Azidothymidine induces apoptosis and inhibits cell growth and telomerase activity of human parathyroid cancer cells in culture.
Telomerase activity has been correlated to parathyroid carcinoma. Because its role in acquisition of a malignant phenotype by parathyroid cells is unclear, we treated telomerase-positive cultured human parathyroid cancer cells with the telomerase inhibitor AZT, evaluating cell telomerase activity, cytotoxic effects, growth, and morphological changes. In vitro exposure of these cells to AZT correlated with inhibition of cell proliferation.


BACKGROUND
Parathyroid carcinoma represents an uncommon cause of primary hyperparathyroidism, whose spectrum of clinical presentation, degree of malignancy, and prognosis are difficult to be properly identified. Neck surgery, specifically an en bloc resection of primary tumor, is the only curative treatment. Alternatively, affected patients could undergo repetitive palliative surgical exeresis of metastatic nodules. It has been previously shown that telomerase activity is specifically present in parathyroid carcinoma cells, being absent in hyperplastic and adenomatous tissues. Thus, determination of telomerase activity could represent either a useful diagnostic molecular marker for human parathyroid carcinoma or a potential target for pharmacological intervention in a malignant neoplasia usually resistant to chemo- and radiotherapeutic interventions.


METHODS
To further investigate the role of telomerase activity in acquisition of a malignant phenotype by parathyroid cells, we treated telomeric repeat amplification protocol-positive cultured human parathyroid cells with the telomerase inhibitor zidovudine, 3'-azido-3'deoxythymidine (AZT), evaluating cell telomerase activity, growth characteristics, potential cytotoxic effects, and morphological changes.


RESULTS
Our findings indicate that in vitro exposure of human parathyroid cancer cells to AZT resulted in intracellular accumulation of AZT-monophosphate (AZT-MP) and inhibition of telomerase, which correlate with inhibition of human parathyroid cancer cell proliferation. Moreover, we also found that AZT induced an apoptotic rather than a necrotic type of cellular death. None of these effects were observed in human adenomatous parathyroid cells in culture.


CONCLUSIONS
Altogether these results indicate that AZT may be a highly effective agent against cancer parathyroid cells proliferation, which is an extremely important observation for a neoplasia which shows lack of response to classical pharmacological and physical antiblastic treatments.
Falchetti
Alberto
A
Department of Internal Medicine, University of Florence, Florence, Italy.
Franchi
Alessandro
A
Bordi
Cesare
C
Mavilia
Carmelo
C
Masi
Laura
L
Cioppi
Federica
F
Recenti
Raffaella
R
Picariello
Lucia
L
Marini
Francesca
F
Del Monte
Francesca
F
Ghinoi
Valentina
V
Martineti
Valentina
V
Tanini
Annalisa
A
Brandi
Maria Luisa
ML
D000368:Aged; D000963:Antimetabolites / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D010282:Parathyroid Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019098:Telomerase / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000494:pharmacology* / Q000627:therapeutic use
D000963:Antimetabolites; D015215:Zidovudine; D019098:Telomerase