Low-level expression of SAMHD1 in acute myeloid leukemia (AML) blasts correlates with improved outcome upon consolidation chemotherapy with high-dose cytarabine-based regimens

Rassidakis, George Z.; Herold, Nikolas; Myrberg, Ida Hed; Tsesmetzis, Nikolaos; Rudd, Sean G.; Henter, Jan Inge; Schaller, Torsten; Ng, Siok Bian; Yan, Benedict; Ng, Chin Hin; Ravandi, Farhad; Andreeff, Michael; Kantarjian, Hagop M.; Medeiros, L. Jeffrey; Xagoraris, Ioanna; Khoury, Joseph D.

doi:10.1038/s41408-018-0134-z

Cited by 32 publications

(40 citation statements)

References 14 publications

(26 reference statements)

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“…SAMHD1 has been shown to affect the efficacy of nucleoside analogs, either used as antiretrovirals [22][23][24][25][26] or as chemotherapeutic drugs [27][28][29]. Active SAMHD1 catalyzes the hydrolysis and inactivation of a number of different nucleoside analogues [30,31], including cytarabine (Cytosar-U ® ,Ara-C), a first line therapeutic agent for acute myelogenous leukaemia (AML) and SAMHD1 expression levels were negatively correlated with Ara-C treatment success in individuals with AML [27,29,32].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Modulation of SAMHD1 Activity by CDK4/6 Inhibitors Improves Anticancer Therapy

Castellví

Felip

Ezeonwumelu

et al. 2020

Cancers

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Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase involved in the regulation of the intracellular dNTP pool, linked to viral restriction, cancer development and autoimmune disorders. SAMHD1 function is regulated by phosphorylation through a mechanism controlled by cyclin-dependent kinases and tightly linked to cell cycle progression. Recently, SAMHD1 has been shown to decrease the efficacy of nucleotide analogs used as chemotherapeutic drugs. Here, we demonstrate that SAMHD1 can enhance or decrease the efficacy of various classes of anticancer drug, including nucleotide analogues, but also anti-folate drugs and CDK inhibitors. Importantly, we show that selective CDK4/6 inhibitors are pharmacological activators of SAMHD1 that act by inhibiting its inactivation by phosphorylation. Combinations of a CDK4/6 inhibitor with nucleoside or folate antimetabolites potently enhanced drug efficacy, resulting in highly synergic drug combinations (CI < 0.04). Mechanistic analyses reveal that cell cycle-controlled modulation of SAMHD1 function is the central process explaining changes in anticancer drug efficacy, therefore providing functional proof of the potential of CDK4/6 inhibitors as a new class of adjuvants to boost chemotherapeutic regimens. The evaluation of SAMHD1 expression in cancer tissues allowed for the identification of cancer types that would benefit from the pharmacological modulation of SAMHD1 function. In conclusion, these results indicate that the modulation of SAMHD1 function may represent a promising strategy for the improvement of current antimetabolite-based treatments.

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Section: Introductionmentioning

confidence: 99%

Pharmacological Modulation of SAMHD1 Activity by CDK4/6 Inhibitors Improves Anticancer Therapy

Castellví

Felip

Ezeonwumelu

et al. 2020

Cancers

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“…The deoxycytidine analogue ara‐C remains the backbone treatment against AML (Mayer et al , ; Lowenberg, ). Clinical responses to ara‐C correlate with accumulation of the active metabolite ara‐CTP in AML cells (Plunkett et al , ), which is strongly regulated by the dNTPase SAMHD1 (Schneider et al , ; Herold et al , ,b,c; Hollenbaugh et al , ; Rudd et al , ; Rassidakis et al , ). Thus, inactivation of SAMHD1 ara‐CTPase is of immediate interest to rationally improve ara‐C therapies.…”

Section: Discussionmentioning

confidence: 99%

Ribonucleotide reductase inhibitors suppress SAMHD 1 ara‐ CTP ase activity enhancing cytarabine efficacy

et al. 2020

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The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML.

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“…Ara-C has remained the backbone of chemotherapy for adult AML patients for decades [6]. Especially, high dose Ara-C is a part of an induction regimen as a rst-line therapy for AML [36]. However, the resistance of AML cells to Ara-C chemotherapy is one of the most important reasons for relapse or chemo-refractoriness in AML patients [37].…”

Section: Discussionmentioning

confidence: 99%

Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death

Heo

Noh

Kim

et al. 2020

Preprint

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Background: Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. Therefore, there is a need for the development of novel chemotherapeutic agents that could treat AML effectively. Radotinib, an oral BCR-ABL tyrosine kinase inhibitor, was developed as a drug for the treatment of chronic myeloid leukemia. Previously, we reported that radotinib exerts increased cytotoxic effects towards AML cells. However, little is known about the effects of combining radotinib with Ara-C, a conventional chemotherapeutic agent for AML, with respect to cell death in AML cells. Therefore, we investigated combination effects of radotinib and Ara-C on AML in this study. Methods: Synergistic anti-cancer effects of radotinib and Ara-C in AML cells including HL60, HEL92.1.7, THP-1 and bone marrow cells from AML patients have been examined. Diverse cell biological assays such as cell viability assay, Annexin V-positive cells, caspase-3 activity, cell cycle distribution, and related signaling pathway have been performed. Results: The combination of radotinib and Ara-C was found to induce AML cell apoptosis, which involved the mitochondrial pathway. In brief, combined radotinib and Ara-C significantly induced Annexin V-positive cells, cytosolic cytochrome C , and the pro-apoptotic protein Bax in AML cells including HL60, HEL92.1.7, and THP-1. In addition, mitochondrial membrane potential and Bcl-xl protein were markedly decreased by radotinib and Ara-C. Moreover, this combination induced caspase-3 activity. Cleaved caspase-3, 7, and 9 levels were also increased by combined radotinib and Ara-C. Additionally, radotinib and Ara-C co-treatment induced G 0 /G 1 arrest via the induction of CDKIs such as p21 and p27 and the inhibition of CDK2 and cyclin E. Thus, radotinib/Ara-C induces mitochondrial-dependent apoptosis and G 0 /G 1 arrest via the regulation of the CDKI–CDK–cyclin cascade in AML cells. In addition, our results showed that combined treatment with radotinib and Ara-C inhibits AML cell growth, including tumor volumes and weights in vivo . Also, the combination of radotinib and Ara-C can sensitize cells to chemotherapeutic agents such as daunorubicin or idarubicin in AML cells. Conclusions: Therefore, our results can be concluded that radotinib in combination with Ara-C possesses a strong anti-AML activity.

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Low-level expression of SAMHD1 in acute myeloid leukemia (AML) blasts correlates with improved outcome upon consolidation chemotherapy with high-dose cytarabine-based regimens

Cited by 32 publications

References 14 publications

Pharmacological Modulation of SAMHD1 Activity by CDK4/6 Inhibitors Improves Anticancer Therapy

Pharmacological Modulation of SAMHD1 Activity by CDK4/6 Inhibitors Improves Anticancer Therapy

Ribonucleotide reductase inhibitors suppress SAMHD 1 ara‐ CTP ase activity enhancing cytarabine efficacy

Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death

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