TY - JOUR
T1 - Breast cancer cell targeting by prenylation inhibitors elucidated in living animals with a bioluminescence reporter
AU - Chinault, Sharon L.
AU - Prior, Julie L.
AU - Kaltenbronn, Kevin M.
AU - Penly, Anya
AU - Weilbaecher, Katherine N.
AU - Piwnica-Worms, David
AU - Blumer, Kendall J.
PY - 2012/8/1
Y1 - 2012/8/1
N2 - Purpose: 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. Experimental Design: 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. Results: In mouse xenograft models of breast cancer, using reporter-bearing mammary fat pad- or bonelocalized 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. Conclusions: 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.
AB - Purpose: 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. Experimental Design: 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. Results: In mouse xenograft models of breast cancer, using reporter-bearing mammary fat pad- or bonelocalized 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. Conclusions: 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.
UR - http://www.scopus.com/inward/record.url?scp=84864420076&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-12-0642
DO - 10.1158/1078-0432.CCR-12-0642
M3 - Article
C2 - 22693355
AN - SCOPUS:84864420076
SN - 1078-0432
VL - 18
SP - 4136
EP - 4144
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -