8‐chloro‐adenosine activity in FLT3‐ITD acute myeloid leukemia

Abstract

Nucleoside analogs represent the backbone of several distinct chemotherapy regimens for acute myeloid leukemia (AML) and combination with tyrosine kinase inhibitors has improved survival of AML patients, including those harboring the poor‐risk FLT3‐ITD mutation. Although these compounds are effective in killing proliferating blasts, they lack activity against quiescent leukemia stem cells (LSCs), which contributes to initial treatment refractoriness or subsequent disease relapse. The reagent 8‐chloro‐adenosine (8‐Cl‐Ado) is a ribose‐containing, RNA‐directed nucleoside analog that is incorporated into newly transcribed RNA rather than in DNA, causing inhibition of RNA transcription. In this report, we demonstrate antileukemic activities of 8‐Cl‐Ado in vitro and in vivo and provide mechanistic insight into the mode of action of 8‐Cl‐Ado in AML. 8‐Cl‐Ado markedly induced apoptosis in LSC, with negligible effects on normal stem cells. 8‐Cl‐Ado was particularly effective against AML cell lines and primary AML blast cells harboring the FLT3‐ITD mutation. FLT3‐ITD is associated with high expression of miR‐155. Furthermore, we demonstrate that 8‐Cl‐Ado inhibits miR‐155 expression levels accompanied by induction of DNA‐damage and suppression of cell proliferation, through regulation of miR‐155/ErbB3 binding protein 1(Ebp1)/p53/PCNA signaling. Finally, we determined that combined treatment of NSG mice engrafted with FLT3‐ITD + MV4−11 AML cells with 8‐Cl‐Ado and the FLT3 inhibitor AC220 (quizartinib) synergistically enhanced survival, compared with that of mice treated with the individual drugs, suggesting a potentially effective approach for FLT3‐ITD AML patients.

8-Chloro-Adenosine Inhibits Proliferation of MDA-MB-231 and SK-BR-3 Breast Cancer Cells by Regulating ADAR1/p53 Signaling Pathway

“…It has been reported that 8-Cl-Ado exhibits its antitumor activity by inducing apoptosis or autophagy in some types of cancer cell lines, including lung cancer cells 23 , leukemia cells 25 , and breast cancer cells 6 . In the present study, we found that 8-Cl-Ado inhibited the breast cancer cell growth by inducing G1 cell cycle arrest and apoptosis at least through downregulating ADAR1 proteins in MDA-MB-231 and SK-BR-3 cells, which is consistent with our previous findings that 8-Cl-Ado downregulates ADAR1 and inhibits cell growth of breast cancer cell lines 7 , 8 .…”

Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine

“…Intracellular concentrations of 8-Cl-ATP were measured using HPLC-tandem mass spectrometry as described previously [ 22 ].…”

“…This chlorinated adenosine has been shown to confer antineoplastic activities in hematological malignancies [ 13 , 16 , 17 , 21 ] as well as in solid tumors [ 19 , 20 ]. Specifically for AML, our preliminary data showed that 8-Cl-Ado can target LSCs while sparing HSCs [ 22 ], inhibits FLT3-ITD signaling [ 22 ] and has anti-neoplastic activity in vitro and in vivo [ 14 , 15 , 22 – 24 ]. The unique mechanism of action of 8-Cl-Ado as well as the preliminary encouraging results observed in an ongoing clinical trial of 8-Cl-Ado monotherapy in patients with refractory/relapsed (R/R) AML has led us to hypothesize that the combination of VEN and 8-Cl-Ado may provide synergistic antileukemic activity in AML cells.…”

Transcription and Translation Inhibitors in Cancer Treatment

“…8-Cl-Ado is in phase I clinical trials for acute myeloid leukemia and chronic lymphocytic leukemia (Stellrecht et al, 2017). Recently, 8-Cl-Ado showed a positive synergistic effect with another cancer drug in a mice xenograft model of acute myeloid leukemia (Buettner et al, 2019).…”