“…The stronger antiproliferative and/or proapoptotic effect of nitrogen-containing bisphosphonates compared to nonaminobisphosphonates was also reported in other cell types such as macrophages (Benford et al , 1999; Rogers et al , 1999), breast cancer cells (Senaratne et al , 2000), multiple myeloma (Shipman et al , 1998; Shipman et al , 2000) or colon adenocarcinoma (Suri et al , 2001), and this effect appears to be related to the ability of nitrogen-containing bisphosphonates to inhibit the mevalonate pathway and thereby the prenylation of signalling proteins such as the small GTPases. Both pamidronate and zoledronate were shown to inhibit specifically the enzyme FPP synthase (Bergstrom et al , 2000; Dunford et al , 2001), and the depletion of cellular pools of GGPP and FPP has been demonstrated to be a key mechanism in the induction of apoptosis and reduction of cell viability by nitrogen-containing bisphosphonates (Benford et al , 1999; Jagdev et al , 2001; Reszka et al , 2001).…”
Cutaneous melanoma is one of the highly malignant human tumours, due to its tendency to generate early metastases and its resistance to classical chemotherapy. We recently demonstrated that pamidronate, a nitrogen-containing bisphosphonate, has an antiproliferative and proapoptotic effect on different melanoma cell lines. In the present study, we compared the in vitro effects of three different bisphosphonates on human melanoma cell lines and we demonstrated that the two nitrogen-containing bisphosphonates pamidronate and zoledronate inhibited the proliferation of melanoma cells and induced apoptosis in a dose- and time-dependent manner. Moreover, cell cycle progression was altered, the two compounds causing accumulation of the cells in the S phase of the cycle. In contrast, the nonaminobisphosphonate clodronate had no effect on melanoma cells. These findings suggest a direct antitumoural effect of bisphosphonates on melanoma cells in vitro and further support the hypothesis of different intracellular mechanisms of action for nitrogen-containing and nonaminobisphosphonates. Our data indicate that nitrogen-containing bisphosphonates may be a useful novel therapeutic class for treatment and/or prevention of melanoma metastases.
“…The stronger antiproliferative and/or proapoptotic effect of nitrogen-containing bisphosphonates compared to nonaminobisphosphonates was also reported in other cell types such as macrophages (Benford et al , 1999; Rogers et al , 1999), breast cancer cells (Senaratne et al , 2000), multiple myeloma (Shipman et al , 1998; Shipman et al , 2000) or colon adenocarcinoma (Suri et al , 2001), and this effect appears to be related to the ability of nitrogen-containing bisphosphonates to inhibit the mevalonate pathway and thereby the prenylation of signalling proteins such as the small GTPases. Both pamidronate and zoledronate were shown to inhibit specifically the enzyme FPP synthase (Bergstrom et al , 2000; Dunford et al , 2001), and the depletion of cellular pools of GGPP and FPP has been demonstrated to be a key mechanism in the induction of apoptosis and reduction of cell viability by nitrogen-containing bisphosphonates (Benford et al , 1999; Jagdev et al , 2001; Reszka et al , 2001).…”
Cutaneous melanoma is one of the highly malignant human tumours, due to its tendency to generate early metastases and its resistance to classical chemotherapy. We recently demonstrated that pamidronate, a nitrogen-containing bisphosphonate, has an antiproliferative and proapoptotic effect on different melanoma cell lines. In the present study, we compared the in vitro effects of three different bisphosphonates on human melanoma cell lines and we demonstrated that the two nitrogen-containing bisphosphonates pamidronate and zoledronate inhibited the proliferation of melanoma cells and induced apoptosis in a dose- and time-dependent manner. Moreover, cell cycle progression was altered, the two compounds causing accumulation of the cells in the S phase of the cycle. In contrast, the nonaminobisphosphonate clodronate had no effect on melanoma cells. These findings suggest a direct antitumoural effect of bisphosphonates on melanoma cells in vitro and further support the hypothesis of different intracellular mechanisms of action for nitrogen-containing and nonaminobisphosphonates. Our data indicate that nitrogen-containing bisphosphonates may be a useful novel therapeutic class for treatment and/or prevention of melanoma metastases.
“…Once internalized, N-BPs influence multiple pathways and effectively inhibit osteoclast-mediated bone resorption through inhibition of the mevalonate pathway (Figure 1) [21]. This is an important biochemical pathway involved in the production of cholesterol and isoprenoids, which are required for maintaining cell-membrane integrity, producing steroids, and regulating cellular metabolism.…”
Section: Nitrogen-containing Bisphosphonates and Bonementioning
confidence: 99%
“…anticancer activity).Figure 1The mevalonate pathway is important in the synthesis of cholesterol, and of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which provide the farnesyl and geranylgeranyl groups, respectively, for protein prenylation. Reproduced from Shipman et al [21]. …”
Section: Nitrogen-containing Bisphosphonates and Bonementioning
Recent data from the AZURE, ABCSG-12, and ZO-FAST clinical trials have challenged our understanding of the potential anticancer activity of zoledronic acid (ZOL). Although the results of these studies may appear to be conflicting on the surface, a deeper look into commonalities among the patient populations suggest that some host factors (i.e. patient age and endocrine status) may contribute to the anticancer activity of ZOL. Indeed, data from these large clinical trials suggest that the potential anticancer activity of ZOL may be most robust in a low-estrogen environment. However, this may be only part of the story and many questions remain to be answered to fully explain the phenomenon. Does estrogen override the anticancer activity of ZOL seen in postmenopausal women? Are hormones other than estrogen involved that contribute to this effect? Does the role of bone turnover in breast cancer (BC) growth and progression differ in the presence of various estrogen levels? Here, we present a review of the multitude of factors affected by different endocrine environments in women with BC that may influence the potential anticancer activity of ZOL.
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