Letter to the Editor Bioluminescence Imaging of Prenylation Inhibition–Letter Philippe Clezardin 1,2 We read with great interest the recent article by Chinault and colleagues (1), providing evidence that aminobispho- sphonate zoledronic acid (ZOL) does not exert a direct antitumor activity against breast cancer cells in vivo. There is extensive preclinical evidence suggesting that aminobi- sphosphonates exhibit antitumor effects in addition to their therapeutic activity in preserving bone tissue. The underly- ing inhibitory mechanisms of aminobisphosphonates against tumor cells are primarily through the blockade of the enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway, which prevents prenylation of signal- ing proteins (e.g., Rho, Ras, Cdc42), leading to the inhibi- tion of tumor cell adhesion, migration, invasion, and pro- liferation in vitro (2). Whether aminobisphosphonates exhibit direct and/or indirect antitumor effects in animal models remains a matter of intense discussion. Here, the authors used a bioluminescence-based imaging reporter system that is inducible by prenylation inhibitors, such as aminobisphosphonates, and they showed that the treat- ment of animals with ZOL fails to induce the reporter in human MDA-MB-231 breast tumor xenografts, indicat- ing that the aminobisphosphonate does not directly target cancer cells in vivo (1). However, we would like to point out an aspect of tumor xenograft experiments not adequate- ly addressed by Chinault and colleagues (1), which deserves a remark. The inhibition of FPPS activity by aminobisphospho- nates leads to the intracellular accumulation of IPP/ ApppI mevalonate metabolites (2). We recently provided in vivo evidence that ZOL (administered at a dose com- patible with clinical dosing regimens) induces accumu- lation of IPP/ApppI in human breast tumors implanted subcutaneously in animals and that human Vg 9Vd2 T cells (a subset of human T cells) infiltrate and inhibit growth of these tumors producing high IPP/ApppI levels, but not those expressing low IPP/ApppI levels (3). IPP and ApppI are recognized by human Vg 9Vd2 T cells as tumor phosphoantigens. Importantly, we showed that estrogen receptor–positive breast tumors (T47D, MCF- 7) were more likely to produce IPP/ApppI after ZOL treatment because of a higher cellular uptake of ZOL and a higher activity of the mevalonate pathway compared with estrogen receptor–negative breast tumors (MDA- MB-231, MDA-MB-435; ref. 3). We believe these findings (3) may likely explain results obtained by Chinault and colleagues (1). It would be therefore very interesting to determine whether ZOL induces bioluminescence-based reporter activity in estrogen receptor–positive breast can- cer cells in vivo. Disclosure of Potential Conflicts of Interest P. Clezardin has served on advisory boards for Novartis and Amgen and has received lecture fees and a research grant from Novartis and Amgen. P. Clezardin also has other commercial research support and a honoraria from Speakers Bureau from Novartis and AMGEN. Received August 11, 2012; accepted August 14, 2012; published OnlineFirst October 8, 2012. References 1. Chinault SL, Prior JL, Kaltenbronn KM, Penly A, Weilbaecher KN, Piwnica-Worms D, et al. Breast cancer cell targeting by prenylation inhibitors elucidated in living animals with a bioluminescence reporter. Clin Cancer Res 2012;18:4136–44. 2. Clezardin P. Bisphosphonates' antitumor activity: an unravelled side of a multifaceted drug class. Bone 2011;48:71–9. 3. Benzaïd I, M€ onkk€ onen H, Stresing V, Bonnelye E, Green J, M€ onkk€ onen J, et al. High phosphoantigen levels in bisphospho- nate-treated human breast tumors promote Vgamma9Vdelta2 T-cell chemotaxis and cytotoxicity in vivo. Cancer Res 2011;71: 4562–72. Authors' Affiliations: 1 INSERM, UMR 1033; and 2 University of Lyon, Lyon, France Corresponding Author: Philippe Cl  ezardin, INSERM, UMR1033, UFR de M edecine Lyon-Est (domaine La€ ennec), Rue G. Paradin, 69372 Lyon cedex 08, France. Phone: 33-478-78-5737; Fax: 33-478-77-8772; E-mail: philippe.clezardin@inserm.fr doi: 10.1158/1078-0432.CCR-12-2569 Ó2012 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 6077 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/18/21/6077/2006293/6077.pdf by guest on 18 June 2022