Combination effect of caffeine and cisplatin on a cisplatin resistant human lung cancer cell line

The development of resistance to anti-cancer drugs is a major factor in limiting the response rate of cancer chemotherapy. Several mechanisms of such resistance are reported. Recently, expression of MDR gene and synthesis of p-glycoprotein by the MDR gene was reported as a mode of multi-drug resistance, but the mechanism of the resistance to cisplatinum (CDDP) remains unclear. Detoxification of CDDP, increase of the efflux of the drug and increase of DNA repair are considered to be the mode of CDDP resistance. It is widely documented that caffeine enhances the cytocidal effect of certain anti-cancer agents. The inhibition of DNA repair by caffeine has been considered to be one mechanism which enhances the cytocidal effect of such agents. We conducted the present study to evaluate the combination effect of caffeine and CDDP on the human lung adenocarcinoma cell line PC9/P and its CDDP resistant cell line PC9/R. Cell growth inhibition was measured by clonogenic assay and cell cycle analysis was performed with propidium iodide (PI) stain using flow cytometer (FCM). Caffeine enhanced the effect of CDDP on PC9/P synergistically. However, the combination effect of the two drugs was not apparent on PC9/R. Caffeine decreased G2M accumulation due to CDDP exposure in both cell lines. The data indicate that caffeine does not overcome the resistance of PC9/R, whereas caffeine enters PC9/R. It is suggested that increase of DNA repair might not be a mode of the CDDP resistance of PC9/R.