Azidothymidine Induces Apoptosis and Inhibits Cell Growth and Telomerase Activity of Human Parathyroid Cancer Cells in Culture

Abstract

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. Introduction: 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. Materials and 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, 3Ј-azido-3Јdeoxythymidine (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.

Characterization of the functional and growth properties of long-term cell cultures established from a human somatostatinoma

“…This study indicates that in vitro exposure of SS-C cells to AZT results in inhibition both of telomerase and of cell proliferation. We also found that AZT induced an apoptotic cell death in SS-C cells, as previously shown in Herpes virus-associated lymphomas (Lee et al 1999) and in parathyroid carcinoma (Falchetti et al 2005).…”

Pierwotna nadczynność przytarczyc w przebiegu raka przytarczyc — wyzwanie diagnostyczne i terapeutyczne

“…An in vitro study on human parathyroid cancer cells showed that the anti-retroviral agent zidovudyne could be a potential therapeutic target in patients with parathyroid carcinoma [68]. It is known that zidovudyne…”

“…Falchetti et al [68] demonstrated that zidovudine accumulates in malignant parathyroid cells and thus induces their apoptosis. However, additional studies are required to confirm these findings in humans.…”

“…Badanie in vitro prowadzone z wykorzystaniem ludzkich komórek raka przytarczyc pokazało, że lek antyretrowirusowy -zidowudyna, mogłaby być stosowana u pacjentów z rakiem przytarczyc [68]. Mechanizm działania zidowudyny polega na hamowaniu telomerazy, enzymu, który jest aktywny w komórkach raka przytarczyc.…”

“…Falchetti i wsp. [68] wykazali, że zidowudyna ulega akumulacji w komórkach raka przytarczyc i w ten sposób indukuje ich apoptozę. Jakkolwiek, dodatkowe badania są niezbędne do potwierdzenia tego zjawiska u ludzi.…”