The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro

Abstract

Pamidronate belongs to the class of nitrogen-containing bisphosphonates that are potent inhibitors of bone resorption frequently used for the treatment of osteoporosis and cancer-induced osteolysis. The inhibition of osteoclasts' growth has been suggested as the main mechanism of the inhibitory effect of pamidronate on bone metastases. Recent findings indicated that bisphosphonates also have a direct apoptotic effect on other types of tumour cells. Nitrogen-containing bisphosphonates were shown to inhibit farnesyl diphosphate synthase, thus blocking the synthesis of higher isoprenoids. By this mechanism they inactivate monomeric G-proteins of the Ras and Rho families for which prenylation is a functional requirement. On the background of the known key role of G-proteins in tumorigenesis, we investigated a possible beneficial use of pamidronate in the treatment of malignant melanoma. Our results indicate that pamidronate inhibits the cell growth and induces apoptosis in human melanoma cells in vitro. Susceptibility to pamidronate did not correlate to CD95 ligand sensitivity or p53 mutational status. Furthermore it is interesting to note that overexpression of bcl-2 did not abolish pamidronate-induced apoptosis. These data suggests that pamidronate has a direct anti-tumour effect on malignant melanoma cells, independently of the Bax/Bcl-2 level.

Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro

“…This proapoptotic ability of BPs has been strongly correlated with the specific antiresorptive potency of each compound. Specifically, it has been demonstrated that ZOL has a direct effect on human multiple myeloma (Shipman et al, 1997), breast cancer (Senaratne et al, 2000), prostate cancer (Lee et al, 2001) and melanoma cells (Riebeling et al, 2002).…”

AMP-activated Protein Kinase Is Required for the Lipid-lowering Effect of Metformin in Insulin-resistant Human HepG2 Cells

“…To ensure cell viability during prolonged incubation of metformin in serum-free medium, cell viability was assessed with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay performed according to the manufacturer's suggestions (Sigma). In addition, cytotoxicity was assessed by measuring lactate dehydrogenase release into the culture medium using the cytotoxicity detection kit (Roche Applied Science) as described previously (26). Under the conditions of our studies, treatment of HepG2 cells with metformin had no detectable cell toxicity.…”

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

“…Furthermore, zoledronic acid has shown synergistic induction of cancer cell apoptosis in vitro when combined with a variety of agents, e.g., with imatinib mesylate in leukemia cells 19 or in lung cancer cells, 20 with gemcitabine in prostate cancer cells, 21 with paclitaxel or tamoxifen 22,23 or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) 24 in breast cancer cells and with dexamethasone in myeloma cells. 25 Other bisphosphonates investigated for synergistic cell death in combination with chemotherapeutic agents have shown either no effect (pamidronate with DTIC in melanoma cell lines) 26 or additive activity at best (ibandronate with taxanes in breast cancer cells). 27 Anthracyclines such as doxorubicin and epirubicin are commonly used to manage early and metastatic breast cancer.…”