191 research outputs found
Editorial: Anakoinosis: An Innovative Anticancer Therapy Targeting the Aberrant Cancer Tissue Homeostasis
No full textNEATG_A
No full textThis is the source code for the NEATG_A model, as described in the paper 'A Computational Model of TumorGrowth and Anakoinosis' by Pan Pantziarka, Lina Ghibelli and Albrecht Reichle (2019).</div
Lowering etoposide doses shifts cell demise from caspase-dependent to differentiation and caspase-3-independent apoptosis via DNA damage response, inducing AML culture extinction
No full textCytotoxic chemotherapy, still the most widely adopted anticancer treatment, aims at eliminating cancer cells inducing apoptosis with DNA damaging agents, exploiting the differential replication rate of cancer vs. normal cells; efficiency is evaluated in terms of extent of induced apoptosis, which depends on the individual cell sensitivity to a given drug, and on the dose. In this in vitro study, we report that the concentration of etoposide, a topoisomerase II poison widely used in clinics, determines both the kinetics of cell death, and the type of apoptosis induced. We observed that on a set of myeloid leukemia cell lines, etoposide at high (50 uM) dose promoted a rapid caspase-3-mediated apoptosis, whereas at low (0.5 uM) dose, it induced morphological and functional granulocytic differentiation and caspase-2-dependent, but caspase-3-independent, cell death, displaying features consistent with apoptosis. Both differentiation and caspase-2- (but not 3)-mediated apoptosis were contrasted by caffeine, a well-known inhibitor of the cellular DNA damage response (DDR), which maintained cell viability and cycling, indicating that the effects of low etoposide dose are not the immediate consequence of damage, but the result of a signaling pathway. DDR may be thus the mediator responsible for translating a mere dosage-effect into different signal transduction pathways, highlighting a strategic action in regulating timing and mode of cell death according to the severity of induced damage. The evidence of different molecular pathways induced by high vs. low drug doses may possibly contribute to explain the different effects of cytotoxic vs. metronomic therapy, the latter achieving durable clinical responses by treating cancer patients with stable, low doses of otherwise canonical cytotoxic drugs; intriguingly caspase-3, a major promoter of wounded tissue regeneration, is also a key factor of post-therapy cancer repopulation. All this suggests that cancer control in response to cytotoxic drugs arises from complex reprogramming mechanisms in tumor tissue, recently described as anakoinosis
Molecular cross-talk between nuclear receptors and nuclear factor-kB
No full textAbstract Nuclear receptors can function as ligand-activated transcription factors but can even so cross-talk with other transcription factors. In this respect, NF-kB, a central regulator of both inflammation and tumorigenesis, can cross-react with and is negatively affected by these nuclear receptors. In current medicine, the nuclear receptor ligands for the glucocorticoid receptor form still the mainstay for treatment
of inflammation-based afflictions. However, also other nuclear receptor ligands can affect inflammatory processes. In this respect, the cross-talk of various nuclear receptors with each other has been given renewed attention in recent literature. We
will discuss the cross-talk of nuclear receptors with NF-kB and each other in the context of the attenuating control of inflammatory and tumor-promoting mechanisms, using the well described glucocorticoid receptor as a focal point
Addressing Genetic Tumor Heterogeneity, Post-Therapy Metastatic Spread, Cancer Repopulation, and Development of Acquired Tumor Cell Resistance
No full textThe concept of post-therapy metastatic spread, cancer repopulation and acquired tumor cell resistance (M-CRAC) rationalizes tumor progression because of tumor cell heterogeneity arising from post-therapy genetic damage and subsequent tissue repair mechanisms. Therapeutic strategies designed to specifically address M-CRAC involve tissue editing approaches, such as low-dose metronomic chemotherapy and the use of transcriptional modulators with or without targeted therapies. Notably, tumor tissue editing holds the potential to treat patients, who are refractory to or relapsing (r/r) after conventional chemotherapy, which is usually based on administering a maximum tolerable dose of a cytostatic drugs. Clinical trials enrolling patients with r/r malignancies, e.g., non-small cell lung cancer, Hodgkin's lymphoma, Langerhans cell histiocytosis and acute myelocytic leukemia, indicate that tissue editing approaches could yield tangible clinical benefit. In contrast to conventional chemotherapy or state-of-the-art precision medicine, tissue editing employs a multi-pronged approach targeting important drivers of M-CRAC across various tumor entities, thereby, simultaneously engaging tumor cell differentiation, immunomodulation, and inflammation control. In this review, we highlight the M-CRAC concept as a major factor in resistance to conventional cancer therapies and discusses tissue editing as a potential treatment
Bridging Theory and Therapeutic Practice: From Generalized Disease Models to Particular Patients
No full textCommunication—Evolution—Pathophysiology: An Endogenous Conjunction—Instead of an Introduction
No full textBridging a Diagnostic and Therapeutic Gap: Selecting, Assessing and Categorizing, Tumor-associated Normative Notions
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