Increased sensitivity to cisplatin in non-small cell lung cancer cell lines after FHIT gene transfer.
To evaluate the relevance of fragile histidine triad (FHIT) status in relation to drug treatment, we analyzed the sensitivity of the Fhit-negative non-small cell lung cancer (NSCLC) cell line NCI-H460 to different drugs, after treatment with an adenoviral vector expressing the FHIT transgene. Expression of Fhit resulted in reduced sensitivity to etoposide, doxorubicin, and topotecan. This feature was associated with Fhit-induced downregulation of DNA topoisomerases I and II. In contrast, expression of Fhit did not modulate sensitivity to Taxol, but produced a slight increase in sensitivity to cisplatin, as shown by colony-forming assays. Analysis of apoptosis revealed that, after cisplatin exposure, the number of apoptotic cells was two-fold higher in Fhit-expressing H460 cells. Moreover, it appeared that wildtype p53 was required for sensitization to cisplatin because the effect was marginal in A549 and Calu-1 cells, where the p53 pathway is altered and simultaneous restoration of p53 and Fhit in Calu-1 cells increased cisplatin sensitivity. Fhit could also partially restore sensitivity to cisplatin in Bcl-2- and Bcl-x(L)-overexpressing H460 cells that are normally resistant to this drug. Our results support the possible relevance of FHIT in cisplatin-based chemotherapy as well as in the reversal of drug resistance in NSCLC.
Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
F
F
Andriani
P
P
Perego
N
N
Carenini
G
G
Sozzi
L
L
Roz
D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000188:drug therapy*; D009363:Neoplasm Proteins / Q000235:genetics*; D019076:Transgenes; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D000970:Antineoplastic Agents; D002945:Cisplatin; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase