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Review
. 2016 Sep;142(9):2013-22.
doi: 10.1007/s00432-016-2144-1. Epub 2016 Apr 4.

Hematologic malignancies: newer strategies to counter the BCL-2 protein

Abdul Shukkur Ebrahim  1 , Hussam Sabbagh  1 , Allison Liddane  1 , Ali Raufi  1 , Mustapha Kandouz  2 , Ayad Al-Katib  3
Affiliations
Review

Hematologic malignancies: newer strategies to counter the BCL-2 protein

Abdul Shukkur Ebrahim et al. J Cancer Res Clin Oncol. 2016 Sep.

Abstract

Introduction: 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).

Results and conclusion: 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.

Keywords: Antisense oligonucleotides; BCL-2; DNA interference; Non-Hodgkin lymphoma; Small-molecule inhibitors.

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