| 1. |
- Bottone, Maria Grazia, et al.
(author)
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Multiple effects of paclitaxel are modulated by a high c-myc amplification level.
- 2003
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In: Experimental cell research. - 0014-4827. ; 290:1, s. 49-59
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Journal article (peer-reviewed)abstract
- Paclitaxel affects microtubule stability by binding to beta-tubulin, thus leading to cell accumulation in the G(2)/M phase, polyploidization, and apoptosis. Because both cell proliferation and apoptosis could be somehow regulated by the protooncogene c-myc, in this work we have investigated whether the c-myc amplification level could modulate the multiple effects of paclitaxel. To this aim, paclitaxel was administered to SW613-12A1 and -B3 human colon carcinoma cell lines (which are characterized by a high and low c-myc endogenous amplification level, respectively), and to the B3mycC5 cell line, with an enforced exogenous expression of c-myc copies. In this experimental system, we previously demonstrated that a high endogenous/exogenous level of amplification of c-myc enhances serum deprivation- and DNA damage-induced apoptosis. Accordingly, the present results indicate that a high c-myc amplification level potentiates paclitaxel cytotoxicity, confers a multinucleated phenotype, and promotes apoptosis to a great extent, thus suggesting that c-myc expression level is relevant in modulating the cellular responses to paclitaxel. We have recently shown in HeLa cells that the phosphorylated form of c-Myc accumulates in the nucleus, as distinct nucleolar and extranucleolar spots; here, we demonstrated that, after the treatment with paclitaxel, phosphorylated c-Myc undergoes redistribution, becoming diffused in the nucleoplasm.
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| 2. |
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| 3. |
- D'Incalci, Maurizio, et al.
(author)
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Unique features of the mode of action of ET-743.
- 2002
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In: The oncologist. - 1083-7159. ; 7:3, s. 210-6
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Research review (peer-reviewed)abstract
- This paper describes the current knowledge of the primary mode of action of a natural product, ecteinascidin 743 (ET-743), derived from the marine tunicate Ecteinascidia turbinata. ET-743 was initially selected for preclinical development because of its potent antitumor activity observed against several human solid tumor types. In vitro, the drug is cytotoxic in the nanomolar range, and in the case of some very sensitive cell lines, in the picomolar range. The large potency differences observed among several solid tumor types indicate that this compound possesses some tumor selectivity, but the molecular basis of these differential effects remains to be elucidated. The present studies were undertaken to evaluate the mechanism of action of ET-743 in this context. The available information on ET-743 binding to DNA and its effects on transcriptional regulation point to a unique behavior of this drug, as it independently affects specific gene transcription in a promoter-dependent way. In addition, ET-743 shows a peculiar pattern of selectivity in cells with different defects in their DNA-repair pathways. These results highlight a unique property of ET-743, possibly explaining why it possesses antitumor activity against tumors that are refractory to standard anticancer drugs, all of which certainly act by mechanisms that are different from that of ET-743.
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| 4. |
- Erba, E, et al.
(author)
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Effect of Aplidin in acute lymphoblastic leukaemia cells.
- 2003
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In: British journal of cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 89:4, s. 763-73
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Journal article (peer-reviewed)abstract
- The cytotoxic effect of Aplidin was investigated on fresh leukaemia cells derived from children with B-cell-precursor (BCP) acute lymphoblastic leukaemia (ALL) by using stromal-layer culture system and on four cell lines, ALL-PO, Reh, ALL/MIK and TOM-1, derived from patients with ALL with different molecular genetic abnormalities. In ALL cell lines Aplidin was cytotoxic at nanomolar concentrations. In the ALL cell lines the drug-induced cell death was clearly related to the induction of apoptosis and appeared to be p53-independent. Only in ALL-PO 20 nM Aplidin treatment caused a block of vascular endothelial growth factor (VEGF) secretion and downregulation of VEGF-mRNA, but Aplidin cytotoxicity does not seem to be related to VEGF inhibition since the sensitivity of ALL-PO cells to Aplidin is comparable to that observed for the other cells used. Aplidin induced a G(1) and a G(2) M block in ALL cell lines. In patient-derived leukaemia cells, Aplidin induced a strong cytotoxicity evidenced in a stroma-supported immunocytometric assay. Cells from children with genetic abnormalities such as t(9;22) and t(4;11) translocations, associated with an inferior treatment outcome, were sensitive to Aplidin to the same extent as that observed in other BCP-ALL cases. Aplidin exerted a strong cell killing effect (>88%) against primary culture cells from five relapsed ALL cases, at concentrations much lower than those reported to be achieved in plasma of patients receiving Aplidin at recommended doses. Taken together these data suggest that Aplidin could be a new anticancer drug to be investigated in ALL patients resistant to available therapy.
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| 5. |
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| 6. |
- Soldani, C, et al.
(author)
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Poly(ADP-ribose) polymerase cleavage during apoptosis: when and where?
- 2001
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In: Experimental cell research. - : Elsevier BV. - 0014-4827. ; 269:2, s. 193-201
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Journal article (peer-reviewed)abstract
- Poly(ADP-ribose) polymerase-1 (PARP-1) plays the active role of "nick sensor" during DNA repair and apoptosis, when it synthesizes ADP-ribose from NAD(+) in the presence of DNA strand breaks. Moreover, PARP-1 becomes a target of apoptotic caspases, which originate two proteolytic fragments of 89 and 24 kDa. The precise relationship between PARP-1 activation and degradation during apoptosis is still a matter of debate. In human Hep-2 cells driven to apoptosis by actinomycin D, we have monitored PARP-1 activity by the mAb 10H, which is specific for the ADP-ribose polymers, and we have observed that poly(ADP-ribose) synthesis is a very early response to the apoptotic stimulus. The analysis of the presence and fate of the p89 proteolytic fragment revealed that PARP-1 proteolysis by caspases is concomitant with poly(ADP-ribose) synthesis and that p89 migrates from the nucleus into the cytoplasm in late apoptotic cells with advanced nuclear fragmentation.
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