ABSTRACT
The activity of the enzyme steroid sulfatase (STS) is high in breast tumors and elevated levels of STS mRNA expression have been associated with a poor prognosis. Potent STS irreversible inhibitors have been developed, paving the way to use this new type of therapy for the treatment of breast cancer. Several small molecules belonging to a natural products-inspired library of previously obtained inhibitors of tumor cell growth and new molecules planned to be reversible inhibitors of this enzyme were docked into STS. Some of the synthesized xanthone derivatives, which revealed high scores against STS, namely oxo-9H-xanthene-3,6-diyl bis(3-chlorobenzoate) (5), 9-oxo-9H-xanthene-3,6-diyl bis(4-tertbutylbenzoate) (6) and 9-oxo-9H-xanthene-3,6-diyl bis(4-methoxybenzoate) (7) showed poor water solubility. Therefore, formulations of these derivatives with cyclodextrins were prepared and characterized. The compounds were evaluated regarding their effect on the in vitro growth of various human tumor cell lines, as well as the effect in STS inhibition, for the compounds with the most favorable ΔG values. Additionally, the capacity of these derivatives and of some prenyl and acetoxy-benzophenone and xanthones to inhibit the in vitro growth of MCF-7 ER(+) and/or to inhibit STS in a micromolar range was also assessed. Some compounds developed in the present work were shown to be potential STS inhibitors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Steryl-Sulfatase/antagonists & inhibitors , Cell Line, Tumor , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
The effect of downregulation of the expression of the antiapoptotic protein XIAP with antisense oligonucleotides was evaluated in the K562 chronic myeloid leukemia (CML) cell line. This was carried out by studying the effects of downregulation of XIAP expression on cellular viability, cellular apoptosis and on the response to two chemotherapeutical drugs, etoposide and doxorubicin. We document that downregulation of XIAP expression decreased cellular viability, increased cellular apoptosis and enhanced the effects of doxorubicin.
Subject(s)
Oligonucleotides, Antisense/pharmacology , X-Linked Inhibitor of Apoptosis Protein/metabolism , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Cell Survival/drug effects , Down-Regulation , Doxorubicin/pharmacology , Etoposide/pharmacology , Humans , K562 Cells/drug effects , K562 Cells/pathology , X-Linked Inhibitor of Apoptosis Protein/antagonists & inhibitorsABSTRACT
Tarsal coalition is abnormal fusion of two or more tarsal bones. The union may be fibrous, cartilaginous, or osseous and can be congenital or acquired in response to infection, articular disorders, trauma, or surgery. We report a case of fibrous talocalcaneal coalition in a 15-year-old boy in whom bone scintigraphy employing pinhole lateral views confirmed the clinical diagnosis when plain radiographs showed minimal changes and computed tomography was equivocal. The diagnosis of symptomatic tarsal coalition is important in that it is a common remediable cause of peroneal spastic flat foot, a frequently encountered condition. Scintigraphy provides important information about the presence and localization of this condition.
