Telomere dysfunction induced by chemotherapeutic agents and radiation in normal human cells.
The number of long-term survivors of patients with various malignancies (>5 years) is increasing mainly owing to advances in cancer therapeutics, but long-term side effects of the cancer treatment in this population have emerged as an important health and socio-economical issue. Telomeres and telomerase are known to be essential for regulation of cellular life-span and maintenance of genomic stability, and earlier studies have demonstrated that cancer patients who receive chemotherapy have shorter telomeres in their blood cells, indicating accelerated telomere erosion and a potential contribution of telomere loss to late side-effects. Little is currently known about the effect of chemotherapeutic agents and radiation on telomere dynamics including potential effects on telomere length, structure, function, telomerase activity, and telomere shelterin proteins in normal human cells. In the present study, we had addressed this issue experimentally. The treatment of normal human T lymphocytes and fibroblasts with chemotherapeutic agents doxorubicin (DOX) or etoposide (VP16) led to significant shortening of telomeres, down-regulation of telomerase activity, and diminished expression of telomerase reverse transcriptase (hTERT) and the telomere binding proteins TPP1 and POT1. More importantly, telomere dysfunction was observed in cells treated with DOX or VP16. Furthermore, all the above alterations were similarly found in the cells receiving γ-irradiation. Taken together, both chemotherapy and radiotherapy significantly impair telomere maintenance and function in normal human cells. Conceivably telomere dysfunction causes shortened life-span and genomic instability of normal human cells, and thereby contributes to tissue/organ damage and secondary malignancies in long-term survivors of cancer.
Department of Medicine, Division of Haematology and Centre for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
Ping
P
Li
Mi
M
Hou
Fenglan
F
Lou
Magnus
M
Björkholm
Dawei
D
Xu
D000970:Antineoplastic Agents / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects; D005047:Etoposide / Q000009:adverse effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D005720:Gamma Rays / Q000009:adverse effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000089804:Shelterin Complex; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects*; D059506:Telomere Shortening / Q000187:drug effects / Q000528:radiation effects; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism
C495876:ACD protein, human; D000970:Antineoplastic Agents; C440849:POT1 protein, human; D012333:RNA, Messenger; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D005047:Etoposide; D004317:Doxorubicin; D019098:Telomerase