Bisphosphonates

Sigma^® is pleased to make these important compounds available to cancer researchers.

Clodronate disodium salt (Dichloromethylenediphosphonic acid disodium salt) – Product No. D4434

Etidronate disodium salt – Product No. P5248

Alendronate sodium salt trihydrate – Product No. A4978

Pamindronate disodium salt – Product No. P2371

Bone Resorption Inhibitors that Interfere with Metastasis and Cancer Mechanisms

Bisphosphonates are pyrophosphate analogs in which the two phosphorus atoms are linked by a carbon atom (P-C-P) instead of an oxygen atom (P-O-P). The first generation bisphosphonates, such as clodronate and etidronate, do not contain amino groups. They are metabolized to form cytotoxic ATP-analogs that accumulate intracellularly in osteoclasts and induce apoptosis.^1,2 Newer, nitrogen-containing bisphosphonates (N-BPs), including alendronate and pamidronate, interfere with the mevalonate pathway by inhibiting farnesyl diphosphate synthetase (FPPS), thus blocking isoprenoid phosphate biosynthesis and preventing the formation of the geranylgeranylated GTPases that are required for osteoclast formation.^3,4

Bisphosphonates inhibit the resorption of bone matrix by osteoclasts, and have been used pharmacologically to treat osteoclast-mediated bone diseases such as osteoporosis and cancer metastases to bone.⁵ Recent studies have demonstrated that the bisphosphonates, especially the nitrogen-containing structures, also may interfere directly with cancer mechanisms.^6,7,8,9 N-BPs have been shown to inhibit A431 human epidermoid carcinoma cell proliferation¹⁰ and reduce invasion through the extracellular matrix¹¹. Pamidronate has been shown to interact synergistically with 1,24(S)-dihydroxyvitamin D2 to inhibit cancer cell growth.¹²

References

1. Reszka, A.A. and Rodan, G.A., Mechanism of action of bisphosphonates (Review). Curr. Osteoporos. Rep., 1, 45-52 (2003).
2. Lehenkari, P.P, et al., Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol. Pharmacol., 61, 1255-62 (2002)
3. Reszka, A.A. and Rodan, G.A., Nitrogen-containing bisphosphonate mechanism of action. (Review) Mini Rev. Med. Chem., 4, 711-9 (2004)
4. Rogers, M.J., New insights into the molecular mechanisms of action of bisphosphonates. (Review) Curr. Pharm. Des., 9, 2643-58 (2003)
5. Lourwood, D.L., The pharmacology and therapeutic utility of bisphosphonates. (Review) Pharmacotherapy, 18, 779-89 (1998).
6. Clezardin, P., et al., Bisphosphonates and cancer-induced bone disease: beyond their antiresorptive activity. (Review) Cancer Res., 65, 4971-4 (2005).
7. Santini, D., et al., Bisphosphonate effects in cancer and inflammatory diseases: in vitro and in vivo modulation of cytokine activities. (Review) BioDrugs, 18, 269-78 (2004).
8. Heymann, D., et al., Bisphosphonates: new therapeutic agents for the treatment of bone tumors. (Review) Trends Mol. Med., 10, 337-43 (2004).
9. Oades, G.M., et al., Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization to prostate cancer cells. J. Urol., 170, 246-52 (2003)
10. Muller, S., et al., Alendronate inhibits proliferation and invasion of human epidermoid carcinoma cells in vitro. Anticancer Res., 25, 2655-60 (2005).
11. Green, J.R., Antitumor effects of bisphosphonates. (Review) Cancer, 97, 840-7 (2003).
12. Wigington, D.P., et al., Pamidronate and 1,24(S)-dihydroxyvitamin D2 synergistically inhibit the growth of myeloma, breast and prostate cancer cells. Anticancer Res., 25, 1909-17 (2005).

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