Author: Nguyen, Le Xuan Truong ; Li, Zhenlong ; Marcucci, Guido ; Ma, Rui ; Chen, Jianjun ; Wang, Lili ; Horne, David ; Su, Rui ; Patrick, Pirrotte ; Liu, Wei ; Rosen, Steven T ; Moore, Roger E ; Du, Li ; Guo, Jiamin ; Yang, Yanzhong ; Zhang, Yi ; Chen, Min-Hsuan ; Wu, Xiwei ; Buettner, Ralf ; Khyatiben, Pathak ; Chen, Zhenhua ; Che, Yuan

AbstractTargeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

01 Mar 2024·Cancer

A phase 1 trial of 8‐chloro‐adenosine in relapsed/refractory acute myeloid leukemia: An evaluation of safety and pharmacokinetics

Article

Author: Truong Nguyen, Le Xuan ; Marcucci, Guido ; Zhang, Jianying ; Pullarkat, Vinod ; Buettner, Ralf ; Rosen, Steven T ; Palmer, Joycelynne ; Chen, Lisa S ; Synold, Timothy W ; Gandhi, Varsha ; Wang, Yan ; O'Hearn, James ; Tsai, Ni-Chun

AbstractBackgroundThis study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 8‐chloro‐adenosine (8‐Cl‐Ado) in patients with relapsed/refractory acute myeloid leukemia (AML).Methods8‐Cl‐Ado was administered daily for 5 days; the starting dose was 100 mg/m2, the highest dose tested was 800 mg/m2. The end points were toxicity, disease response, and PK/PD measurements.ResultsThe predominant nonhematologic toxicity was cardiac with grade ≥3 toxicity. Plasma PK in all patients suggested heterogeneity among patients, yet, some dose‐dependency for the accumulation of 8‐Cl‐Ado. Two 8‐Cl‐Ado metabolites accumulated at similar levels to 8‐Cl‐Ado. Cellular PK in eight patients indicated accumulation of 8‐Cl‐ATP, which was associated with AML blast cytoreduction in peripheral blood. The authors determined the RP2D of 8‐Cl‐Ado to be 400 mg/m2.ConclusionsGiven the cardiac adverse events observed, patients require monitoring for arrhythmias and QT interval during infusion. Although peripheral blood cytoreduction was observed, responses were transient, suggesting combination strategies will be required.

01 Dec 2023·Anticancer Research

8-Chloroadenosine Induces ER Stress and Apoptotic Cell Death in Cholangiocarcinoma Cells

Article

Author: Svasti, Jisnuson ; Lertsuwan, Jomnarong ; Satayavivad, Jutamaad

BACKGROUND/AIMCholangiocarcinoma is a lethal cancer, and current chemotherapeutic drugs are not very effective. Recent studies reported that cholangiocarcinoma cells were sensitive to adenosine. One adenosine analog, 8-chloroadenosine (8-CA), was shown to be more potent than adenosine and induced apoptosis in leukemia cells. This study examined effects of 8-CA in cholangiocarcinoma cells and immortalized cholangiocytes.MATERIALS AND METHODSCell growth was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell invasion was examined by transwell assay. Cell cycle and cell death were evaluated by flow cytometry. Colorimetric absorbance assay was used to assessed RNA and protein synthesis as well as mitochondrial membrane potential. Protein levels were examined by western blot analysis. Animal experiment was performed in Balb/cAJcl-Nu mice.RESULTS8-CA reduced cholangiocarcinoma cell growth, prevented colony formation and caused endoplasmic reticulum stress and cell-cycle arrest. Eventually, apoptosis was induced. However, treatment with 8-CA did not interfere with RNA synthesis or protein synthesis and did not alter mitochondrial membrane potential. Combination of 8-CA with several chemotherapeutic drugs in vitro was less effective than 8-CA alone and the drugs alone, except for the combination of 8-CA with hydroxychloroquine, which had an additive effect on RMCCA-1 cells. However, further in vivo study showed that treatment with 8-CA alone inhibited tumor growth more than treatment with a combination of 8-CA with hydroxychloroquine.CONCLUSION8-Chloroadenosine inhibited CCA cells by inducing endoplasmic reticulum stress and apoptosis. In vivo study showed that 8-CA inhibited cholangiocarcinoma tumor growth better when administered alone as compared to a combination with hydroxychloroquine.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic Lymphocytic Leukemia	Phase 1	-	Peking University Health Science Center	-
Chronic Lymphocytic Leukemia	Phase 1	-	National Cancer Institute	-

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EORTC 20012 (ASCO2012)	Phase 3	Hodgkin's Lymphoma	549	ABVD (8 cycles)	(ianlhunrkv) = kmpcamlrrg wghskswgry (ulzdtfjrzw ) View more	-	20 May 2012
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