Breast cancer cell targeting by prenylation inhibitors elucidated in living animals with a bioluminescence reporter.
OBJECTIVE
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.


METHODS
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 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.


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.
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Sharon L
SL
Chinault
Julie L
JL
Prior
Kevin M
KM
Kaltenbronn
Anya
A
Penly
Katherine N
KN
Weilbaecher
David
D
Piwnica-Worms
Kendall J
KJ
Blumer
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004002:Clodronic Acid / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009154:Mutation; D017368:Protein Prenylation / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D000077211:Zoledronic Acid
D001549:Benzamides; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; C102521:GGTI 298; D007093:Imidazoles; D011993:Recombinant Fusion Proteins; D004002:Clodronic Acid; D049452:Green Fluorescent Proteins; D000077211:Zoledronic Acid; D008156:Luciferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I