G-quadruplex ligands exert their antiproliferative effects through telomere-dependent and telomere-independent mechanisms, but the inter-relationships among autophagy, cell growth arrest and cell death induced by these ligands remain largely unexplored. Here, we demonstrate that the G-quadruplex ligand 20A causes growth arrest of cancer cells in culture and in a HeLa cell xenografted mouse model. This response is associated with the induction of senescence and apoptosis. Transcriptomic analysis of 20A treated cells reveals a significant functional enrichment of biological pathways related to growth arrest, DNA damage response and the lysosomal pathway. 20A elicits global DNA damage but not telomeric damage and activates the ATM and autophagy pathways. Loss of ATM following 20A treatment inhibits both autophagy and senescence and sensitizes cells to death. Moreover, disruption of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation by 20A and subsequently increased cell death. Our results, therefore, identify the activation of ATM by 20A as a critical player in the balance between senescence and apoptosis and autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal anticancer effect of this compound.

• MeSH
• apoptóza účinky léků   genetika   MeSH
• ATM protein * antagonisté a inhibitory   metabolismus   MeSH
• autofagie účinky léků   genetika   MeSH
• buňky A549 MeSH
• G-kvadruplexy * MeSH
• HeLa buňky MeSH
• lidé MeSH
• ligandy MeSH
• myši inbrední NOD MeSH
• myši knockoutované MeSH
• myši SCID MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory genetika   patologie   MeSH
• poškození DNA účinky léků   MeSH
• signální transdukce účinky léků   genetika   MeSH
• stárnutí buněk účinky léků   genetika   MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

PURPOSE: To study the outcome of histologic transformation (HT) in a large prospective cohort of patients with follicular lymphoma (FL) who previously responded to immunochemotherapy. PATIENTS AND METHODS: After a median 6-year follow-up of 1,018 randomly assigned patients from the PRIMA trial, disease progression was observed in 463 patients, 194 of whom had histologic documentation. RESULTS: Forty patients had histology consistent with HT, and 154 had untransformed FL (median time to recurrence, 9.6 v 22.8 months, respectively; P = .018). Thirty-seven percent of biopsies performed during the first year of follow-up showed HT corresponding to 58% of all HTs. Altered performance status, anemia, high lactate dehydrogenase level, "B" symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis were identified as HT risk factors. Response (complete v partial) to immunochemotherapy or rituximab maintenance had no impact on the risk of HT. After salvage treatment, patients with HT had less frequent complete response (50.3% v 67.4%; P = .03) and more disease progression (28.2% v 9.6%; P < .001) than patients without HT. Estimated overall survival for the patients with HT was poorer (median, 3.8 v 6.4 years; hazard ratio, 3.9; 95% CI, 2.2 to 6.9). Autologous stem cell transplantation improved the outcomes of patients with HT (median overall survival, not reached v 1.7 years) but not of patients with persistent FL histology. CONCLUSION: HT in patients with FL who previously responded to immunochemotherapy is an early event associated with a poor outcome that may deserve intensive salvage with autologous stem cell transplantation. These data emphasize the necessity for biopsy at the first recurrence of FL.

• MeSH
• biopsie MeSH
• dospělí MeSH
• folikulární lymfom farmakoterapie   patologie   terapie   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• progrese nemoci MeSH
• prospektivní studie MeSH
• rituximab terapeutické užití   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transplantace kmenových buněk MeSH
• výsledek terapie MeSH
• záchranná terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

• MeSH
• anemie MeSH
• erythropoetin MeSH
• nádory krev   MeSH
• Publikační typ
• kongresy MeSH
• sborníky MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• hematologie a transfuzní lékařství
• onkologie