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L’inibizione della separazione dei centrosomi determina catastrofe mitotica caspasi indipendente in cellule HeLa ma non in fibroblasti primari umani
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DNA Damage in Stem Cells
Full text linkBoth embryonic and adult stem cells are endowed with a superior capacity to prevent the accumulation of genetic lesions, repair them, or avoid their propagation to daughter cells, which would be particularly detrimental to the whole organism. Inducible pluripotent stem cells also display a robust DNA damage response, but the stability of their genome is often conditioned by the mutational history of the cell population of origin, which constitutes an obstacle to clinical applications. Cancer stem cells are particularly tolerant to DNA damage and fail to undergo senescence or regulated cell death upon accumulation of genetic lesions. Such a resistance contributes to the genetic drift of evolving tumors as well as to their limited sensitivity to chemo- and radiotherapy. Here, we discuss the pathophysiological and therapeutic implications of the molecular pathways through which stem cells cope with DNA damage
Spindle checkpoint activatio is required for Combrestatin ST2151 and CA4-phpsphate induced-mitotic catastrophe in primary endothelial and lung tumor-treated cells
No full textCombretastatins are tubulin binding agents, structurally related to colchicines and with a high potential as vascular targeting agents for their capability to induce vascular-mediated tumour necrosis. Molecular mechanisms leading to checkpoint apoptosis have been investigated in endothelial primary cells (HUVEC) and tumor cancer cells (H460) after treatment with ST2151 or combretastatin CA4. We found that both compounds induce depolymerisation and rearrangement of spindle microtubules and an increasingly aberrant organization of metaphase chromosomes in a dose- and time-dependent manner. Both H460 and HUVEC cells were arrested at the pro-metaphase stage at different extent (44,0% vs 17,8% for CA4; 42,6% vs 18,8% for ST2151, respectively) with consequent p53 accumulation and spindle assembly checkpoint activation as evaluated by kinetochore localization of Bub-1 and MAD1 antibodies. Prolonged checkpoint activation led to mitochondrial membrane permeabilization (MMP) alterations, partial activation of caspase-3 and –9, PARP cleavage and DNA fragmentation. On the other hand caspase-2 and -8 were not activated by drug treatment. Interestingly, after 24 h exposure the percentage of cell death was far higher in H460 compared to HUVEC (94,5 % vs 31,5% for CA4; 59,3% vs 20,3% for ST2151). The presence of multinucleated cells, strongly supported the notion that combretastatin, particularly the ST2151 triggers a mitotic catastrophe pathway. Furthermore, we found persistence of cell death induction as evaluated at 24-72 hours from drug washout (in H460 cells persistence of 80-85% cell death). Experiments are in progress, to ascertain the activation of checkpoints at long times from drug removal. Hundred % of cells arrested in metaphase after drugs washout displayed mitotic chechkpoint activation The different pharmacological behaviour of ST2151 respect to CA-4 does not simply correlate with an anti-tubulin mechanism, suggesting that additional molecular targets may be involved, or alternatively, ST molecules might have different binding site or mode of interaction with tubulin
Tubulin binding agents induce gamma-tubulin displacement frmom centrosome to kinetochores
No full textL’inibizione della separazione dei centrosomi induce arresto in prometafase e catastrofe mitotica caspasi-3 indipendente in cellule HeLa ma non in fibroblasti primari umani
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Role of autophagy in the maintenance and function of cancer stem cells
Full text linkRecent advances in experimental technologies and cancer models have made possible to demonstrate that the tumor is a dynamic system comprising heterogeneous populations of cancer cells organized in a hierarchical fashion with cancer stem cells (CSCs) at the apex. CSCs are immature cells characterized by self-renewal property and long-term repopulation potential. CSCs have been causally linked to cancer initiation, propagation, spreading, recurrence and relapse as well as to resistance to anticancer therapy. A growing body of evidence suggests that the function and physiology of CSCs may be influenced by genetic/epigenetic factors and tumor environment. In this context, macroautophagy is a lysosomal degradative process (herein referred to as autophagy) critical for the adaptive response to stress and the preservation of cellular and tissue homeostasis in all eukaryotes that may have a crucial role of in the origin, maintenance and invasiveness of CSCs. The activation of the autophagic machinery is also considered as an adaptive response of CSCs to perturbation of tumor microenvironment, caused for instance by anticancer therapy. Nevertheless, compelling preclinical and clinical evidence on the cytoprotective role of autophagy for CSCs is still missing. Here, we summarize the results on the contribution of autophagy in CSCs and how it impacts tumorigenesis and tumor progression. We also discuss the therapeutical potential of the modulation of autophagy as a means to eradicate CSCs
Mitotic catastrophe and pericentriolar matrix dismantling are induced by the tubulin-depolymerising agent combretastatin-4 in lung cancer cells H460
No full textTubulin binding agents induce gamma-tubulin displacement from centrosome to kinetochores.
No full textCombretastatin CA-4 and combretastatin derivative induce mitotic catastrophe dependent on spindle checkpoint and caspase-3 activation in non small cell lung cancer cells
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