Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis, and shows combined effects with other anticancer agents

Abstract

Third-generation bisphosphonates are known to inhibit bone resorption and also appear to exhibit direct anti-tumour activity. We previously reported that third-generation bisphosphonates such as zoledronic acid (ZOL) have a direct antitumour effect, and synergistically augment the effects of antitumor agents in osteosarcoma cells. There has been no report on the antitumor effect of ZOL against soft tissue sarcoma. The aim of this study was to evaluate the antitumor effect of this drug on a human fibrosarcoma cell line, in terms of proliferation and apoptosis, and, moreover, to evaluate the combined effects of ZOL with other antitumor drugs against the human fibrosarcoma cell line. HT1080 cells were treated with ZOL at various concentrations up to 10 microM, and then cell proliferation, cell cycle, nuclear morphology, and Western blot analyses were performed to study the antitumor effects of ZOL alone, and, moreover, HT1080 cells were treated with ZOL and other anticancer drugs such as paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, cisplatin, or methotrexate to investigate the combined effects using proliferation and cell cycle analyses. We found that ZOL strongly inhibited in vitro proliferation, arrested the cell cycle between S and G2/M phases, and induced the apoptosis of human fibrosarcoma cells. Moreover, ZOL augmented the effect of antitumor agents when administered concurrently with paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, and cisplatin in human fibrosarcoma cells. The treatment of fibrosarcoma with ordinary antitumor drugs is not fully effective. These findings suggest that ZOL directly affects the proliferation and survival of fibrosarcoma cells, and that the combined administration of ZOL with other antitumor agents may improve the efficacy of fibrosarcoma treatment. These results support the possibility that their combined use could be beneficial in the treatment of patients not only with various types of cancer or osteosarcoma, but also with soft tissue sarcoma.