Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction.

Previous studies documented the ability of quinazoline-based alpha1-adrenoceptor antagonists to induce apoptosis in prostate cancer cells via an alpha 1-adrenoceptor-independent mechanism. In this study we investigated the molecular events initiating this apoptotic effect. Since transforming growth factor-beta 1 (TGF-beta 1) mediates prostate epithelial cell apoptosis, we hypothesised that the activation of the TGF-beta 1 pathway underlies the quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the androgen-independent human prostate cancer cells PC-3 with doxazosin resulted in a strong caspase-3 activation within 24 h, whereas tamsulosin, a sulphonamide-based alpha 1-adrenoceptor antagonist, had no significant apoptotic effect against prostate cancer cells. To identify the molecular components involved in this quinazoline-mediated apoptosis, cDNA microarray analysis of PC-3 prostate cancer cells treated with doxazosin (3 h) was performed. Induced expression of several genes was observed including p21(WAF-1) and I kappa B alpha (inhibitor of NF-kappa B alpha). Relative quantitative reverse transcription-polymerase chain reaction analysis revealed induction of several TGF-beta1 signalling effectors: Induction of mRNA for Smad4 and the TGF-beta1-regulated apoptosis-inducing transcription factor TGF-beta1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatment. Upregulation of I kappa B alpha at both the mRNA and protein level was also detected after 6 h of treatment. Furthermore, doxazosin resulted in a considerable elevation in Smad4 and TIEG protein expression (6 h). A 'latent' increase in TGF-beta mRNA expression was detected after 48 h of treatment. These findings suggest that the quinazoline-based doxazosin mediates prostate cancer apoptosis by initially inducing the expression of TGF-beta1 signalling effectors and subsequently I kappa B alpha. The present study provides an initial insight into the molecular targets of the apoptotic action of quinazolines against prostate cancer cells.

Induction of prostate apoptosis by alpha1-adrenoceptor antagonists: mechanistic significance of the quinazoline component.

alpha(1)-Adrenoceptor antagonists, have been documented to induce apoptosis and reduce prostate tumor vascularity in benign and malignant prostate cells. The quinazoline based alpha(1)-antagonists, doxazosin and terazosin but not tamsulosin (a sulphonamide derivative) suppress prostate growth without affecting cell proliferation. These quinazoline-mediated apoptotic effects occur via an alpha(1)-adrenoceptor independent mechanism potentially involving activation of the TGF-beta signal transduction pathway. This review discusses the current knowledge of the action of quinazoline-derived alpha(1)-adrenoceptor antagonists in the benign and malignant prostate and their potential therapeutic use in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Finally, a molecular pathway is proposed for their observed apoptotic function against prostate cells. Increased understanding of the action of these established and clinically accepted agents would provide a basis for the design of safe, effective therapeutic regimens in the treatment of prostatic diseases.

TENB2, a proteoglycan identified in prostate cancer that is associated with disease progression and androgen independence.

TENB2 encodes a putative transmembrane proteoglycan, related to the EGF/heregulin family of growth factors and follistatin, which has been identified through the application of a differential display technique to a xenograft model of prostate cancer. Northern analysis and competitive PCR were used to demonstrate significantly increased TENB2 expression (p = 0.0003) on the acquisition of androgen independence in the model system. TENB2 is also overexpressed in clinical prostate carcinoma vs. its benign counterpart (p < 0.0001), with particular prominence in high-grade tumours, and shows a high degree of tissue specificity, being detected on a multitissue Northern array exclusively in brain and prostate material. Studies of recombinant protein expression demonstrate that TENB2 is a chondroitin sulphate proteoglycan. The presence of an EGF and 2 follistatin domains suggests a role in the regulation of growth factor signalling either as a ligand precursor, a membrane-bound receptor or as a binding protein for growth factors. These data are indicative of a significant role for TENB2 in the progression of poorly differentiated tumour types, with implications for prostate cancer detection, prognosis and therapy.

Collagen VII expression in human chronic wounds and scars.

Collagen VII is the major structural component of the anchoring fibrils that stabilize the cutaneous basement membrane on the dermis. Disruption and, more usually, destruction of the basement membrane are characteristic of wounds that are slow, or fail, to heal, such as chronic lower-limb or pressure ulcers. In this study, the expression of collagen VII was analysed in 28 human chronic cutaneous wounds or scars using a reverse transcription-polymerase chain reaction (RT-PCR) technique. Collagen VII expression was detected in 26 of these 28 cutaneous wounds, but not in two wounds, neither of which showed any clinical evidence of healing.

From the Journals.

Wound care in patients with HIV The development of pressure sores Gene transcription factors.