Abstract

Bisphosphonates have been used for the treatment of hypercalcemia associated with malignancies and osteoporosis. Recent reports have suggested that bisphosphonates may also exert direct antitumor effects on several cancers, in addition to their therapeutic antiresorptive properties. Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by infection with human T-cell leukemia virus type I (HTLV-I), and remains incurable. ATL is associated with osteolytic bone lesions and hypercalcemia, which are major factors in the morbidity of ATL. Therefore, the search for anti-ATL agents that have antitumor and antiresorptive effects is warranted. The aim of this study was to determine the effect of bisphosphonate, incadronate, on HTLV-I-infected T-cell lines and primary ATL cells. Incadronate prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells, but not of uninfected T-cell lines and normal PBMCs. Incadronate induced S-phase cell cycle arrest and apoptosis in HTLV-I-infected T-cell lines. Treatment of HTLV-I-infected T-cell lines with cell-permeable substrates for mevalonate pathways, geranylgeraniol and farnesol, prevented incadronate-mediated growth suppression. Incadronate also prevented the prenylation of Ras proteins. These results demonstrate that incadronate-induced growth suppression is the result of inhibition of the mevalonate pathway. On the other hand, incadronate did not affect NF-κB and AP-1 pathways. Importantly, treatment with incadronate reduced tumor formation from an HTLV-I-infected T-cell line, HUT-102, when these cells were inoculated s.c. into severe combined immunodeficient mice. These findings indicate that incadronate may become a novel molecular therapeutic class for treatment of ATL.

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