5-Azacitidine Exerts Prolonged Pro-Apoptotic Effects and Overcomes Cisplatin-Resistance in Non-Seminomatous Germ Cell Tumor Cells
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5-Azacitidine Exerts Prolonged Pro-Apoptotic Effects and Overcomes Cisplatin-Resistance in Non-Seminomatous Germ Cell Tumor Cells. / Oing, Christoph; Verem, Izudin; Mansour, Wael Y; Bokemeyer, Carsten; Dyshlovoy, Sergey; Honecker, Friedemann.
In: INT J MOL SCI, Vol. 20, No. 1, 21.12.2018, p. 21.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - 5-Azacitidine Exerts Prolonged Pro-Apoptotic Effects and Overcomes Cisplatin-Resistance in Non-Seminomatous Germ Cell Tumor Cells
AU - Oing, Christoph
AU - Verem, Izudin
AU - Mansour, Wael Y
AU - Bokemeyer, Carsten
AU - Dyshlovoy, Sergey
AU - Honecker, Friedemann
PY - 2018/12/21
Y1 - 2018/12/21
N2 - Despite high cure rates, about 20% of patients with advanced germ cell tumors (GCTs) fail cisplatin-based chemotherapy. High levels of DNA methylation have been identified in GCTs and linked to cisplatin resistance. Here, we examined the effects of DNA hypomethylating 5-azacitidine (5-aza) on two embryonal carcinoma cell lines (NCCIT, 2102Ep) and their cisplatin-resistant isogenic derivatives. Effects on cell viability and cisplatin sensitivity were assessed by the trypan blue exclusion method. Western blotting was used to examine induction of apoptosis 5-aza and results were validated by flow cytometry. Single agent treatment with 5-aza strongly impacted viability and induced apoptosis at low nanomolar concentrations, both in cisplatin-sensitive and -resistant cell lines. 5-aza exerted an immediate apoptotic response, followed by a prolonged inhibitory effect on cell viability and cell-cycle progression. Sequential treatment with 5-aza and cisplatin reduced cellular survival of the cisplatin-resistant sublines already at nanomolar concentrations, suggesting a partial restoration of cisplatin sensitivity by the compound. 5-aza demonstrated anti-tumor activity as a single agent at low nanomolar concentrations in GCT cells, irrespective of cisplatin-sensitivity. 5-aza may also have the potential at least to partially restore cisplatin-sensitivity in non-seminoma cells, supporting the hypothesis that combining DNA demethylating agents with cisplatin-based chemotherapy may be a valid therapeutic approach in patients with refractory GCTs.
AB - Despite high cure rates, about 20% of patients with advanced germ cell tumors (GCTs) fail cisplatin-based chemotherapy. High levels of DNA methylation have been identified in GCTs and linked to cisplatin resistance. Here, we examined the effects of DNA hypomethylating 5-azacitidine (5-aza) on two embryonal carcinoma cell lines (NCCIT, 2102Ep) and their cisplatin-resistant isogenic derivatives. Effects on cell viability and cisplatin sensitivity were assessed by the trypan blue exclusion method. Western blotting was used to examine induction of apoptosis 5-aza and results were validated by flow cytometry. Single agent treatment with 5-aza strongly impacted viability and induced apoptosis at low nanomolar concentrations, both in cisplatin-sensitive and -resistant cell lines. 5-aza exerted an immediate apoptotic response, followed by a prolonged inhibitory effect on cell viability and cell-cycle progression. Sequential treatment with 5-aza and cisplatin reduced cellular survival of the cisplatin-resistant sublines already at nanomolar concentrations, suggesting a partial restoration of cisplatin sensitivity by the compound. 5-aza demonstrated anti-tumor activity as a single agent at low nanomolar concentrations in GCT cells, irrespective of cisplatin-sensitivity. 5-aza may also have the potential at least to partially restore cisplatin-sensitivity in non-seminoma cells, supporting the hypothesis that combining DNA demethylating agents with cisplatin-based chemotherapy may be a valid therapeutic approach in patients with refractory GCTs.
KW - Journal Article
U2 - 10.3390/ijms20010021
DO - 10.3390/ijms20010021
M3 - SCORING: Journal article
C2 - 30577584
VL - 20
SP - 21
JO - INT J MOL SCI
JF - INT J MOL SCI
SN - 1661-6596
IS - 1
ER -