JC-1: a very sensitive fluorescent probe to test Pgp activity in adult acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (2) ◽  
pp. 502-508 ◽  
Author(s):  
Ollivier Legrand ◽  
Jean-Yves Perrot ◽  
Ghislaine Simonin ◽  
Marion Baudard ◽  
Jean-Pierre Marie
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Resistance Mechanisms ◽  
Rhodamine 123 ◽  
Clinical Samples ◽  
Highly Sensitive ◽  
Intermediate Expression ◽  
Acute Myeloid

Abstract One of the best-characterized resistance mechanisms in acute myeloid leukemia (AML) is the drug extrusion mediated by P-glycoprotein (Pgp). Recently the results of workshops organized by several groups concluded that accurate measurement of low activity of Pgp is a difficult goal in clinical samples. Therefore, highly sensitive and specific assays were developed to assess the functionality of Pgp using JC-1, a fluorescent molecule with the different emission wavelength (green and red fluorescence) according to its concentration in 129 AML samples. It was shown that JC-1 (green and red bands) may define 3 groups of patients: resistant (R) (29% of patients), intermediate (I) (36%), and sensitive (S) (35%). In contrast, rhodamine 123 assay detected only the R group defined by JC-1. Nevertheless, the I group has an intermediate expression of Pgp (0.39, 0.29, and 0.19 for the R, I, and S groups, respectively, P = .002), an intermediate biologic profile (percentage of CD34, 95%, 67%, and 44%, respectively, P < .0001; in vitro resistance to daunorubicin, 94 μM, 20 μM, and 12 μM, respectively,P = .02), and an intermediate prognosis (achievement of complete remission, 55%, 65%, and 87%, P = .006; 3-year disease-free survival, 11%, 16%, and 36%, respectively,P = .005; and 3-year overall survival, 0%, 20%, and 51%, respectively, P < .0001). Therefore, JC-1 appeared to be a more convenient and simple way to detect a functional Pgp in clinical AML samples than rhodamine 123.

scholarly journals Clinical and experimental efficacy of gemtuzumab ozogamicin in core binding factor acute myeloid leukemia

2017 ◽  
Vol 9 (3) ◽  
Author(s):  
Michele Gottardi ◽  
Federico Mosna ◽  
Sergio De Angeli ◽  
Cristina Papayannidis ◽  
Anna Candoni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Gemtuzumab Ozogamicin ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
Clonogenic Potential ◽  
Acute Myeloid

Leukemia-initiating cells of core binding factor (CBF) acute myeloid leukemia (AML) likely derive from early committed hematopoietic precursors expressing CD33. As such, targeting CD33 could ameliorate the chance of cure of CBF AML patients. We compared 12 CBF AML patients treated with Fludarabine, Cytarabine, Idarubicin and Gemtuzumab Ozogamicin (FLAI-GO regimen) with 25 CBF AML patients treated with the same schedule, but without GO. With the limit of small numbers, we observed a consistent trend toward better overall survival, disease free survival and event free survival in the FLAI-GO group. We also demonstrated the ability of GO to induce the disappearance <em>in vitro</em> of the AML1-ETO molecular transcript in a polymerase chain reaction-positive graft without decreasing the clonogenic potential of CD34+/CD38- cells. This represent the proof of principle for using GO in a purging strategy before autologous stem cell transplantation. Therefore, our data argue in favor of the reinstitution of GO in the therapy of CBF AML.

scholarly journals Potentially Curative Therapeutic Activity of NEO212, a Perillyl Alcohol-Temozolomide Conjugate, in Preclinical Cytarabine-Resistant Models of Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3385
Author(s):  
Axel H. Schönthal ◽  
Steve Swenson ◽  
Radu O. Minea ◽  
Hye Na Kim ◽  
Heeyeon Cho ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Side Effects ◽  
Anticancer Activity ◽  
Myeloid Leukemia ◽  
Perillyl Alcohol ◽  
Therapeutic Activity ◽  
Acute Myeloid

Despite progress in the treatment of acute myeloid leukemia (AML), the clinical outcome remains suboptimal and many patients are still dying from this disease. First-line treatment consists of chemotherapy, which typically includes cytarabine (AraC), either alone or in combination with anthracyclines, but drug resistance can develop and significantly worsen prognosis. Better treatments are needed. We are developing a novel anticancer compound, NEO212, that was created by covalent conjugation of two different molecules with already established anticancer activity, the alkylating agent temozolomide (TMZ) and the natural monoterpene perillyl alcohol (POH). We investigated the anticancer activity of NEO212 in several in vitro and in vivo models of AML. Human HL60 and U937 AML cell lines, as well as different AraC-resistant AML cell lines, were treated with NEO212 and effects on cell proliferation, cell cycle, and cell death were investigated. Mice with implanted AraC-sensitive or AraC-resistant AML cells were dosed with oral NEO212, and animal survival was monitored. Our in vitro experiments show that treatment of cells with NEO212 results in growth inhibition via potent G2 arrest, which is followed by apoptotic cell death. Intriguingly, NEO212 was equally potent in highly AraC-resistant cells. In vivo, NEO212 treatment strikingly extended survival of AML mice and the majority of treated mice continued to thrive and survive without any signs of illness. At the same time, we were unable to detect toxic side effects of NEO212 treatment. All in all, the absence of side effects, combined with striking therapeutic activity even in an AraC-resistant context, suggests that NEO212 should be developed further toward clinical testing.

scholarly journals ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

2016 ◽  
Vol 113 (43) ◽  
pp. E6669-E6678 ◽  
Author(s):  
Mark A. Gregory ◽  
Angelo D’Alessandro ◽  
Francesca Alvarez-Calderon ◽  
Jihye Kim ◽  
Travis Nemkov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mitochondrial Oxidative Stress ◽  
Flt3 Inhibitor ◽  
A Genome ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

scholarly journals In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia

PLoS ONE ◽  
2016 ◽  
Vol 11 (12) ◽  
pp. e0166891 ◽  
Author(s):  
Kentaro Minagawa ◽  
Muhammad O. Jamil ◽  
Mustafa AL-Obaidi ◽  
Larisa Pereboeva ◽  
Donna Salzman ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Antigen Receptor ◽  
Suicide Gene ◽  
Clinical Validation ◽  
Acute Myeloid

A novel prognostic model in elderly patients with acute myeloid leukemia: results of 909 patients entered into the prospective AML96 trial

Blood ◽  
2010 ◽  
Vol 116 (6) ◽  
pp. 971-978 ◽  
Author(s):  
Christoph Röllig ◽  
Christian Thiede ◽  
Martin Gramatzki ◽  
Walter Aulitzky ◽  
Heinrich Bodenstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Model ◽  
Cox Model ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Intermediate Risk ◽  
Npm1 Mutation ◽  
Prognostic Groups ◽  
Acute Myeloid

Abstract We present an analysis of prognostic factors derived from a trial in patients with acute myeloid leukemia older than 60 years. The AML96 trial included 909 patients with a median age of 67 years (range, 61-87 years). Treatment included cytarabine-based induction therapy followed by 1 consolidation. The median follow-up time for all patients is 68 months (5.7 years). A total of 454 of all 909 patients reached a complete remission (50%). Five-year overall survival (OS) and disease-free survival were 9.7% and 14%, respectively. Multivariate analyses revealed that karyotype, age, NPM1 mutation status, white blood cell count, lactate dehydrogenase, and CD34 expression were of independent prognostic significance for OS. On the basis of the multivariate Cox model, an additive risk score was developed that allowed the subdivision of the largest group of patients with an intermediate-risk karyotype into 2 groups. We are, therefore, able to distinguish 4 prognostic groups: favorable risk, good intermediate risk, adverse intermediate risk, and high risk. The corresponding 3-year OS rates were 39.5%, 30%, 10.6%, and 3.3%, respectively. The risk model allows further stratification of patients with intermediate-risk karyotype into 2 prognostic groups with implications for the therapeutic strategy. This study was registered at www.clinicaltrials.gov as #NCT00180115.

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