Geranylgeranyl transferase type II inhibition prevents myeloma bone disease

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Abstract

Geranylgeranyl transferase II (GGTase II) is an enzyme that plays a key role in the isoprenylation of proteins. 3-PEHPC, a novel GGTase II inhibitor, blocks bone resorption and induces myeloma cell apoptosis in vitro. Its effect on bone resorption and tumor growth in vivo is unknown. We investigated the effect of 3-PEHPC on tumor burden and bone disease in the 5T2MM model of multiple myeloma in vivo. 3-PEHPC significantly reduced osteoclast numbers and osteoclast surface. 3-PEHPC prevented the bone loss and the development of osteolytic bone lesions induced by 5T2MM myeloma cells. Treatment with 3-PEHPC also significantly reduced myeloma burden in bone. The magnitude of response was similar to that seen with the bisphosphonate, risedronate. These data show that targeting GGTase II with 3-PEHPC can prevent osteolytic bone disease and reduce tumor burden in vivo, and represents a novel approach to treating tumors that grow in bone.

Section snippets

Materials and methods

The 5T2MM syngeneic model of multiple myeloma. The 5T2MM murine model of multiple myeloma originated spontaneously in elderly C57BL/KaLwRij mice [16]. 5T2MM cells have been propagated since, in vivo, by the intravenous transfer of diseased bone marrow into young syngeneic mice [17]. Male 6-week-old C57BL/KaLwRijHsd mice were obtained from Harlan CPD (Horst, The Netherlands). 5T2MM cells were isolated from the bone marrow of disease-bearing animals, purified, and injected, via the tail vein,

Inhibiting GGTase II with 3-PEHPC decreases osteoclast numbers in vivo

We first examined the affects of 3-PEHPC on osteoclast number and the bone surface occupied by osteoclasts. TRAP-positive osteoclasts were seen lining the cortico-endosteal bone surfaces of naïve and 5T2MM-bearing mice (Fig. 2A). There was a significant increase in osteoclast surface in 5T2MM-bearing mice when compared to naive mice (p < 0.01) (Fig. 2B). In contrast, 5T2MM-bearing mice treated with either 3-PEHPC or risedronate had a reduction in osteoclast surface compared to 5T2MM-bearing mice

Discussion

Compounds that inhibit enzymes in the mevalonate pathway have been shown to be associated with anti-myeloma effects in vivo[20], [21], [22], [23]. However, it is unclear whether these are direct effects or indirect effects via the inhibition of bone resorption. Less is known about whether downstream inhibitors of this pathway also induce anti-myeloma effects in vivo. Given that myeloma cell survival in vitro requires geranylgeranylated proteins [11] we assessed the role of 3-PEHPC, a specific

Acknowledgments

We thank the Leukaemia Research Fund for supporting this work: O. Gallagher, M. Prideaux, A. Willems and C. Seynaeve for expert technical assistance; and the Alliance for Better Bone Health (Proctor & Gamble and Sanofi-Aventis).

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