Dual treatments targeting IGF-1R, PI3K, mTORC or MEK synergize to inhibit cell growth, induce apoptosis, and arrest cell cycle at G1 phase in MDA-MB-231 cell line

Biomed Pharmacother. 2015 Oct;75:40-50. doi: 10.1016/j.biopha.2015.08.031. Epub 2015 Sep 2.

Abstract

Triple-negative breast cancers (TNBCs) are aggressive cancers that do not benefit from hormonal therapy or therapies that target HER2 receptors. Insulin-like growth factor 1 receptor (IGF-1R), which has been shown to be overexpressed in breast cancer, activates numerous downstream kinases that associate with cell proliferation and survival. This study compared the effects caused by dual treatments targeting IGF-1R, PI3K, mTORC, or MEK with those by single treatments in a TNBC cell line, MDA-MB-231. We used small-molecule kinase inhibitors, namely, NVP-AEW541, NVP-BKM120, KU0063794, and PD0325901 to target IGF-1R, PI3K, mTORC, and MEK, respectively. Combination treatments of PD0325901 with NVP-AEW541, NVP-BKM120 or KU0063794 and NVP-AEW541 with KU0063794 demonstrated a significant synergistic growth inhibition. These dual treatments increased apoptosis and/or cell cycle arrest at G0/G1 phase and enhanced the inhibition of phosphorylation of Akt or downstream molecules of mTORC1, as compared to the single treatments. Our study suggests that targeting multiple kinases in IGF-1R signaling may be a promising therapeutic approach.

Keywords: IGF-1R; MEK; PI3K; Synergism; Triple-negative breast cancer; mTORC.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects*
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / antagonists & inhibitors*
  • Multiprotein Complexes / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Receptors, Somatomedin / antagonists & inhibitors*
  • Receptors, Somatomedin / metabolism
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / enzymology
  • Triple Negative Breast Neoplasms / pathology

Substances

  • IGF1R protein, human
  • Multiprotein Complexes
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Receptors, Somatomedin
  • TOR Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinase
  • Mechanistic Target of Rapamycin Complex 1
  • MAP Kinase Kinase Kinases