Insulin-like growth factor-I promotes multidrug resistance in MCLM colon cancer cells

J Cell Physiol. 1998 May;175(2):141-8. doi: 10.1002/(SICI)1097-4652(199805)175:2<141::AID-JCP3>3.0.CO;2-O.


Insulin-like growth factor-I (IGF-I) is known as a potent mitogen for a variety of cell types, including colon cancer cell lines. The objective of this study was to determine the effect of IGF-I on cell death induced by cytotoxic agents actinomycin D (Act-D), lovastatin (LOV), and doxorubicin (DOX) in the MCLM mouse colon cancer cell line, and the mechanisms involved. Subconfluent monolayer MCLM cells were treated with IGF-I (25 ng/ml) for 12 h in serum-free media. Various concentrations of cytotoxic agents then were added to the cells that were incubated continually at 37 degrees C for 24 h. Cell survival was determined with the MTT (3-[4-5-dimenthylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, which assesses mitochondrial function in living cells. The mRNA expression for multidrug resistance gene-1 (mdr-1), c-H-ras, and manganese superoxide dismutase (MnSOD) in cells treated with IGF-I was examined by Northern blot or RNase protection assays. The levels of p-glycoprotein, a drug efflux pump encoded by the mdr-1 gene, were assessed by Western immunoblotting. Results demonstrated that 1) IGF-I significantly inhibited the cell death and apoptosis of MCLM cells treated with Act-D, LOV, or DOX; 2) IGF-I increased mRNA expression for mdr-1, c-H-ras, and MnSOD; 3) the p-glycoproteins in cells treated with IGF-I or stably transfected with c-H-ras were elevated when compared with control. These results suggest that IGF-I protects MCLM cells against death induced by cytotoxic agents; this acquired drug resistance may be mediated by multiple mechanisms, including promoting expression of mdr-1, c-H-ras, and MnSOD; whereas, the p-glycoprotein level stimulated by IGF-I may result partly from the increase of c-H-ras in the cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Apoptosis / drug effects
  • Cell Survival / drug effects*
  • Colonic Neoplasms / metabolism*
  • Dactinomycin / pharmacology
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple / physiology*
  • Gene Expression Regulation / drug effects
  • Genes, MDR / drug effects
  • Genes, ras / drug effects
  • Insulin-Like Growth Factor I / pharmacology*
  • Lovastatin / pharmacology
  • Mice
  • Mitochondria / physiology
  • RNA, Messenger / metabolism
  • Superoxide Dismutase / genetics
  • Tetrazolium Salts / metabolism
  • Thiazoles / metabolism
  • Tumor Cells, Cultured


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • RNA, Messenger
  • Tetrazolium Salts
  • Thiazoles
  • Dactinomycin
  • Insulin-Like Growth Factor I
  • Doxorubicin
  • Lovastatin
  • Superoxide Dismutase
  • thiazolyl blue