this article, we briefly review previous strategies to target the BCL-2 gene and focus on a new approach to silence DNA, DNA interference (DNAi).
  
  
  CONCLUSIONS
  DNA interference is aimed at blocking BCL-2 gene transcription. Evaluations of this technology in preclinical and early clinical studies are very encouraging and strongly support further development of DNAi as cancer therapeutics. A pilot phase II clinical trial in patients with relapsed or refractory non-Hodgkin lymphoma, PNT2258 demonstrated clinical benefit in 11 of 13 patients with notable responses in diffuse large B cell lymphoma and follicular lymphoma. By targeting the DNA directly, the DNAi technology promises to be more effective compared with other gene-interference strategies that target the RNA or protein but leaves the dysregulated DNA functional.
authors.affiliation: Department of Internal Medicine-Lymphoma Research Lab, Wayne State University and School of Medicine, 8229 Scott Hall, 540 E. Canfield, Detroit, MI, 48201, USA.
authors.forename: Abdul Shukkur
authors.initials: AS
authors.lastname: Ebrahim
authors.affiliation: Department of Internal Medicine-Lymphoma Research Lab, Wayne State University and School of Medicine, 8229 Scott Hall, 540 E. Canfield, Detroit, MI, 48201, USA.
authors.forename: Hussam
authors.initials: H
authors.lastname: Sabbagh
authors.affiliation: Department of Internal Medicine-Lymphoma Research Lab, Wayne State University and School of Medicine, 8229 Scott Hall, 540 E. Canfield, Detroit, MI, 48201, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Liddane
authors.affiliation: Department of Internal Medicine-Lymphoma Research Lab, Wayne State University and School of Medicine, 8229 Scott Hall, 540 E. Canfield, Detroit, MI, 48201, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Raufi
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, 48201, USA.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Kandouz
authors.affiliation: Department of Internal Medicine-Lymphoma Research Lab, Wayne State University and School of Medicine, 8229 Scott Hall, 540 E. Canfield, Detroit, MI, 48201, USA. alkatib@med.wayne.edu.
authors.forename: Ayad
authors.identifier: http://orcid.org/0000-0002-5684-948X
authors.initials: A
authors.lastname: Al-Katib
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000627:therapeutic use*; D019254:Genes, bcl-2 / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D054852:Small Molecule Libraries
keywords: Antisense oligonucleotides; BCL-2; DNA interference; Non-Hodgkin lymphoma; Small-molecule inhibitors