Efficacy of signal pathway inhibitors alone and in combination with Cisplatin varies between human non-small cell lung cancer lines.
BACKGROUND
Signal pathway inhibitors (SPI) are designed to act synergistically with conventional cytotoxic drugs to control cancer progression. The objective of this study was to evaluate the effect of various SPI, both alone and in combination with cisplatin, on three different non-small cell lung cancer (NSCLC) cell lines.


METHODS
Cell lines (A549, 201T, 273T) representing NSCLC were treated for 72 h in the presence or absence of inhibitors to PI3K (LY-294002; Tocris Bioscience, Ellisville, MO), BCL-2 (Gossypol; Sigma-Aldrich, St. Louis, MO), Cox-2 (NS-398 [Sigma-Aldrich] or Celecoxib [Pfizer]), MAPK (U0126 [Sigma-Aldrich]), and EGFR (Iressa; AstraZeneca, Macclesfield, United Kingdom) both alone and in combination with 10 or 30 mum cisplatin (Sigma-Aldrich) (18 possible regimens for each cell line). MTT assay (Trevigen, Gaithersburg, MD) was used to measure cytotoxicity. Controls were represented by cells with either a pure culture medium (monotherapy regimen control) or culture medium with the corresponding dose of cisplatin (combination regimen control). Unpaired t-test was used to classify response to therapy as highly sensitive (P < 0.01), sensitive (0.01 < or = P < 0.05), or resistant (P > or = 0.05). Concordance was defined as a similar response category between cell lines.


RESULTS
The concordance rate was 50% between each of the three cell lines when SPI were used as monotherapy. In combination regimens, the concordance rates were 33% (A549 and 273T), 17% (A549 and 201T), and 75% (273T and 201T). The 273T cells were most susceptible to therapy, having 11 (61%) highly sensitive responses, whereas A549 cells were least susceptible with 14 (78%) resistant responses.


CONCLUSIONS
There is a substantial degree of variability between NSCLC cell lines in response to SPI, both alone and in combination with cisplatin.
Kilic
Arman
A
Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15232, USA.
Schuchert
Matthew J
MJ
Luketich
James D
JD
Landreneau
Rodney J
RJ
El-Hefnawy
Talal
T
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002867:Chromones / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006072:Gossypol / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D009025:Morpholines / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000627:therapeutic use
D002867:Chromones; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D009025:Morpholines; D011720:Pyrazoles; D013449:Sulfonamides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000068579:Celecoxib; D006072:Gossypol; D002945:Cisplatin