Resistance to Ara-C Up-Regulates the Activation of NF-.KAPPA.B, Telomerase Activity and Fas Expression in NALM-6 Cells

Kanno, Syu‐ichi; Hiura, Takako; Shouji, Ai; Osanai, Yuu; Ujibe, Mayuko; Ishikawa, Masaaki

doi:10.1248/bpb.30.2069

Cited by 13 publications

(8 citation statements)

References 40 publications

(38 reference statements)

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“…The deoxycytidine kinase (dCK) deWciency has been believed to be one of the mechanisms of Ara-C resistance (Bhalla et al 1984). Other mechanisms include the loss of function of hENT1/SLC29A1 (a nucleoside transporter used by Ara-C) (Cai et al 2008), activation of NF-B, telomerase activity and Fas expression (Kanno et al 2007) and enhanced degradation of Ara-C (Momparler and Laliberte 1990). However, the detailed molecular mechanisms that contribute to Ara-C resistance are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

miR-181a sensitizes resistant leukaemia HL-60/Ara-C cells to Ara-C by inducing apoptosis

Bai

Cao

Deng

et al. 2012

J Cancer Res Clin Oncol

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Section: Introductionmentioning

confidence: 99%

miR-181a sensitizes resistant leukaemia HL-60/Ara-C cells to Ara-C by inducing apoptosis

Bai

Cao

Deng

et al. 2012

J Cancer Res Clin Oncol

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“…38 Activation of NF-kB may be accompanied by the acquisition of cytarabine resistance; the activation is assumed to induce transcription of genes that function in a feedback and block apoptosis. 39 Constitutive activation of NF-kB is found in human leukemia stem cells but not in normal hematopoietic stem cells. 40 Interestingly, the tumor suppressor gene MCC has been shown to be a transcriptional regulator of the NF-kB pathway in colorectal cells 41 and HEK293 cells.…”

mentioning

confidence: 99%

Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients

Gamazon

Lamba

Pounds

et al. 2013

Blood

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Key Points• A preclinical cell-based model identifies SNPs associated with cytarabine sensitivity that also associate with outcome in leukemia patients.• SNPs within the MCC gene were associated with cytarabine sensitivity in lymphoblastoid cell lines and leukemic blasts from patients.A whole-genome approach was used to investigate the genetic determinants of cytarabineinduced cytotoxicity. We performed a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines (LCLs) from individuals of European, African, Asian, and African American ancestry. Several of the highest-ranked single-nucleotide polymorphisms (SNPs) were within the mutated in colorectal cancers (MCC) gene. MCC expression was induced by cytarabine treatment from 1.7-to 26.6-fold in LCLs. A total of 33 SNPs ranked at the top of the meta-analysis (P < 10 25) were successfully tested in a clinical trial of patients randomized to receive low-dose or high-dose cytarabine plus daunorubicin and etoposide; of these, 18 showed association (P < .05) with either cytarabine 50% inhibitory concentration in leukemia cells or clinical response parameters (minimal residual disease, overall survival (OS), and treatment-related mortality). This count (n 5 18) was significantly greater than expected by chance (P 5 .016). For rs1203633, LCLs with AA genotype were more sensitive to cytarabine-induced cytotoxicity (P 5 1.31 3 10 26) and AA (vs GA or GG) genotype was associated with poorer OS (P 5 .015), likely as a result of greater treatment-related mortality (P 5 .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084. (Blood. 2013;121(21):4366-4376) IntroductionAcute myeloid leukemia (AML) is the most common form of acute leukemia in adults and also occurs in children. Despite the genetic heterogeneity of the disease, patients have been treated for decades with similar combinations of cytarabine and anthracyclines with little improvement in overall survival (OS).1 Although the majority of patients (50%-60%) under 60 years achieve complete remission with traditional anthracycline-and cytarabine-based induction regimens, the long-term survival rates continue to be around 30% to 40% for adults and 60% for children. [2][3][4][5][6] Outcomes are worse for patients >60 years, with complete response rates in the range of 40% to 55% and poor long-term survival rates. 7 The main reason for treatment failure among patients with AML is resistance to therapy. [8][9][10] In addition, treatment with cytarabine is associated with a number of adverse side effects including myelosuppression, infections, mucositis, neurotoxicity, and acute pulmonary syndrome. 11Cytarabine requires activation through intracellular phosphorylation to araC-triphosphate (ara-CTP). The mechanism of action of cytarabine involves the incorporation of ara-CTP in place of deoxycytidine triphosphate, resulting in chain termination, blocking DNA and RNA synthesis and causing leukemic cell de...

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“…The association of NF-κB with progression of malignancy is undisputable and AML is no exception. Constitutive activation of NF-κB has been reported in almost 40% of AML cases [ 34 ] and studies indicate that aberrant activation of NF-κB is a crucial event responsible for resistance to cytarabine [ 35 ]. Several anti-apoptotic proteins and signaling molecules that offer survival advantages to leukemic cells are transcriptional targets of NF-κB.…”

Section: Discussionmentioning

confidence: 99%

Heteronemin, a marine natural product, sensitizes acute myeloid leukemia cells towards cytarabine chemotherapy by regulating farnesylation of Ras

et al. 2018

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Cytarabine is a conventionally used chemotherapeutic agent for treating acute myeloid leukemia (AML). However, chemoresistance, toxic side-effects and poor patient survival rates retard the efficacy of its performance. The current study deals with the chemosensitization of AML cells using heteronemin, a marine natural product towards cytarabine chemotherapy. Heteronemin could effectively sensitize HL-60 cells towards sub-toxic concentration of cytarabine resulting in synergistic toxicity as demonstrated by MTT assay and [3H] thymidine incorporation studies, while being safe towards healthy blood cells. Flow cytometry for Annexin-V/PI and immunoblotting for caspase cleavage proved that the combination induces enhancement in apoptosis. Heteronemin being a farnesyl transferase inhibitor (FTI) suppressed cytarabine-induced, farnesyl transferase-mediated activation of Ras, as assessed by Ras pull-down assay. Upon pre-treating cells with a commercial FTI, L-744,832, the synergism was completely lost in the combination, confirming the farnesyl transferase inhibitory activity of heteronemin as assessed by thymidine incorporation assay. Heteronemin effectively down-regulated cytarabine-induced activation of MAPK, AP-1, NF-κB and c-myc, the down-stream targets of Ras signaling, which again validated the role of Ras in regulating the synergism. Hence we believe that the efficacy of cytarabine chemotherapy can be improved to a significant extent by combining sub-toxic concentrations of cytarabine and heteronemin.

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Resistance to Ara-C Up-Regulates the Activation of NF-.KAPPA.B, Telomerase Activity and Fas Expression in NALM-6 Cells

Cited by 13 publications

References 40 publications

miR-181a sensitizes resistant leukaemia HL-60/Ara-C cells to Ara-C by inducing apoptosis

miR-181a sensitizes resistant leukaemia HL-60/Ara-C cells to Ara-C by inducing apoptosis

Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients

Heteronemin, a marine natural product, sensitizes acute myeloid leukemia cells towards cytarabine chemotherapy by regulating farnesylation of Ras

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