The bisphosphonate pamidronate is a potent inhibitor of human osteosarcoma cell growth in vitro

Abstract

Bisphosphonates (BPs), such as pamidronate and clodronate, are an important class of drugs for the treatment of bone diseases. It is widely recognized that they inhibit bone resorption by suppressing the action of osteoclasts through antagonizing the mevalonate pathway, thereby reducing osteolytic bone metastases derived from different cancers, i.e. breast carcinoma and multiple myeloma. In contrast, the effects of BPs on primary bone tumors is an issue still to be resolved. Therefore, a systematic approach was set up to test the hypothesis that BPs could act directly on osteosarcoma cells. The effects of pamidronate and clodronate on seven osteosarcoma cell lines (HOS, MG-63, OST, SaOS-2, SJSA-1, U(2)OS and ZK-58) were studied. Pamidronate inhibited cell growth in a time- and dose-dependent manner, and decreased proliferation for up to 73% at 50 microM after 72 h, whereas its monophosphonate analog 3-aminopropyl phosphonate did not reduce cell viability at concentrations up to 2 mM. Clodronate showed less inhibitory effects (maximally 38% reduction at 1 mM after 72 h). Importantly, cell growth of fibroblasts was only very weakly affected by treatment with pamidronate. These results suggest that pamidronate may be a useful agent for the treatment of patients with osteosarcoma.

Zoledronic acid slows down rat primary chondrosarcoma development, recurrent tumor progression after intralesional curretage and increases overall survival

“…41 Moreover, the peak plasma levels of ZOL appear to be around 1 lM as shown by Skerjanec et al 42 which is in agreement with the IC50 of ZOL measured on cancer cells, thus then strengthening an in vivo potential effect of ZOL even at a low concentration. ZOL has been reported to inhibit cell cycle progression and increase the proportion of cells arrested in S-phase in rat and human osteosarcoma, 21,23 that was not confirmed in the present study with RCS cells. This observation can be explained by the slow proliferation rate of the RCS cells as shown in the control condition (Fig.…”

“…40 Potential direct antitumor effect of pamidronate and clodronate have been suggested in 2 in vitro studies showing inhibition of osteosarcoma cell growth proliferation. 20,21 Morever, ZOL induced in a dose-and time-dependant decrease in cell proliferation in osteosarcoma cell lines in vitro, and reduced tumor progression and metastatic lung spreading in vivo. 23,24 The present study reports a significant decrease of chondrosarcoma cell proliferation and an increase of cell death at 1 and 10 lM in vitro with an IC50 comparable to those observed on osteosarcoma and breast carcinoma cells.…”

“…17,18 A clear direct antitumor activity on breast cancer cells has been demonstrated in vitro. 19 In primary malignant bone tumor, inhibition of human osteosarcoma cell growth by pamidronate and clodronate 20,21 and zoledronic acid (ZOL) 22 have been reported in vitro. These results are consistent with our in vitro and in vivo studies demonstrated efficacy of ZOL on osteosarcoma tumor progression and metastatic spreading.…”

Clodronate alleviates cachexia and prolongs survival in nude mice xenografted with an anaplastic thyroid carcinoma cell line

“…The anti-tumor effect of clodronate was associated with dose and time of exposure (Shipman et al 1997, Senaratne et al 2000, Sonnemann et al 2001. Previous studies, complimented by our results, suggest that the anti-tumor effect of clodronate is cell-type specific.…”

Synergistic Cytotoxic Effect of Statins and Bisphosphonates on Squamous Cell Carcinoma Cell Line

“…They also possess an immunomodulatory effect and can decrease tumor cell adhesion and invasion. In conclusion, bisphosphonates are considered by many researchers as antiproliferative, pro-apoptotic, anti-angiogenic (decrease VEGF and PDGF) [12][13][14][15][16][17][18][19].…”