Contributions
Abstract: PB1655
Type: Publication Only
Background
Lots of conventional chemotherapeutic drugs are confirmed to take participate in DNA damage generation and initiation of DNA damage response, ultimately leading to apoptosis. However, they fail to completely eliminate leukemia stem cells (LSCs) on account of higher DNA repair capacity of cancer stem cells than bulk cancer cells, which become the root of resistance and recurrence. Thus, new strategy to eliminate LSCs in AML is urgently needed.
Aims
To observe the effect of low dose chidamide in combination with chemotherapeutic agents on eliminating AML stem cells.
Methods
we uesed a novel benzamide-type HDAC inhibitors, chidamide,in combination with DNA-damaging agents (daunorubicin, idarubicin and cytarabine) to treat CD34+CD38- KG1α cells and primary refractory or relapsed AML CD34+ cells.
Results
Here, we report that low dose chidamide, a novel benzamide-type HDAC inhibitors, which selectively targeted HDAC 1, 2, 3, 10, could enhances cytotoxicity of DNA-damaging agents (daunorubicin, idarubicin and cytarabine) in CD34+CD38- KG1α cells and primary refractory or relapsed AML CD34+ cells, reflected by inhibition of cell proliferation and induction of apoptosis in vitro. Mechanistically, these events were associated with DNA damage accumulation and repair defects. Co-treatment with chidamide and DNA-damaging agents IDA gave rise to production of γH2A.X, inhibited ATM, BRCA1, checkpoint kinase 1 (Chk1) and 2 (Chk2) phosphorylation. Finally, the combination initiated caspase-3 and PARP cleavage and ultimately induced CD34+CD38- KG1α cells apoptosis. Further analysis on AML patients’ clinical characteristics revealed that the ex vivo efficacy of chidamide in combination with IDA in primary CD34+ samples was significantly correlated to peripheral blood WBC counts at diagnosis, while status, LDH level, karyotype had no effect, indicating that the combination regimen of chidamide and IDA could rapidly diminish tumor burden in a patient with R/R AML.
Conclusion
these findings provide preclinical evidence for low dose chidamide in combination with chemotherapeutic agents to treat recurrent/resistant AML as an alternative salvage regimen, especially those possessed stem and progenitor cells.
Session topic: 3. Acute myeloid leukemia - Biology
Keyword(s): Leukemic Stem Cell, HDAC inhibitor, Drug resistance, DNA Damage
Abstract: PB1655
Type: Publication Only
Background
Lots of conventional chemotherapeutic drugs are confirmed to take participate in DNA damage generation and initiation of DNA damage response, ultimately leading to apoptosis. However, they fail to completely eliminate leukemia stem cells (LSCs) on account of higher DNA repair capacity of cancer stem cells than bulk cancer cells, which become the root of resistance and recurrence. Thus, new strategy to eliminate LSCs in AML is urgently needed.
Aims
To observe the effect of low dose chidamide in combination with chemotherapeutic agents on eliminating AML stem cells.
Methods
we uesed a novel benzamide-type HDAC inhibitors, chidamide,in combination with DNA-damaging agents (daunorubicin, idarubicin and cytarabine) to treat CD34+CD38- KG1α cells and primary refractory or relapsed AML CD34+ cells.
Results
Here, we report that low dose chidamide, a novel benzamide-type HDAC inhibitors, which selectively targeted HDAC 1, 2, 3, 10, could enhances cytotoxicity of DNA-damaging agents (daunorubicin, idarubicin and cytarabine) in CD34+CD38- KG1α cells and primary refractory or relapsed AML CD34+ cells, reflected by inhibition of cell proliferation and induction of apoptosis in vitro. Mechanistically, these events were associated with DNA damage accumulation and repair defects. Co-treatment with chidamide and DNA-damaging agents IDA gave rise to production of γH2A.X, inhibited ATM, BRCA1, checkpoint kinase 1 (Chk1) and 2 (Chk2) phosphorylation. Finally, the combination initiated caspase-3 and PARP cleavage and ultimately induced CD34+CD38- KG1α cells apoptosis. Further analysis on AML patients’ clinical characteristics revealed that the ex vivo efficacy of chidamide in combination with IDA in primary CD34+ samples was significantly correlated to peripheral blood WBC counts at diagnosis, while status, LDH level, karyotype had no effect, indicating that the combination regimen of chidamide and IDA could rapidly diminish tumor burden in a patient with R/R AML.
Conclusion
these findings provide preclinical evidence for low dose chidamide in combination with chemotherapeutic agents to treat recurrent/resistant AML as an alternative salvage regimen, especially those possessed stem and progenitor cells.
Session topic: 3. Acute myeloid leukemia - Biology
Keyword(s): Leukemic Stem Cell, HDAC inhibitor, Drug resistance, DNA Damage