Breast Cancer Cell Targeting by Prenylation Inhibitors Elucidated in Living Animals with a Bioluminescence Reporter

• Published in: Clinical cancer research Vol. 18; no. 15; pp. 4136 - 4144
• Main Authors: CHINAULT, Sharon L, PRIOR, Julie L, KALTENBRONN, Kevin M, PENLY, Anya, WEILBAECHER, Katherine N, PIWNICA-WORMS, David, BLUMER, Kendall J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2012
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Alkyl and Aryl Transferases - metabolism; Animals; Antineoplastic agents; Benzamides - pharmacology; Biological and medical sciences; Blotting, Western; Bone Density Conservation Agents - pharmacology; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Clodronic Acid - pharmacology; Diphosphonates - pharmacology; Female; Genes, Reporter - genetics; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Gynecology. Andrology. Obstetrics; HEK293 Cells; Humans; Imidazoles - pharmacology; Luciferases - genetics; Luciferases - metabolism; Luminescent Measurements - methods; Mammary gland diseases; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Medical sciences; Mice; Mice, Nude; Microscopy, Confocal; Mutation; Pharmacology. Drug treatments; Protein Prenylation - drug effects; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Transplantation, Heterologous; Tumors; Mammary gland diseases; Bioluminescence; Target; Breast disease; Targeting; Animal; Breast cancer; Inhibitor; Malignant tumor; Tumor cell; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-12-0642

Inhibitors of protein prenylation, including prenyltransferase inhibitors and aminobisphosphonates such as zoledronic acid, are being investigated intensively as therapeutics in cancer and other diseases. Determining whether prenylation inhibitors directly or indirectly target tumor and/or host cells is key to understanding therapeutic mechanisms. To determine which cell types can be targeted directly by distinct classes of prenylation inhibitors in vivo, we describe herein the development and implementation of a sensitive and pharmacologically specific bioluminescence-based imaging reporter that is inducible by prenylation inhibitors. In mouse xenograft models of breast cancer, using reporter-bearing mammary fat pad- or bone-localized tumor cells, we show that a prenyltransferase inhibitor robustly induces reporter activity in vivo. In contrast, zoledronic acid, a bone-associated aminobisphosphonate that exerts adjuvant chemotherapeutic activity in patients with breast cancer, fails to induce reporter activity in tumor cells of either model. Although a prenyltransferase inhibitor can directly target breast cancer cells in vivo, zoledronic acid and related aminobisphosphonates are likely to exert antitumor activity indirectly by targeting host cells. Accordingly, these findings shift attention toward the goal of determining which host cell types are targeted directly by aminobisphosphonates to exert adjuvant chemotherapeutic activity.