Bisphosphonates' antitumor activity: An unravelled side of a multifaceted drug class

doi:10.1016/j.bone.2010.07.016

Bone

Volume 48, Issue 1, 1 January 2011, Pages 71-79

https://doi.org/10.1016/j.bone.2010.07.016 Get rights and content

Abstract

Bisphosphonates, especially nitrogen-containing bisphosphonates (N-BPs), are widely used to preserve and improve bone health in patients with cancer because they inhibit osteoclast-mediated bone resorption. In addition to their effects on bone, preclinical evidence strongly suggests that N-BPs exert anticancer activity without the involvement of osteoclasts by interacting with macrophages, endothelial cells and tumor cells, and by stimulating the cytotoxicity of γδ T cells, a subset of human T cells. This review examines the current insights and fronts of ongoing preclinical research on N-BPs' antitumor activity.

Introduction

Bisphosphonates are degradation-resistant structural analogues of pyrophosphates, which are all characterized by two phosphonate groups linked to a central carbon atom, forming a P-C-P structure [1]. Two side chains (referred to as R₁ and R₂) are covalently bound to the carbon atom of the common P-C-P structure. The P-C-P backbone and the R₁ side chain (preferably a hydroxyl group) allow the bisphosphonates to bind avidly to hydroxyapatite crystals [1]. Consistent with these data, studies in animals have shown that bisphosphonates are primarily deposited in newly formed bone and under osteoclasts [2], where they inhibit osteoclast-mediated bone resorption [1]. In this respect, the anti-resorptive potency of bisphosphonates may be broadly classified on the basis of whether or not they contain a nitrogen moiety in their R₂ side chain; nitrogen-containing bisphosphonates (N-BPs) being more potent than non-N-BPs in inhibiting bone resorption [1].

Non-N-BPs (e.g., etidronate and clodronate) are metabolically incorporated into non-hydrolyzable analogues of ATP (AppCp) that leads to inhibition of mitochondrial ADP/ATP translocase and osteoclast apoptosis [3] (Fig. 1). N-BPs (e.g., pamidronate, alendronate, risedronate, ibandronate, zoledronate and minodronate) specifically interfere with farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway that catalyzes the condensation of isopentenyl pyrophosphate (IPP) to dimethylallyl pyrophosphate (DMAPP) to form farnesyl pyrophosphate (FPP) [4], [5] (Fig. 1). In addition, N-BPs interfere with an enzyme that is downstream of FPPS in the mevalonate pathway, the geranylgeranyl pyrophosphate synthase (GGPPS) [6] (Fig. 1). As a consequence, the covalent attachment of isoprenyl chains to small GTPases (e.g., Ras, Rac, Rho, and CDC42) is blocked, thereby inhibiting their intracellular localization and functions in osteoclasts. Moreover, the disruption of the mevalonate pathway by N-BPs results in the accumulation of isopentenyl pyrophosphate (IPP), which is then converted to a cytotoxic ATP analogue called ApppI [7] (Fig. 1). Thus, N-BPs may exert their pharmacological effects on osteoclasts through the formation of ApppI or via the inhibition of protein prenylation, particularly of small GTPases.

In addition to their therapeutic activity in preserving bone tissue, emerging preclinical and clinical evidence suggest that N-BPs have anticancer benefits that may be ascribed to their effects on cells other than osteoclasts, such as tumor cells, macrophages, endothelial cells, and γδ T cells, a subset of T cells that exhibits anticancer activity. The following is an overview over the current insights and fronts of ongoing preclinical research on N-BPs' antitumor activity.

Section snippets

Effects of N-BPs on tumor cells in vitro

There is abundant evidence of the inherent antitumor activity of N-BPs in vitro, including induction of tumor cell apoptosis, inhibition of tumor cell proliferation, migration, and invasion [8]. The potency of antitumor effects of N-BPs in vitro generally mirrors the anti-resorptive potency in vivo, indicating that underlying inhibitory mechanisms are primarily through the blockade of the mevalonate pathway. For example, alendronate-mediated inhibition of prostate cancer cell invasion and

Effects of N-BPs on experimental angiogenesis in vitro and in vivo

Angiogenesis, the formation of new blood vessels from existing ones, involves a series of events, including endothelial cell proliferation and migration, and endothelial cells' realignment to form new capillaries. In vitro, N-BPs (zoledronate, risedronate, alendronate, ibandronate) interfere with all major steps of the angiogenic process, such as endothelial cell migration, proliferation and tube formation [8]. In vivo, zoledronate and neridronate exhibit antiangiogenic activity in the chick

Animal models of cancer-induced bone lesions

There is ample evidence that N-BPs reduce skeletal tumor burden and metastatic incidence in bone in animal models of breast, prostate and lung cancer, neuroblastoma, multiple myeloma, osteosarcoma and chondrosarcoma [8]. The antitumor activity of N-BPs in bone has been attributed to their ability to inhibit osteoclast-mediated bone resorption. This leads to a reduced release of bone-derived growth factors, such as transforming growth factor-β (TGF-β), which are stored in the mineralized bone

Effects of N-BPs on human Vγ9Vδ2 T cell cytotoxicity

N-BPs stimulate the expansion and antitumor activity of human Vγ9Vδ2 T cells, a particular subset of human γδ T cells, which are strongly activated by phosphoantigens from bacteria and parasites and by IPP from eukaryotic cells [51]. By contrast, ApppI has little stimulatory activity on Vγ9Vδ2 T cells; it could represent an inactive storage form of phosphoantigen which would require conversion to IPP to activate γδ T cells [52].

Evidence for the stimulation of Vγ9Vδ2 T cells by N-BPs was first

Concluding comments and future directions

There is now a growing body of preclinical evidence that N-BPs exhibit direct and indirect antitumor activities. First, they can make the bone marrow a less favorable environment for cancer cell colonization by inhibiting the release of bone-derived growth factors during bone resorption. Second, they may interfere with the functions of bone marrow-derived cells (endothelial progenitor cells, mesenchymal cells, monocytes and macrophages) which, by enabling angiogenesis and the formation of

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ReviewBisphosphonates' antitumor activity: An unravelled side of a multifaceted drug class

Abstract

Introduction

Section snippets

Effects of N-BPs on tumor cells in vitro

Effects of N-BPs on experimental angiogenesis in vitro and in vivo

Animal models of cancer-induced bone lesions

Effects of N-BPs on human Vγ9Vδ2 T cell cytotoxicity

Concluding comments and future directions

Bone

Cancer Lett

Biochem Pharmacol

Bone

J Biol Chem

Cancer Lett

Cancer Lett

Bone

Bone

Neoplasia

Biochem Biophys Res Commun

Lung Cancer

Cancer Lett

Cancer Lett

Blood

Blood

Curr Opin Immunol

Lancet Oncol

Development of bisphosphonates

Breast Cancer Res

Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite

Mol Pharmacol

The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs

Proc Natl Acad Sci U S A

Structural basis for the exceptional in vivo efficacy of bisphosphonate drugs

Chem Med Chem

Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases

Proc Natl Acad Sci U S A

A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates

Br J Pharmacol

Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells

Mol Cancer

Cyr61 downmodulation potentiates the anticancer effects of zoledronic acid in androgen-independent prostate cancer cells

Int J Cancer

Protein-tyrosine phosphatase activity regulates osteoclast formation and function: inhibition by alendronate

Proc Natl Acad Sci U S A

Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells

Int J Cancer

The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K-Akt-NFκB pathway in osteosarcoma cells

Br J Pharmacol

Identification of secondary targets of N-containing bisphosphonates in mammalian cells via parallel competition analysis of the barcoded yeast deletion collection

Genome Biol

Synergistic activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid and the bisphosphonate zoledronic acid against prostate cancer cells in vitro

Mol Cancer Ther

Combined effects of the bisphosphonate, zoledronic acid and the aromatase inhibitor letrozole on breast cancer cells in vitro: evidence of synergistic interaction

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Review
Bisphosphonates' antitumor activity: An unravelled side of a multifaceted drug class