The
isoprenoid biosynthetic pathway (
IBP) is critical for providing substrates for the post-translational modification of
proteins key in regulating malignant cell properties, including proliferation, invasion, and migration. Inhibitors of the
IBP, including
statins and nitrogenous
bisphosphonates, are used clinically for the treatment of
hypercholesterolemia and
bone disease respectively. The
statins work predominantly in the liver, while the nitrogenous
bisphosphonates are highly sequestered to bone. Inhibition of the entire
IBP is limited by organ specificity and side effects resulting from depletion of all
isoprenoids. We have developed a novel compound, disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-
tetraen-9-yl]
phosphonate (GGOHBP), which selectively targets
geranylgeranyl diphosphate synthase, reducing post-translational protein geranylgeranylation. Intracardiac injection of
luciferase-expressing human-derived 22Rv1 PCa cells into SCID mice resulted in
tumor development in bone (100 %), adrenal glands (72 %), mesentery (22 %), liver (17 %), and the thoracic cavity (6 %). Three weeks after
tumor inoculation, daily subcutaneous (SQ)
injections of 1.5 mg/kg GGOHBP or the vehicle were given for one month. Dissected
tumors revealed a reduction in adrenal gland
tumors corresponding to a 54 % (P < 0.005) reduction in total adrenal gland
tumor weight of the treated mice as compared to vehicle-treated controls. Western blot analysis of the harvested tissues showed a reduction in Rap1A geranylgeranylation in adrenal glands and mesenteric
tumors of the treated mice while non-tumorous tissues and control mice showed no Rap1A alteration. Our findings detail a novel
bisphosphonate compound capable of preferentially altering the
IBP in
tumor-burdened adrenal glands of a murine model of PCa
metastasis.