Association of telomerase activity with radio- and chemosensitivity of neuroblastomas.
BACKGROUND
Telomerase activity compensates shortening of telomeres during cell division and enables cancer cells to escape senescent processes. It is also supposed, that telomerase is associated with radio- and chemoresistance. In the here described study we systematically investigated the influence of telomerase activity (TA) and telomere length on the outcome of radio- and chemotherapy in neuroblastoma.


METHODS
We studied the effects on dominant negative (DN) mutant, wild type (WT) of the telomerase catalytic unit (hTERT) using neuroblastoma cell lines. The cells were irradiated with 60Co and treated with doxorubicin, etoposide, cisplatin and ifosfamide, respectively. Viability was determined by MTS/MTT-test and the GI50 was calculated. Telomere length was measured by southernblot analysis and TA by Trap-Assay.


RESULTS
Compared to the hTERT expressing cells the dominant negative cells showed increased radiosensitivity with decreased telomere length. Independent of telomere length, telomerase negative cells are significantly more sensitive to irradiation. The effect of TA knock-down or overexpression on chemosensitivity were dependent on TA, the anticancer drug, and the chemosensitivity of the maternal cell line.


CONCLUSIONS
Our results supported the concept of telomerase inhibition as an antiproliferative treatment approach in neuroblastomas. Telomerase inhibition increases the outcome of radiotherapy while in combination with chemotherapy the outcome depends on drug- and cell line and can be additive/synergistic or antagonistic. High telomerase activity is one distinct cancer stem cell feature and the here described cellular constructs in combination with stem cell markers like CD133, Aldehyddehydrogenase-1 (ALDH-1) or Side population (SP) may help to investigate the impact of telomerase activity on cancer stem cell survival under therapy.
Wesbuer
Simone
S
Department of Radiotherapy -Radiooncology-, University Hospital Münster, Albert-Schweitzer-Strasse 33, D-48149 Münster.
Lanvers-Kaminsky
Claudia
C
Duran-Seuberth
Ines
I
Bölling
Tobias
T
Schäfer
Karl-Ludwig
KL
Braun
Yvonne
Y
Willich
Normann
N
Greve
Burkhard
B
D015139:Blotting, Southern; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology*; D011836:Radiation Tolerance / Q000502:physiology*; D019098:Telomerase / Q000378:metabolism*; D014162:Transfection
D019098:Telomerase