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1.
Cancers (Basel) ; 12(8)2020 Aug 04.
Article in English | MEDLINE | ID: mdl-32759730

ABSTRACT

Induction of mitotic catastrophe through the disruption of microtubules is an established target in cancer therapy. However, the molecular mechanisms determining the mitotic catastrophe and the following apoptotic or non-apoptotic cell death remain poorly understood. Moreover, many existing drugs targeting tubulin, such as vincristine, have reduced efficacy, resulting from poor solubility in physiological conditions. Here, we introduce a novel small molecule 2-aminoimidazoline derivative-OAT-449, a synthetic water-soluble tubulin inhibitor. OAT-449 in a concentration range from 6 to 30 nM causes cell death of eight different cancer cell lines in vitro, and significantly inhibits tumor development in such xenograft models as HT-29 (colorectal adenocarcinoma) and SK-N-MC (neuroepithelioma) in vivo. Mechanistic studies showed that OAT-449, like vincristine, inhibited tubulin polymerization and induced profound multi-nucleation and mitotic catastrophe in cancer cells. HeLa and HT-29 cells within 24 h of treatment arrested in G2/M cell cycle phase, presenting mitotic catastrophe features, and 24 h later died by non-apoptotic cell death. In HT-29 cells, both agents altered phosphorylation status of Cdk1 and of spindle assembly checkpoint proteins NuMa and Aurora B, while G2/M arrest and apoptosis blocking was consistent with p53-independent accumulation in the nucleus and largely in the cytoplasm of p21/waf1/cip1, a key determinant of cell fate programs. This is the first common mechanism for the two microtubule-dissociating agents, vincristine and OAT-449, determining the cell death pathway following mitotic catastrophe demonstrated in HT-29 cells.

2.
Wiad Lek ; 72(10): 2024-2032, 2019 Oct 31.
Article in English | MEDLINE | ID: mdl-31983147

ABSTRACT

Atypical hemolytic-uremic syndrome (aHUS) results from excessive, uncontrolled activation of the alternative pathway of the complement system. It is important to distinguish aHUS from other thrombotic microangiopathies. The aim of this paper is to discuss the complexity and relevance of the genetic background of aHUS patients. The review discusses the genetic variants that are important for diagnosis, treatment and prognosis of patients, which is inevitably important for the qualification of patients for treatment with eculizumab. These variants are not only found in the genes involved in the control of complement system but are also related to the coagulation system. The paper emphasizes the diagnostic difficulties resulting from the extremely diverse genetic background of the patients. It is important to conduct further genetic studies of aHUS patients, also paying attention to genes unrelated to the complement system. The paper contains information on the role of genetic predisposition in tailoring the risk for aHUS and determining its clinical outcome, including qualification for eculizumab therapy.


Subject(s)
Atypical Hemolytic Uremic Syndrome , Thrombotic Microangiopathies , Blood Coagulation , Genetic Background , Humans , Prognosis
3.
Int J Mol Sci ; 19(4)2018 Mar 29.
Article in English | MEDLINE | ID: mdl-29596317

ABSTRACT

Feline injection site sarcomas (FISS) are malignant skin tumors with high recurrence rates despite the primary treatment of radical surgical resections. Adjunctive radiotherapy or chemotherapy with doxorubicin is mostly ineffective. Cellular and molecular causes of multidrug resistance, specific physio-chemical properties of solid tumors impairing drug transport, and the tumor microenvironment have been indicated for causing standard chemotherapy failure. Gold nanoparticles are promising imaging tools, nanotherapeutics, and drug delivery systems (DDS) for chemotherapeutics, improving drug transport within solid tumors. This study was conducted to assess the distribution of 4-nm glutathione-stabilized gold nanoparticles in FISS and their influence on kidney and liver parameters in nude mice. The role of gold nanoparticles as a doxorubicin DDS in FISS was examined to determine the potential reasons for failure to translate results from in vitro to in vivo studies. Grade III tumors characterized by a large area of necrosis at their core displayed positive immuneexpression of tumor-associated macrophages (TAM) at both the periphery and within the tumor core near the area of necrosis. Gold nanoparticles did not cause necrosis at the injection site and had no negative effect on liver and kidney parameters in nude mice. Gold nanoparticles accumulated in the tumor core and at the periphery and co-internalized with TAM-an important observation and potential therapeutic target warranting further investigation. The large area of necrosis and high immunoexpression of TAM, indicating "pro-tumor macrophages", may be responsible for FISS tumor progression and therapeutic failure. However, further studies are required to test this hypothesis.


Subject(s)
Antibiotics, Antineoplastic , Doxorubicin , Drug Delivery Systems/methods , Glutathione , Gold , Metal Nanoparticles , Sarcoma , Skin Neoplasms , Animals , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacokinetics , Antibiotics, Antineoplastic/pharmacology , Cell Line, Tumor , Doxorubicin/chemistry , Doxorubicin/pharmacokinetics , Doxorubicin/pharmacology , Glutathione/chemistry , Glutathione/pharmacokinetics , Glutathione/pharmacology , Gold/chemistry , Gold/pharmacology , Metal Nanoparticles/chemistry , Metal Nanoparticles/therapeutic use , Mice , Mice, Nude , Sarcoma/drug therapy , Sarcoma/metabolism , Sarcoma/pathology , Skin Neoplasms/drug therapy , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Xenograft Model Antitumor Assays
4.
Oncotarget ; 8(6): 9303-9322, 2017 Feb 07.
Article in English | MEDLINE | ID: mdl-28030837

ABSTRACT

Anticancer therapies that induce DNA damage tend to trigger senescence in cancer cells, a process known as therapy-induced senescence (TIS). Such cells may undergo atypical divisions, thus contributing to tumor re-growth. Accumulation of senescent cancer cells reduces survival of patients after chemotherapy. As senescence interplays with autophagy, a dynamic recycling process, we sought to study whether inhibition of autophagy interferes with divisions of TIS cells. We exposed human colon cancer HCT116 cells to repeated cycles of a chemotherapeutic agent - doxorubicin (doxo) and demonstrated induction of hallmarks of TIS (e.g. growth arrest, hypertrophy, poliploidization and secretory phenotype) and certain properties of cancer stem cells (increased NANOG expression, percentages of CD24+ cells and side population). Colonies of small and highly proliferative progeny appeared shortly after drug removal. Treatment with bafilomycin A1 (BAF A1), an autophagy inhibitor, postponed short term in vitro cell re-population. It was associated with reduction in the number of diploid and increase in the number of poliploid cells. In a long term, a pulse of BAF A1 resulted in reactivation of autophagy in a subpopulation of HCT116 cells and increased proliferation. Accordingly, the senescent HCT116 cells treated with BAF A1 when injected into NOD/SCID mice formed tumors, in contrast to the controls.Our results suggest that senescent cancer cells that appear during therapy, can be considered as dormant cells that contribute to cancer re-growth, when chemotherapeutic treatment is stopped. These data unveil new mechanisms of TIS-related cancer maintenance and re-population, triggered by a single pulse of BAF A1 treatment.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Cell Proliferation/drug effects , Cellular Senescence/drug effects , Colonic Neoplasms/drug therapy , Doxorubicin/pharmacology , Macrolides/pharmacology , Neoplastic Stem Cells/drug effects , Side-Population Cells/drug effects , Animals , Autophagy/drug effects , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Mice, Inbred NOD , Mice, SCID , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Phenotype , Ploidies , Side-Population Cells/metabolism , Side-Population Cells/pathology , Signal Transduction/drug effects , Time Factors , Tumor Burden
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