Induction of chemosensitivity to cisplatin in non small cell lung cancer by 9-cis retinoic acid: Modulation by the specific erbB-2/p185 tyrosine kinase inhibitor CP127, 374

Dao Nguyen, J. Q. Kuang, M. N. Duong, M. Alaoui-Jamali

Research output: Contribution to journalArticle

Abstract

Purpose: We have recently observed significant enhancement of sensitivity to cisplatin (CDDP) in 5 out of 8 non-small cell lung cancer (NSCLC) cell lines in vitro by exposure of cells to 9-cis retinoic acid (9cRA). Minor or absence of RA-induced chemosensitization is noted in 4 cell lines that overexpress the oncogene erbB-2/p185. The aim of this project is to determine if RA-induced CDDP chemosensitization can be achieved in these cells by downregulating erbB-2/p185 gene functions with CP127,374 (CP). Methods: Cells with low to medium (H358, H322) or high (H661, H522) levels of erbB-2/p185 expression were exposed to 9cRA (5μM) for 2 days prior to coincubation with CDDP (0.25 to 8 μg/ml) with CP (10,20,40 nM) for 4 more days (9cRA/9cRA+CP+CDDP). Controls are cells treated either with CDDP alone, with 9cRA/9cRA+CDDP or with CDDP+CP. Cell growth is quantitated by MTT assays. Cisplatin IC50 values of each treatment group are calculated. Results: 9cRA, CP or CP+9cRA treatments have no effect on cell growth. As expected, 9cRA fails to induce chemosensitization in medium to high erbB-2/p185 expressing cells. CP alone at 20 and 40 nM slightly sensitizes these cells to CDDP. The combination of CP and 9cRA, on the other hand, significantly induces chemosensitivity as shown by drastic reduction of CDDP IC50 (Mean (SEM), μg/ml, n=4, p<0.01 of all groups by ANOVA except # showing no significant difference vs CDDP)(see attached table) Conclusions: The addition of CP127,374 to NSCLC that overexpress erbB-2/p185 results in significant 9cRA-induced sensitization to CDDP. The synergistic chemosensitization effect is dependent on CP doses employed and the magnitude of enhancement by CP+9cRA combination is inversely correlated with the quantitative expression of the erbB-2 oncogene. Clinical Implications: 30% of NSCLC over-expresses erbB-2/p185 and exhibits resistance to chemosensitization. Downregulation of erbB-2/ p185 gene function by CP127,374 allows induction of CDDP sensitivity by 9cRA in this subgroup of NSCLC that are otherwise resistant to such maneuver. H358 H322 H661 H552 CDDP 4.73 (0.36) 6.38 (0.91) 2.21 (0.32) 2.50(0.17) CDDP+9cRA 3.05 (0.60) 6.21 (0.66)# 2.20 (0.40)* 2.48 (0.83)# + CP (10nM) 0.45 (0.21) 2.08 (0.44) 3.03 (0.76)# 1.35 (0.18) + CP (20nM) 0.32 (0.11) 1.58 (0.26) 0.25 (0.11) 0.53 (0.14) + CP (40nM) 0.11 (0.02) 0.58 (0.33) 0.11 (0.03) 0.44 (0.15) Increasing erbB-2 expression.

Original languageEnglish (US)
Pages (from-to)268S
JournalCHEST
Volume114
Issue number4 SUPPL.
StatePublished - Oct 1 1998
Externally publishedYes

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Cardiology and Cardiovascular Medicine

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