Targeting Mcl-1 for the therapy of cancer.

Abstract

INTRODUCTION:

Human cancers are genetically and epigenetically heterogeneous and have the capacity to commandeer a variety of cellular processes to aid in their survival, growth and resistance to therapy. One strategy is to overexpress proteins that suppress apoptosis, such as the Bcl-2 family protein Mcl-1. The Mcl-1 protein plays a pivotal role in protecting cells from apoptosis and is overexpressed in a variety of human cancers.

AREAS COVERED:

Targeting Mcl-1 for extinction in these cancers, using genetic and pharmacological approaches, represents a potentially effectual means of developing new efficacious cancer therapeutics. Here we review the multiple strategies that have been employed in targeting this fundamental protein, as well as the significant potential these targeting agents provide in not only suppressing cancer growth, but also in reversing resistance to conventional cancer treatments.

EXPERT OPINION:

We discuss the potential issues that arise in targeting Mcl-1 and other Bcl-2 anti-apoptotic proteins, as well problems with acquired resistance. The application of combinatorial approaches that involve inhibiting Mcl-1 and manipulation of additional signaling pathways to enhance therapeutic outcomes is also highlighted. The ability to specifically inhibit key genetic/epigenetic elements and biochemical pathways that maintain the tumor state represent a viable approach for developing rationally based, effective cancer therapies.

• Authors: Bridget A Quinn, Rupesh Dash, Belal Azab, Siddik Sarkar, Swadesh K Das, Sachin Kumar, Regina A Oyesanya, Santanu Dasgupta, Paul Dent, Steven Grant, Mohamed Rahmani, David T Curiel, Igor Dmitriev, Michael Hedvat, Jun Wei, Bainan Wu, John L Stebbins, John C Reed, Maurizio Pellecchia, Devanand Sarkar, Paul B Fisher
• Journal: Expert opinion on investigational drugs (Expert Opin Investig Drugs) Vol. 20 Issue 10 Pg. 1397-411 (Oct 2011) ISSN: 1744-7658 [Electronic] England
• PMID: 21851287 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antineoplastic Agents
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols
• Drug Design
• Humans
• Molecular Targeted Therapy
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasms (drug therapy, metabolism, physiopathology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)