Scripties UMCG - Rijksuniversiteit Groningen
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Azacitidine as a potential chemo sensitizing drug for AML-cells

(2011) Helm, Lieke van der

Acute myeloid leukemia (AML) is a malignant hematopoietic disease that is currently being treated by induction chemotherapy, including cytarabine (ara-C), followed by consolidation therapy. However, not all patients benefit from or are eligible for intensive chemotherapy. Hypomethylating agents such as azacitidine (AZA) provide new options for treatment strategies in AML. By demethylating tumor suppressor genes that are frequently hypermethylated in leukemia, AZA might sensitize leukemia cells for chemotherapeutic agents. Recently, the cytostatic agent cladribine (CdA) has been shown to have hypomethylating activity as well.
To investigate whether AZA has a chemo sensitizing effect in combination with ara-C and whether AZA and CdA act synergistically, we incubated four human leukemia cell lines (HL-60, KG-1a, KG-1 and Kasumi) with increasing concentrations of AZA followed by ara-C and with increasing concentrations of combined AZA and CdA. Viability, induction of apoptosis and induction of tumor suppressor gene p15 expression were measured.
Ara-C alone and AZA alone reduced viability in a dose-dependent manner. The combination showed an enhanced effect on reduction of viability in HL-60 and KG-1 cells, and showed an increase in apoptosis induction. The combination of AZA and CdA however, did not result in a larger decrease of viability in KG-1a cells. P15 was not expressed in untreated KG-1, KG-1a and Kasumi cells. The p15 expression could be induced in KG-1 by AZA and CdA, but the combination did not induce the highest expression. CdA alone in low and high concentrations (20 and 100 nM) stronger reduced viability and cell count, and induced more p15 re-expression than AZA.
In conclusion, a chemo sensitizing effect of AZA was observed. No synergistic effect of combining AZA and CdA was observed. However, CdA alone may be a strong cytotoxic and hypomethylating agent in leukemia cells that should be further explored.

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