Effect Of The Specific Src Kinase Inhibitor AZD0530 On Osteolytic Lesions In Prostate Cancer

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 13 Jun 2008 - 7:00 PDT

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ORLANDO, FL (UroToday.com) - Advanced prostate cancer becomes androgen independent and causes bone metastasis with resulting patient morbidity. Although osteoblastogenesis is mostly observed in patients through autopsy, it is believed that bone resorption is the prerequisite for osteoblastic lesions. Src kinase has been identified to play an important role in tumor growth and metastasis. In this study, a specific Src kinase inhibitor, AZD0530 was tested for its effect on the osteolytic prostate cancer cell line PC-3 both in vitro and in vivo.

PC-3 cells were treated with various doses of AZD0530 for different time periods, their growth curves and phosphorylation status of Src kinase and its downstream kinases were measured by MTT assay and Western blot analysis. Effect of AZD0530 on the expression of IL-8, u-PA and MMP-9, molecules responsible for metastasis, was determined by RT-PCR and gelatin zymography. For in vivo study, 2 x 105 PC-3 cells were injected into the tibia of 24 SCID mice. Mice were divided into two groups with the treatment group receiving 25 mg/kg daily of AZD0530 and the control buffer only. Bone resorption was monitored by X-ray radiography weekly. At the end of eight weeks, mice were sacrificed and tissue and serum samples subjected for pathological staining and the pyridinoline (PYD) crosslink assay.

AZD0530 inhibits PC-3 cell growth in a dose-dependent manner. Phosphorylation of Src, FAK, paxillin and P130cas was inhibited by AZD0530 at the nM magnitude. RTPCR analysis showed the expression of IL-8 and u-PA was reduced by the AZD0530 treatment. Secretion of MMP-9 decreased in PC-3 cells treated with AZD0530. For the in vivo study, at the end of 5 weeks from surgery, 9 out of 12 control mice showed osteolytic lesions compared with only 4 in the treatment group. Both H & E and the Tartrate-resistant acid phosphatase (TRAP) stainings revealed populated osteoclasts in the bone sections of control mice but not in the treated mice. Serum PYD assay showed almost twice the amount of PYD crosslinks detected in the control samples than in the treatment.

They conclude that the specific Src kinase inhibitor AZD0530 inhibits the activities of Src and FAK kinases and their downstream substrates. This inhibition affects cell proliferation and the expression of IL-8, u-PA and MMP-9 which suggests AZD0530 may inhibit cancer cell invasion into the bone matrix. The animal study further demonstrates the ability of AZD0530 to retard the osteolytic lesions, which would be a therapeutic advantage in treating patients with prostate cancer.

Presented by Joy C Yang, MD, Lanfang Bai, MD, Hsing-Jien Kung, MD, and Christopher P. Evans, MD, at the Annual Meeting of the American Urological Association (AUA) - May 17 - 22, 2008. Orange County Convention Center - Orlando, Florida, USA.

Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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