High-Risk neuroblastoma therapeutics Topotecan and
13-cis-Retinoic acid modulate autophagy and induce DNA damage
response in hematopoietic stem cells and monocytes

J 2025

High-Risk neuroblastoma therapeutics Topotecan and 13-cis-Retinoic acid modulate autophagy and induce DNA damage response in hematopoietic stem cells and monocytes

LÁZNIČKOVÁ, Petra; Federico TIDU; Jiri HRDY; Kristyna BORAKOVA; Marcela HORTOVÁ KOHOUTKOVÁ et al.

Základní údaje

Originální název

High-Risk neuroblastoma therapeutics Topotecan and 13-cis-Retinoic acid modulate autophagy and induce DNA damage response in hematopoietic stem cells and monocytes

Autoři

LÁZNIČKOVÁ, Petra ; Federico TIDU; Jiri HRDY; Kristyna BORAKOVA; Marcela HORTOVÁ KOHOUTKOVÁ a Jan FRIČ

Vydání

Scientific Reports, Berlin, NATURE RESEARCH, 2025, 2045-2322

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.900 v roce 2024

Označené pro přenos do RIV

Ano

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

Hematopoietic stem and progenitor cell; Monocyte; Topotecan; 13-cis-retinoic acid; Cord blood; Senescence

Štítky

14110132, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 6. 11. 2025 08:24, Mgr. Tereza Miškechová

Anotace

V originále

Autologous hematopoietic stem and progenitor cell (HSPC) transplantation is performed after myeloablation in cancer treatment to restore blood cell production and support immune recovery. Despite its success in achieving survivorship, many recipients later suffer from recurrent infections and pulmonary complications. The mechanisms driving the complications after HSPC transplantation later in life are unknown. However, the induction and/or maintenance therapeutics might be driving the negative outcomes in treated patients. We investigated the effects of the cancer therapeutics topotecan and 13-cis-retinoic acid (13cisRA) on cell phenotype and functions of HSPCs isolated from cord blood and primary monocytes from adult donors. In HSPCs, 13cisRA reduced autophagy and lysosomal activity, triggered a DNA damage response through increased gamma H2A.X and CDKN2 expression (including the spliced p14ARF isoform), and upregulated the epigenetic regulator SIRT3. 13cisRA also activated primary monocytes, inducing CXCL8 and CCL2 production. By contrast, topotecan had no effects on mature monocytes but induced DNA damage, metabolic remodeling, and epigenetic alterations in HSPCs. These changes included increased CDKN1A expression, higher gamma H2A.X-positive cell frequency, autophagy activation, and SIRT1 upregulation. The differential effects of 13cisRA and topotecan on HSPCs and monocytes might underlie the long-term complications of autologous HSPC transplantation. By modulating DNA damage, autophagy, and epigenetic pathways, these therapies could influence hematopoietic recovery and immune reconstitution, offering insights for improving transplantation outcomes.

Návaznosti

NW24J-09-00054, projekt VaV

Název: Nové metody posouzení kvality a fitness CD34+ buněk a CD34-derivovaných myeloidních buněk z mobilizované krve

Investor: Ministerstvo zdravotnictví ČR, Nové metody posouzení kvality a fitness CD34+ buněk a CD34-derivovaných myeloidních buněk z mobilizované krve, Podprogram 2 - juniorský

Citovat

LÁZNIČKOVÁ, Petra; Federico TIDU; Jiri HRDY; Kristyna BORAKOVA; Marcela HORTOVÁ KOHOUTKOVÁ a Jan FRIČ. High-Risk neuroblastoma therapeutics Topotecan and 13-cis-Retinoic acid modulate autophagy and induce DNA damage response in hematopoietic stem cells and monocytes. Scientific Reports. Berlin: NATURE RESEARCH, 2025, roč. 15, č. 1, s. 1-18. ISSN 2045-2322. Dostupné z: https://doi.org/10.1038/s41598-025-19454-0.

@article{2530998,
   author = {Lázničková, Petra and Tidu, Federico and Hrdy, Jiri and Borakova, Kristyna and Hortová Kohoutková, Marcela and Frič, Jan},
   article_location = {Berlin},
   article_number = {1},
   doi = {https://doi.org/10.1038/s41598-025-19454-0},
   keywords = {Hematopoietic stem and progenitor cell; Monocyte; Topotecan; 13-cis-retinoic acid; Cord blood; Senescence},
   language = {eng},
   issn = {2045-2322},
   journal = {Scientific Reports},
   title = {High-Risk neuroblastoma therapeutics Topotecan and 13-cis-Retinoic acid modulate autophagy and induce DNA damage response in hematopoietic stem cells and monocytes},
   url = {https://www.nature.com/articles/s41598-025-19454-0},
   volume = {15},
   year = {2025}
}

TY  - JOUR
ID  - 2530998
AU  - Lázničková, Petra - Tidu, Federico - Hrdy, Jiri - Borakova, Kristyna - Hortová Kohoutková, Marcela - Frič, Jan
PY  - 2025
TI  - High-Risk neuroblastoma therapeutics Topotecan and 13-cis-Retinoic acid modulate autophagy and induce DNA damage response in hematopoietic stem cells and monocytes
JF  - Scientific Reports
VL  - 15
IS  - 1
SP  - 1-18
EP  - 1-18
PB  - NATURE RESEARCH
SN  - 20452322
KW  - Hematopoietic stem and progenitor cell
KW  - Monocyte
KW  - Topotecan
KW  - 13-cis-retinoic acid
KW  - Cord blood
KW  - Senescence
UR  - https://www.nature.com/articles/s41598-025-19454-0
N2  - Autologous hematopoietic stem and progenitor cell (HSPC) transplantation is performed after myeloablation in cancer treatment to restore blood cell production and support immune recovery. Despite its success in achieving survivorship, many recipients later suffer from recurrent infections and pulmonary complications. The mechanisms driving the complications after HSPC transplantation later in life are unknown. However, the induction and/or maintenance therapeutics might be driving the negative outcomes in treated patients. We investigated the effects of the cancer therapeutics topotecan and 13-cis-retinoic acid (13cisRA) on cell phenotype and functions of HSPCs isolated from cord blood and primary monocytes from adult donors. In HSPCs, 13cisRA reduced autophagy and lysosomal activity, triggered a DNA damage response through increased gamma H2A.X and CDKN2 expression (including the spliced p14ARF isoform), and upregulated the epigenetic regulator SIRT3. 13cisRA also activated primary monocytes, inducing CXCL8 and CCL2 production. By contrast, topotecan had no effects on mature monocytes but induced DNA damage, metabolic remodeling, and epigenetic alterations in HSPCs. These changes included increased CDKN1A expression, higher gamma H2A.X-positive cell frequency, autophagy activation, and SIRT1 upregulation. The differential effects of 13cisRA and topotecan on HSPCs and monocytes might underlie the long-term complications of autologous HSPC transplantation. By modulating DNA damage, autophagy, and epigenetic pathways, these therapies could influence hematopoietic recovery and immune reconstitution, offering insights for improving transplantation outcomes.
ER  -

LÁZNIČKOVÁ, Petra; Federico TIDU; Jiri HRDY; Kristyna BORAKOVA; Marcela HORTOVÁ KOHOUTKOVÁ a Jan FRIČ. High-Risk neuroblastoma therapeutics Topotecan and 13-cis-Retinoic acid modulate autophagy and induce DNA damage response in hematopoietic stem cells and monocytes. \textit{Scientific Reports}. Berlin: NATURE RESEARCH, 2025, roč.~15, č.~1, s.~1-18. ISSN~2045-2322. Dostupné z: https://doi.org/10.1038/s41598-025-19454-0.

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