Cisplatin enhances apoptosis induced by a tumor-selective adenovirus expressing tumor necrosis factor-related apoptosis-inducing ligand.
BACKGROUND
Cancer cells frequently exhibit resistance to the cytotoxic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Pretreatment of TRAIL-resistant cells with cisplatin sensitizes them to this ligand. Cisplatin also has been shown to enhance adenoviral transgene expression.


OBJECTIVE
This study aims to evaluate the ability of cisplatin to enhance the expression and the cytotoxic effect of the tumor-specific adenoviral vector Ad/gTRAIL, which expresses a green fluorescent protein-TRAIL fusion protein.


METHODS
Cultured cancer cells and normal human cells were infected with Ad/gTRAIL with or without cisplatin pretreatment. Adenoviral transgene expression was determined by using flow cytometry to measure green fluorescent protein fluorescence. Cytotoxicity was measured by using thiazolyl blue tetrazolium bromide assays and an apoptosis enzyme-linked immunosorbent assay kit.


RESULTS
Green fluorescent protein-TRAIL fusion protein expression was significantly enhanced by cisplatin pretreatment in cancer cells. Cisplatin treatment before Ad/gTRAIL infection resulted in a 2- to 12-fold increase in green fluorescent protein fluorescence intensity across cancer lines. Although Ad/gTRAIL induced mild cytotoxicity in all cancer lines (inhibitory concentration of 50% values of >500 pfu/cell), pretreatment with cisplatin resulted in a dose-dependent enhancement of Ad/gTRAIL-mediated cytotoxicity, as indicated by the drastic reduction of inhibitory concentration of 50% values to 4 to 42 pfu/cell in all cell lines. There was no cytotoxicity noted in normal cells treated with both cisplatin and Ad/gTRAIL.


CONCLUSIONS
Cisplatin pretreatment enhances Ad/gTRAIL cytotoxicity in malignant cells while not affecting normal cells. The mechanisms underlying this effect might include both enhancement of the susceptibility of cisplatin-treated cells to TRAIL and cisplatin-mediated enhancement of TRAIL expression in Ad/gTRAIL infected cells. These findings provide a rationale for development of Ad/gTRAIL-based therapy for thoracic malignancies.
Reddy
Rishindra M
RM
Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD 20892, USA.
Tsai
Wilson S
WS
Ziauddin
M Firdos
MF
Zuo
Jingtong
J
Cole
George W
GW
Maxhimer
Justin B
JB
Fang
BingLiang
B
Schrump
David S
DS
Nguyen
Dao M
DM
D000256:Adenoviridae; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000187:drug effects*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D002945:Cisplatin