title: Targeting Mcl-1 for the therapy of cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, USA. pbfisher@vcu.edu
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Quinn
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Belal
authors.initials: B
authors.lastname: Azab
authors.forename: Siddik
authors.initials: S
authors.lastname: Sarkar
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Sachin
authors.initials: S
authors.lastname: Kumar
authors.forename: Regina A
authors.initials: RA
authors.lastname: Oyesanya
authors.forename: Santanu
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Mohamed
authors.initials: M
authors.lastname: Rahmani
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Igor
authors.initials: I
authors.lastname: Dmitriev
authors.forename: Michael
authors.initials: M
authors.lastname: Hedvat
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Bainan
authors.initials: B
authors.lastname: Wu
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2