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Biomedical subjects

Abebe Akalu

Publications and source records attributed to Abebe Akalu.

7 recordsLinked to original sources
PubMed2006

The vitamin-like dietary supplement para-aminobenzoic acid enhances the antitumor activity of ionizing radiation.

PURPOSE: To determine whether para-aminobenzoic acid (PABA) alters the sensitivity of tumor cells to ionizing radiation in vitro and in vivo. METHODS AND MATERIALS: Cellular proliferation was assessed by WST-1 assays. The effects of PABA and radiation on tumor growth were examined with chick embryo and murine models. Real-time reverse transcriptase-polymerase chain reaction and Western blotting were used to quantify p21CIP1 and CDC25A levels. RESULTS: Para-aminobenzoic acid enhanced (by 50%) the growth inhibitory activity of radiation on B16F10 cells, whereas it had no effect on melanocytes. Para-aminobenzoic acid enhanced (50-80%) the antitumor activity of radiation on B16F10 and 4T1 tumors in vivo. The combination of PABA and radiation therapy increased tumor apoptosis. Treatment of tumor cells with PABA increased expression of CDC25A and decreased levels of p21CIP1. CONCLUSIONS: Our findings suggest that PABA might represent a compound capable of enhancing the antitumor activity of ionizing radiation by a mechanism involving altered expression of proteins known to regulate cell cycle arrest.

4-Aminobenzoic Acid↗
PubMed2006

Inhibition of experimental metastasis by targeting the HUIV26 cryptic epitope in collagen.

Metastasis from the primary tumor to distant sites involves an array of molecules that function in an integrated manner. Proteolytic remodeling and subsequent tumor cell interactions with the extracellular matrix regulate tumor invasion. In previous studies, we have identified a cryptic epitope (HUIV26) that is specifically exposed after alterations in the triple helical structure of type IV collagen. Exposure of this cryptic epitope plays a fundamental role in the regulation of angiogenesis in vivo. However, little is known concerning the ability of tumor cells to interact with this cryptic site or whether this site regulates tumor cell metastasis in vivo. In this regard, many of the same cellular processes that regulate angiogenesis also contribute to tumor metastasis. Here we provide evidence that tumor cells such as B16F10 melanoma interact with denatured collagen type IV in part by recognizing the HUIV26 cryptic site. Systemic administration of a HUIV26 monoclonal antibody inhibited experimental metastasis of B16F10 melanoma in vivo. Taken together, our findings suggest that tumor cell interactions with the HUIV26 cryptic epitope play an important role in regulating experimental metastasis and that this cryptic element may represent a therapeutic target for controlling the spread of tumor cells to distant sites.

Animals↗
PubMed2005

Recombinant alpha2(IV)NC1 domain inhibits tumor cell-extracellular matrix interactions, induces cellular senescence, and inhibits tumor growth in vivo.

Cellular interaction with the extracellular matrix is thought to be a critical event in controlling angiogenesis and tumor growth. In our previous studies, genetically distinct noncollagenous (NC) domains of type-IV collagen were shown to interact with integrin receptors expressed on the surface of endothelial cells. Moreover, these NC1 domains were shown to inhibit angiogenesis in vivo. Here, we provide evidence that a recombinant form of the alpha2(IV)NC1 domain of type-IV collagen could bind integrins alpha1beta1 and alphavbeta3 expressed on melanoma cells and inhibit tumor cell adhesion in a ligand-specific manner. Systemic administration of recombinant alpha2(IV)NC1 domain potently inhibited M21 melanoma tumor growth within full thickness human skin and exhibited a dose-dependent inhibition of tumor growth in nude mice. Interestingly, alpha2(IV)NC1 domain enhanced cellular senescence in tumor cells in vitro and in vivo. Taken together, these results suggest that recombinant alpha2(IV)NC1 domain is not only a potent anti-angiogenic reagent, but it also directly impacts tumor cell behavior. Thus, alpha2(IV)NC1 domain represents a potent inhibitor of tumor growth by impacting both endothelial and tumor cell compartments.

Animals↗
PubMed2005

Targeting integrins for the control of tumour angiogenesis.

The crucial role of cell extracellular matrix communication in angiogenesis is well established; thus, it is not surprising that integrins have gained considerable attention as targets for the treatment of neovascular disease. Given the diversity of ligands and complexity of integrin signalling, a new appreciation for the divergent roles of integrins in angiogenesis is emerging. It is becoming clear that integrins regulate angiogenesis in both a positive and negative manner. New studies have provided a better understanding of integrin structure as it relates to ligand binding and signalling. This new insight has opened exciting possibilities for the design of novel inhibitors for clinical applications. In this review, studies concerning the cooperative interactions between integrins and regulatory molecules and possible new strategies for controlling angiogenesis will be discussed.

Angiogenesis Inhibitors↗
PubMed2004

Identification and characterization of somatic steroid 5alpha-reductase (SRD5A2) mutations in human prostate cancer tissue.

Prostate cancer is a very common disease in industrialized countries and it is known to be androgen-dependent. The human SRD5A2 gene encodes the prostatic (or type II) steroid 5alpha-reductase, which catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate. We have sequenced the entire protein-coding region of this locus in 30 microdissected prostate adenocarcinomas. We identified a total of 17 de novo amino-acid substitutions in 13 of these tumors. We also identified six additional silent substitutions. In total, 18 out of 30 (60%) of the tumors examined had de novo somatic substitutions in the prostatic steroid 5alpha-reductase-coding region. We also characterized all of the SRD5A2 missense substitutions biochemically and pharmacologically, using three 5alpha-reductase inhibitors, including finasteride. The biochemical parameters of the distinct 5alpha-reductase missense substitutions varied substantially. We note that two out of the three recurrent SRD5A2 missense substitutions increased 5alpha-reductase in vitro activity, while the third one is essentially neutral. These findings are consistent with a role for increased DHT levels in the prostate through increased activity of the SRD5A2 locus in prostate cancer progression, in a subset of patients. Our pharmacologic studies also reveal substantial variability for each 5alpha-reductase inhibitor. These data, therefore, should be taken into account in both prevention as well as therapeutic trials of prostate cancer utilizing 5alpha-reductase inhibitors.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2004

Challenges facing antiangiogenic therapy for cancer: impact of the tumor extracellular environment.

It is well known that angiogenesis plays an important role in malignant tumor progression. Thus, a great deal of effort has been focused on the development and evaluation of novel angiogenesis inhibitors for the treatment of human malignancies. In this review, the role of angiogenesis in tumor growth will be examined, as well as efforts to develop and use antiangiogenic therapies to treat malignant tumors. In particular, focus will be on the extracellular environment and the challenges of using antiangiogenic therapy in the clinical setting, in terms of toxicities, potential mechanisms of tumor resistance and optimization of clinical trial design. Attention will be focused upon a mechanistic understanding of the variability and dynamic nature of individual tumor microenvironments, and the potential impact this has on antiangiogenic therapies.

Angiogenesis Inhibitors↗