Paclitaxel and vincristine potentiate adenoviral oncolysis that is associated with cell cycle and apoptosis modulation, whereas they differentially affect the viral life cycle in non-small-cell lung cancer cells.
Chemotherapy, including microtubule (MT)-interacting agents, can enhance the tumor-eradicating activity of replication-competent adenoviruses. The purpose of this study was to obtain more insight into the mechanism underlying this enhancement that may be exploited for the development of improved therapy. Two MT-interacting agents with opposite activity, paclitaxel (PTX) that stabilizes and vincristine (VCR) that destabilizes MTs, were found to synergistically enhance adenoviral oncolysis in non-small-cell lung cancer (NSCLC) cells. To explore the possibility that these drugs affect the viral life cycle by modulating adenoviral gene expression, we used a quantitative reverse transcription-polymerase chain reaction assay and found that PTX, but not VCR, increased the expression of E1A13S, ADP and Penton genes, which correlated with an increase in viral particle assembly and release. Next, the effect of combined treatment on cell-cycle progression was studied. Both drugs suppressed adenovirus-induced S-phase arrest and instead caused G2/M arrest, which was accompanied by an increase in apoptotic cells. Taken together, the enhancement of oncolysis by MT-interacting drugs appears not to require specific MT transport or scaffold functions. Our findings suggest that MT-interacting drug-induced cellular signals that modulate cell-cycle arrest and apoptosis are primarily on the basis of their oncolysis-enhancing activity.
AbouEl Hassan
M A I
MA
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Braam
S R
SR
Kruyt
F A E
FA
D000256:Adenoviridae / Q000187:drug effects / Q000235:genetics*; D017503:Adenovirus E3 Proteins / Q000187:drug effects / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D036022:Capsid Proteins / Q000187:drug effects / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008870:Microtubules / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*
D017503:Adenovirus E3 Proteins; D000972:Antineoplastic Agents, Phytogenic; D036022:Capsid Proteins; C099609:adenovirus death protein, Adenovirus; C043322:penton protein, adenovirus; D014750:Vincristine; D017239:Paclitaxel