The antiretroviral nucleoside analogue Abacavir reduces cell growth and promotes differentiation of human medulloblastoma cells.
Abacavir is one of the most efficacious nucleoside analogues, with a well-characterized inhibitory activity on reverse transcriptase enzymes of retroviral origin, and has been clinically approved for the treatment of AIDS. Recently, Abacavir has been shown to inhibit also the human telomerase activity. Telomerase activity seems to be required in essentially all tumours for the immortalization of a subset of cells, including cancer stem cells. In fact, many cancer cells are dependent on telomerase for their continued replication and therefore telomerase is an attractive target for cancer therapy. Telomerase expression is upregulated in primary primitive neuroectodermal tumours and in the majority of medulloblastomas suggesting that its activation is associated with the development of these diseases. Therefore, we decided to test Abacavir activity on human medulloblastoma cell lines with high telomerase activity. We report that exposure to Abacavir induces a dose-dependent decrease in the proliferation rate of medulloblastoma cells. This is associated with a cell accumulation in the G(2)/M phase of the cell cycle in the Daoy cell line, and with increased cell death in the D283-MED cell line, and is likely to be dependent on the inhibition of telomerase activity. Interestingly, both cell lines showed features of senescence after Abacavir treatment. Moreover, after Abacavir exposure we detected, by immunofluorescence staining, increased protein expression of the glial marker glial fibrillary acidic protein and the neuronal marker synaptophysin in both medulloblastoma cell lines. In conclusion, our results suggest that Abacavir reduces proliferation and induces differentiation of human medulloblastoma cells through the downregulation of telomerase activity. Thus, using Abacavir, alone or in combination with current therapies, might be an effective therapeutic strategy for the treatment of medulloblastoma.
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia PA.
Alessandra
A
Rossi
Giuseppe
G
Russo
Andrew
A
Puca
Raffaele
R
La Montagna
Mariella
M
Caputo
Eliseo
E
Mattioli
Massimo
M
Lopez
Antonio
A
Giordano
Francesca
F
Pentimalli
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D015224:Dideoxynucleosides / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000556:secondary*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016708:Synaptophysin / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099227:Abacavir
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D016708:Synaptophysin; D019098:Telomerase; D000099227:Abacavir; C509186:TERT protein, human