Journal of Cancer Research and Clinical Oncology

, Volume 142, Issue 9, pp 2013–2022 | Cite as

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

  • Abdul Shukkur Ebrahim
  • Hussam Sabbagh
  • Allison Liddane
  • Ali Raufi
  • Mustapha Kandouz
  • Ayad Al-Katib
Review – Clinical Oncology

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

BCL-2 Non-Hodgkin lymphoma DNA interference Antisense oligonucleotides Small-molecule inhibitors 

Notes

Acknowledgments

This study was funded by the St. John Hospital and Medical Center Foundation and by Michigan Corporate Relations Network’s (MCRN) Small Company Innovation Program (SCIP). The authors also wish to thank Dr. Mary Walsh for assistance in editing the manuscript.

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest in this work.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of Internal Medicine-Lymphoma Research LabWayne State University and School of MedicineDetroitUSA
  2. 2.Department of PathologyWayne State UniversityDetroitUSA

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