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. 2009 Jul 21;101(2):263-8.
doi: 10.1038/sj.bjc.6605178.

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

T Koreckij  1 , H Nguyen, L G Brown, E Y Yu, R L Vessella, E Corey
Affiliations

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

T Koreckij et al. Br J Cancer. .

Abstract

Background: Dasatinib is a small molecule kinase inhibitor that has recently been shown to inhibit Src family kinases (SFK) and also has activity against CaP. Of importance to metastatic CaP, which frequently metastasises to bone, SFK are also vital to the regulation of bone remodelling. We sought to determine the ability of dasatinib to inhibit growth of CaP in bone.

Methods: C4-2B CaP cells were injected into tibiae of SCID mice and treated with dasatinib, alone or in combination with docetaxel. Serum prostate-specific antigen levels, bone mineral density, radiographs and histology were analysed.

Results: Treatment with dasatinib alone significantly lowered sacrifice serum prostate-specific antigen levels compared to control, 2.3+/-0.4 vs 9.2+/-2.1 (P=0.004). Combination therapy improved efficacy over dasatinib alone (P=0.010). Dasatinib increased bone mineral density in tumoured tibiae by 25% over control tumoured tibiae (P<0.001).

Conclusion: Dasatinib inhibits growth of C4-2B cells in bone with improved efficacy when combined with docetaxel. Additionally, dasatinib inhibits osteolysis associated with CaP. These data support further study of dasatinib in clinical trials for men with CaP bone metastases.

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Figures

Figure 1
Figure 1
Effects of dasatinib on cellular proliferation: (A) Dasatinib inhibited proliferation of C4-2B cells. The cells were treated with 0, 12, 33, 111, 333, 1000, 3000 or 9000 nM dasatinib for 72 h, ANOVA P<0.0001. Data are plotted as mean±s.e.m. (B) Dasatinib treatment resulted in decreases in total levels of PSA in the culture media from the proliferation studies. (C) Immunoprecipitation (IP) for lyn and src. Treatment with dasatinib decreased phosphorylation of src but not lyn at Tyr416. Western blot analysis of whole cell lysates demonstrates that dasatinib did not affect total protein levels for lyn or src. (D) Western blot analysis – 100 nM dasatinib inhibited src family kinase (SFK) phosphorylation after 0.5, 1, 2, 4, 6 and 24 h.
Figure 2
Figure 2
Effects of dasatinib and docetaxel in vivo: (A) Dasatinib alone and in combination with docetaxel significantly inhibited serum levels of PSA. PSA levels were normalised to enrolment PSA. Doc=docetaxel (5 mg kg−1) alone; Das=dasatinib (50 mg kg−1) alone; Doc/Das=Combination therapy. Data are plotted as mean±s.e.m. (B) Representative radiographs of tibiae taken just before killing: (1) Normal non-tumoured tibiae; (2) C4-2B tumoured tibia – control group; (3) C4-2B tumoured tibia of animal treated with docetaxel; (4) C4-2B tumoured tibia of animal treated with dasatinib alone; (5) C4-2B tumoured tibia of animal treated with dasatinib+docetaxel. Notice the mixed osteolytic/osteoblastic lesions associated with growth of C4-2B in untreated and docetaxel-treated tibiae. (C) Effect of dasatinib of on inhibition of src phosphorylation of C4-2B subcutaneous tumours. Near complete inhibition of src family kinase phosphorylation is demonstrated with dasatinib treatment. Animals treated 2 h before killing. Negative control slides were negative (data not shown). × 10 magnification. (D) H&E of representative tibiae. Note the increasing amounts of bone formation with the administration of dasatinib (black arrows). Doc=docetaxel alone; Das=dasatinib alone; Doc/Das=Combination therapy. × 10 magnification.
Figure 3
Figure 3
Effects of dasatinib and docetaxel on BMD: (A) Comparison BMD of disease tibiae. Analysis via Student's t-test. (B) Comparison of BMD between diseased and non-diseased tibiae. Doc=docetaxel (5 mg kg−1) monotherapy; Das=dasatinib (50 mg kg−1) monotherapy; Doc/Das=Combination therapy; R=right (tumoured tibiae); L=left (non-tumoured tibiae). Numbers above the columns represent the decrease in BMD between normal tibiae and contralateral tumoured tibiae.
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