The development of MDA-7/IL-24 as a cancer therapeutic

Paul Dent, Adly Yacoub, Hossein A. Hamed, Margaret A. Park, Rupesh Dash, Sujit K. Bhutia, Devanand Sarkar, Xiang Yang Wang, Pankaj Gupta, Luni Emdad, Irina V. Lebedeva, Moira Sauane, Zhao zhong Su, Mohamed Rahmani, William C. Broaddus, Harold F. Young, Maciej S. Lesniak, Steven Grant, David T. Curiel, Paul B. Fisher

Research output: Contribution to journalReview articlepeer-review

47 Scopus citations

Abstract

The cytokine melanoma differentiation associated gene 7 (mda-7) was identified by subtractive hybridization as a protein whose expression increased during the induction of terminal differentiation, and that was either not expressed or was present at low levels in tumor cells compared to non-transformed cells. Based on conserved structure, chromosomal location and cytokine-like properties, MDA-7, was classified as a member of the interleukin (IL)-10 gene family and designated as MDA-7/IL-24. Multiple studies have demonstrated that expression of MDA-7/IL-24 in a wide variety of tumor cell types, but not in corresponding equivalent non-transformed cells, causes their growth arrest and rapid cell death. In addition, MDA-7/IL-24 has been noted to radiosensitize tumor cells which in part is due to the generation of reactive oxygen species (ROS) and ceramide that cause endoplasmic reticulum stress and suppress protein translation. Phase I clinical trial data has shown that a recombinant adenovirus expressing MDA-7/IL-24 (Ad.mda-7 (INGN-241)) was safe and had measurable tumoricidal effects in over 40% of patients, strongly arguing that MDA-7/IL-24 could have significant therapeutic value. This review describes what is presently known about the impact of MDA-7/IL-24 on tumor cell biology and its potential therapeutic applications.

Original languageEnglish (US)
Pages (from-to)375-384
Number of pages10
JournalPharmacology and Therapeutics
Volume128
Issue number2
DOIs
StatePublished - Nov 2010

Bibliographical note

Funding Information:
Support was provided by P01-CA104177 , R01-CA108325 , R01-DK52825 ; R01-CA063753 , R01-CA077141 , R01-CA097318 ; R01-CA127641 ; R01-CA098712 ; P01-NS031492 , the Samuel Waxman Cancer Research Foundation (SWCRF) and the National Foundation for Cancer Research (NFCR) . P.D. is the Universal Professor in Signal Transduction and P.B.F. holds the Thelma Newmeyer Corman Chair in Cancer Research and is a SWCRF Investigator.

Keywords

  • Apoptosis
  • Autophagy
  • Ca
  • Ceramide
  • Clinical trial
  • ER stress
  • IL-24
  • MCL-1
  • MDA-7
  • PERK
  • ROS
  • Signal transduction

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