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Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptor-mediated pathway.

ABSTRACT: Quinazoline-based alpha1-adrenoceptor antagonists such as doxazosin and terazosin have been previously shown to induce apoptosis in prostate cancer cells via an alpha1-adrenoceptor-independent pathway, involving activation of transforming growth factor-beta1 (TGF-beta1) signaling. In this study, the molecular events initiating this apoptotic effect were further investigated in vitro using the human androgen-independent prostate cancer cells PC-3 and the human benign prostate epithelial cells BPH-1. Quantitative microarray assays were done in PC-3 and BPH-1 cells after treatment with doxazosin (25 micromol/L, 6 and 24 hours) to identify the early gene changes. Transient changes in the expression of several apoptosis regulators were identified, including up-regulation of Bax and Fas/CD95 and down-regulation of Bcl-xL and TRAMP/Apo3. Moreover, there were significant changes in the expression pattern of signaling components of the extracellular matrix such as integrins alpha2, alphaV, beta1, and beta8. Western blot analysis revealed activation of caspase-8 and caspase-3 within the first 6 to 12 hours of treatment with doxazosin in both PC-3 and BPH-1 cells. Doxazosin-induced apoptosis was blocked by specific caspase-8 inhibitors, supporting the functional involvement of caspase-8 in doxazosin-induced apoptosis. The effect of doxazosin on recruitment of Fas-associated death domain (FADD) and procaspase-8 to the Fas receptor was examined via analysis of death-inducing signaling complex formation. Doxazosin increased FADD recruitment and subsequent caspase-8 activation, implicating Fas-mediated apoptosis as the underlying mechanism of the effect of doxazosin in prostate cells. These results show that doxazosin exerts its apoptotic effects against benign and malignant prostate cells via a death receptor-mediated mechanism with a potential integrin contribution towards cell survival outcomes.

SUBMITTER: Garrison JB

PROVIDER: S-EPMC1850148 | biostudies-literature | 2006 Jan

REPOSITORIES: biostudies-literature

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Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptor-mediated pathway.

Garrison Jason B JB Kyprianou Natasha N

Cancer research 20060101 1

Quinazoline-based alpha1-adrenoceptor antagonists such as doxazosin and terazosin have been previously shown to induce apoptosis in prostate cancer cells via an alpha1-adrenoceptor-independent pathway, involving activation of transforming growth factor-beta1 (TGF-beta1) signaling. In this study, the molecular events initiating this apoptotic effect were further investigated in vitro using the human androgen-independent prostate cancer cells PC-3 and the human benign prostate epithelial cells BPH ...[more]

PMID: 16397262

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Project description:BackgroundColorectal cancer (CRC) is the second most mortality rate causing disease after lung cancer. Though there is a significant improvement in the treatment schedule offered to CRC. However, there is no notable decrease in terms of cases as well as death rate. Hence, there is an urgent need to discover novel cancer therapeutics to treat CRC. Since ancient times, the use of phytochemicals has drawn huge attention as chemo-preventive and chemotherapeutic agents. Earlier studies on Tinospora sinensis (TS) revealed the cytotoxic effect on human colorectal carcinoma (HCT-116) cells, yet the mechanism is to be uncovered. Therefore, the present study was designed to study the cell death mechanism of TS in HCT-116 cells.MethodDifferent extracts such as n-hexane, ethyl acetate, and ethanol extracts from the root part of TS were prepared using a cold maceration process. The extracts were screened against cancer cell lines by methyl thiazoldiphenyltetrazolium bromide (MTT) assay. From the result, the most active extract was subjected to gas chromatography-mass spectrometry (GC-MS) and Fourier-Transform infrared spectroscopy (FTIR) analyses to identify the major constituents. Finally, the mechanism of cytotoxicity to cancer cells for the most active extract was evaluated using various experiments such as cell cycle analysis, Annexin-V assay, and Western blot.ResultsThe results from the MTT assay indicated that the n-hexane extract of TS inhibits the growth of HCT-116 cells more effectively than other cancer cells like Henrietta Lacks cervical cancer cells (Hela), and Michigan cancer foundation-breast cancer (MCF-7). The GC-MS and FT-IR analyses revealed the presence of alkaloids in the n-hexane extract and were responsible for the apoptosis activity in HCT-cells via reactive oxygen species (ROS) generation, and phosphoinositide 3-kinase (PI3K)/ protein Kinase B (Akt)/ mammalian target of rapamycin (mTOR) down-regulation.ConclusionThis study concludes that this finding is unique of its kind, and for the first time. The anticancer effect of TS root is specific to colon cancer cells (HCT-116). This distinctive finding helps the researchers to investigate further, and to identify a novel source for anti-colon cancer drug candidates in near future.

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Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptor-mediated pathway.

Publications

Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptor-mediated pathway.

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