Src kinase inhibitors: an emerging therapeutic treatment option for prostate cancer

2010 ◽  
Vol 19 (5) ◽  
pp. 605-614 ◽  
Author(s):  
Joanne Edwards
2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14542-14542 ◽  
Author(s):  
C. P. Evans ◽  
P. N. Lara ◽  
H. Kung ◽  
J. C. Yang

14542 Background: Cells with neuroendocrine (NE) differentiation are found in prostate cancer and may facilitate the transition to AI by supplying alternate growth factors. Androgen deprivation further induces a subgroup of AI NE cells by transdifferentiation. We hypothesized that androgen receptor (AR)- and src kinase-mediated signaling participates in this NE progression, and tested inhibition using the src kinase inhibitor AZD0530. Methods: The neuropeptide gastrin-releasing peptide (GRP) was minimally expressed in androgen-sensitive LNCaP cells. LNCaP-GRP clones demonstrated androgen- and anchorage-independent growth, developed orthotopic tumors in castrated SCID mice & activated PSA with nuclear localization of AR. LNCap-GRP clones & xenografts showed activation of src kinase. Xenografts were recultured (LNCaP-Pro) & grown in androgen-free soft agar or tissue culture either alone, with synthetic androgen R1881 or with inhibitors including: GRP monoclonal antibody 2A11, 10 μM antiandrogen bicalutamide, Src kinase inhibitors AZM475271, AZD0530 (5 μM) and PP2 (10 μM). Mice bearing orthotopic LNCaP-GRP tumors were treated orally with 50 mg/kg AZD0530 daily for 6 weeks. Results: Androgen-depleted soft agar colony counts showed that LNCaP-Pro cell proliferation was not stimulated by R1881 but was partially inhibited by 2A11 antibody or bicalutamide, when compared to controls. A combination of 2A11 & bicalutamide resulted in significant growth reduction (p < 0.05). R1881 mostly reversed the 2A11 inhibition. The Src kinase inhibitors AZM475271 & PP2 showed greatest colony formation inhibition (p < 0.05). AZD0530 inhibited growth in culture (not tested in soft agar) at micromolar concentrations. Testing in vivo inhibited primary tumor growth in 5 of 7 dosed mice (71%), but completely inhibited metastasis in all AZD0530-treated mice (compared with metastasis in 100% of controls). Conclusions: Neuropeptide-mediated AIPC growth is dependent on both GRP and AR. There appears to be a beneficial role for Src kinase inhibition in this model. A CTEP-sponsored phase II trial of the dual Src/Abl kinase inhibitor AZD0530 in AIPC has been initiated. (KO8 DK60748–01, 2RO1 DK/AG52659–04, DOD PC10520, Astra-Zeneca, NO1 CM17101). [Table: see text]


2012 ◽  
Vol 17 (2) ◽  
pp. 145-159 ◽  
Author(s):  
Helen Creedon ◽  
Valerie G . Brunton

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2228
Author(s):  
Jana Kvízová ◽  
Vladimíra Pavlíčková ◽  
Eva Kmoníčková ◽  
Tomáš Ruml ◽  
Silvie Rimpelová

Prostate cancer is a very common disease, which is, unfortunately, often the cause of many male deaths. This is underlined by the fact that the early stages of prostate cancer are often asymptomatic. Therefore, the disease is usually detected and diagnosed at late advanced or even metastasized stages, which are already difficult to treat. Hence, it is important to pursue research and development not only in terms of novel diagnostic methods but also of therapeutic ones, as well as to increase the effectiveness of the treatment by combinational medicinal approach. Therefore, in this review article, we focus on recent approaches and novel potential tools for the treatment of advanced prostate cancer; these include not only androgen deprivation therapy, antiandrogen therapy, photodynamic therapy, photothermal therapy, immunotherapy, multimodal therapy, but also poly(ADP-ribose) polymerase, Akt and cyclin-dependent kinase inhibitors.


2011 ◽  
Vol 18 (33) ◽  
pp. 5061-5078 ◽  
Author(s):  
S. Schenone ◽  
C. Brullo ◽  
F. Musumeci ◽  
M. Radi ◽  
D. Castagnolo
Keyword(s):  

2005 ◽  
Vol 13 (15) ◽  
pp. 4704-4712 ◽  
Author(s):  
Ram Thaimattam ◽  
Pankaj R. Daga ◽  
Rahul Banerjee ◽  
Javed Iqbal

2011 ◽  
Vol 27 (4) ◽  
pp. 260-266 ◽  
Author(s):  
Josephine Hegarty ◽  
Donald E. Bailey

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