P21 (waf1/cip1) is required for non-small cell lung cancer sensitive to Gefitinib treatment

Biomed Pharmacother. 2011 Jun;65(3):151-6. doi: 10.1016/j.biopha.2011.02.009. Epub 2011 May 5.

Abstract

Lung cancer is the leading cause of death from cancer in the world. Gefitinib is known to its inhibition of EGFR tyrosine kinase and worldwide used for antitumor in non-small cell lung cancer (NSCLC). Here, we show that Gefitinib reduces p-Akt levels, concomitant with elevation of p21 levels and suppression of cdk2/4 and cyclinE/D1 activities which result in impaired cell cycle progression through G1 arrest only in NSCLC cells in which it inhibits growth. We find that Gefitinib-induced p21 protein stability, rather than increased RNA accumulation, was responsible for the elevated p21 levels. More, treatment of beta-elemene, a natural plant drug extracted from Curcuma wenyujin, restored sensitivity to Gefitinib via the mechanism modulated the elevation of p21 levels in the cells which are acquired resistance to Gefitinib. These data suggest that administration of Gefitinib in combination with beta-elemene may offer great opportunities for NSCLC which are acquired resistance to Gefitinib. The p21 effect on the cells to response to Gefitinib was further confirmed by p21 over-expression and knockdown studies pointing to a requirement of p21 for the cells sensitive to Gefitinib. Thus, we propose that p21 is required for Gefitinib-sensitive NSCLC cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Gefitinib
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Oncogene Protein v-akt / metabolism
  • Phosphorylation
  • Quinazolines / pharmacology*
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Quinazolines
  • RNA, Small Interfering
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • ErbB Receptors
  • Oncogene Protein v-akt
  • Gefitinib