scholarly journals From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6425-6437 ◽  
Author(s):  
Sai-Juan Chen ◽  
Guang-Biao Zhou ◽  
Xiao-Wei Zhang ◽  
Jian-Hua Mao ◽  
Hugues de Thé ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Promyelocytic Leukemia ◽  
Magic Bullet ◽  
Therapeutic Effects ◽  
New Paradigm ◽  
Therapeutic Benefits ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Arsenic had been used in treating malignancies from the 18th to mid-20th century. In the past 3 decades, arsenic was revived and shown to be able to induce complete remission and to achieve, when combined with all-trans retinoic acid and chemotherapy, a 5-year overall survival of 90% in patients with acute promyelocytic leukemia driven by the t(15;17) translocation-generated promyelocytic leukemia–retinoic acid receptor α (PML-RARα) fusion. Molecularly, arsenic binds thiol residues and induces the formation of reactive oxygen species, thus affecting numerous signaling pathways. Interestingly, arsenic directly binds the C3HC4 zinc finger motif in the RBCC domain of PML and PML-RARα, induces their homodimerization and multimerization, and enhances their interaction with the SUMO E2 conjugase Ubc9, facilitating subsequent sumoylation/ubiquitination and proteasomal degradation. Arsenic-caused intermolecular disulfide formation in PML also contributes to PML-multimerization. All-trans retinoic acid, which targets PML-RARα for degradation through its RARα moiety, synergizes with arsenic in eliminating leukemia-initiating cells. Arsenic perturbs a number of proteins involved in other hematologic malignancies, including chronic myeloid leukemia and adult T-cell leukemia/lymphoma, whereby it may bring new therapeutic benefits. The successful revival of arsenic in acute promyelocytic leukemia, together with modern mechanistic studies, has thus allowed a new paradigm to emerge in translational medicine.

Proteome Analysis of Apoptotic MR2 Cells, Acute Promyelocytic Leukemia Cell Line with All-Trans Retinoic Acid Resistance, Induced by Arsenic Trioxide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4726-4726
Author(s):  
Pengcheng He ◽  
Mei Zhang ◽  
Xiaoning Wang ◽  
Huaiyu Wang ◽  
Jieying Xi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Complete Remission ◽  
Cell Line ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Promyelocytic Leukemia ◽  
Beta Tubulin ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Although all-trans retinoic acid(ATRA) provides complete remission in 90% patients with untreated acute promyelocytic leukemia(APL), it becomes ineffective to quite a few APL patients who have received ATRA before when their disease relapsed and used ATRA again. Arsenic trioxide(ATO) can make APL patients with ATRA-resistance obtain complete remission again by inducing APL cells apoptosis. However, the molecular mechanisms of apoptosis in ATRA-resistance APL cells induced by ATO remain unclear. For this reason, we take the apoptotic MR2 cells (APL cell line with ATRA-resistance) induced by ATO as a model, to screen and identify the proteins related with ATO-induced apoptosis by comparative proteomics. After MR2 cells were dyed with annexin V and PI staining, the percentage of the apoptotic MR2 cells induced by 1.0μmol/L ATO for 0h, 6h, 12h, 24h and 48h respectively was detected by Flow cytometry. The results showed that the majority of the apoptotic cells were in the earlier and later stage of apoptosis respectively, when MR2 cells were treated with ATO for 24 and 48 hours in sequence. The total proteins of MR2 cells of the control group, the earlier stages apoptosis group and the later stages apoptosis group were separated by two-dimensional electrophoresis(2-DE) respectively. Then, the differences in proteome profile among three groups were analyzed by ImageMaster™ 2D Platinum software. 14 protein pots were selected to be identified by Matrix-assisted laser desorption/ionization time of flight-mass spectrometry(MALDI-TOF-MS), in which the quantity of the protein differentially expressed was more than two times(≥2 or ≤0.5) among MR2-0h, MR2-24h and MR2-48h cells’ 2-DE map. However, only 11 proteins were successfully identified and their definite information was obtained. Among them, there were 8 proteins that were all probably involved in the mechanisms of apoptosis in MR2 cells and they were Calreticulin(CRT), Heat shock 70 kDa protein(HSP70), High mobility group protein B1(HMGB1), Ran-specific GTPase-activating protein(RanGAP1), Elongation factor 1-beta(EF-1β), Beta-tubulin, Cofilin-1, and Prolyl 4-hydroxylase(P4H) respectively. CRT was probably related with the early stage of apoptosis in MR2 cells, while RanGAP1 and HSP70 might related with the late stage of apoptosis in MR2 cells. Moreover, so far there was no related report on the roles of CRT, HMGB1, RanGAP1, cofilin-1 and beta-tubulin in the mechanisms of APL cells apoptosis. These differential proteins identified provide the new clues for further researching the molecular mechanisms of apoptosis in the ATRA-resistance APL cells induced by ATO.

scholarly journals A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients

Blood ◽  
1991 ◽  
Vol 78 (6) ◽  
pp. 1413-1419 ◽  
Author(s):  
ZX Chen ◽  
YQ Xue ◽  
R Zhang ◽  
RF Tao ◽  
XM Xia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Bone Marrow Cells ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Therapeutic Effects ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Fifty patients with acute promyelocytic leukemia (APL) have been treated with all-trans retinoic acid (RA). In vitro induced differentiation of primarily cultured bone marrow cells from the patients, colony-forming unit granulocyte-macrophage (CFU-GM) and L-CFU colony-forming assays, and karyotype analysis were performed over the treatment course. The very high bone marrow complete remission (CR) rate (94%) suggested that all-trans RA was superior to conventional chemotherapeutic regimens for the treatment of APL. The leukemic clone was reduced by RA-induced terminal differentiation and loss of proliferation capacity of leukemic cells. Relapse after CR in about 40% of patients was the major reason for the failure of the RA treatment. Patients who relapsed after a chemotherapy-maintained CR could be effectively reinduced to second CR by RA. However, if relapse occurred after a CR maintained by both RA and chemotherapy, the sensitivity of newly emerged leukemic clones to RA was greatly reduced. Therefore, it is suggested that RA should be replaced by conventional chemotherapy as soon as CR is achieved. Laboratory studies proved valuable in selecting cases for RA therapy and in predicting therapeutic effects and prognosis.

Comparative proteomic analysis of all-trans-retinoic acid treatment reveals systematic posttranscriptional control mechanisms in acute promyelocytic leukemia

Blood ◽  
2004 ◽  
Vol 104 (5) ◽  
pp. 1314-1323 ◽  
Author(s):  
Michael N. Harris ◽  
Bulent Ozpolat ◽  
Fadi Abdi ◽  
Sheng Gu ◽  
Allison Legler ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Growth Inhibition ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Promyelocytic Leukemia ◽  
Initiation Factor ◽  
Control Mechanisms ◽  
Down Regulation ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract All-trans-retinoic acid (ATRA) induces growth inhibition, differentiation, and apoptosis in cancer cells, including acute promyelocytic leukemia (APL). In APL, expression of promyelocytic leukemia protein retinoic acid receptor–α (PML-RARα) fusion protein, owing to the t(15; 17) reciprocal translocation, leads to a block in the promyelocytic stage of differentiation. Here, we studied molecular mechanisms involved in ATRA-induced growth inhibition and myeloid cell differentiation in APL. By employing comprehensive high-throughput proteomic methods of 2-dimensional (2-D) gel electrophoresis and amino acid–coded mass tagging coupled with electrospray ionization (ESI) mass spectrometry, we systematically identified a total of 59 differentially expressed proteins that were consistently modulated in response to ATRA treatment. The data revealed significant down-regulation of eukaryotic initiation and elongation factors, initiation factor 2 (IF2), eukaryotic initiation factor 4AI (eIF4AI), eIF4G, eIF5, eIF6, eukaryotic elongation factor 1A-1 (eEF1A-1), EF-1-δ, eEF1γ, 14-3-3ϵ, and 14-3-3ζ/δ (P < .05). The translational inhibitor DAP5/p97/NAT1 (death-associated protein 5) and PML isoform-1 were found to be up-regulated (P < .05). Additionally, the down-regulation of heterogeneous nuclear ribonucleoproteins (hnRNPs) C1/C2, UP2, K, and F; small nuclear RNPs (snRNPs) D3 and E; nucleoprotein tumor potentiating region (TPR); and protein phosphatase 2A (PP2A) were found (P < .05); these were found to function in pre-mRNA processing, splicing, and export events. Importantly, these proteomic findings were validated by Western blot analysis. Our data in comparison with previous cDNA microarray studies and our reverse transcription–polymerase chain reaction (RT-PCR) experiments demonstrate that broad networks of posttranscriptional suppressive pathways are activated during ATRA-induced growth inhibition processes in APL.

scholarly journals A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients

Blood ◽  
1991 ◽  
Vol 78 (6) ◽  
pp. 1413-1419 ◽  
Author(s):  
ZX Chen ◽  
YQ Xue ◽  
R Zhang ◽  
RF Tao ◽  
XM Xia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Bone Marrow Cells ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Therapeutic Effects ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Fifty patients with acute promyelocytic leukemia (APL) have been treated with all-trans retinoic acid (RA). In vitro induced differentiation of primarily cultured bone marrow cells from the patients, colony-forming unit granulocyte-macrophage (CFU-GM) and L-CFU colony-forming assays, and karyotype analysis were performed over the treatment course. The very high bone marrow complete remission (CR) rate (94%) suggested that all-trans RA was superior to conventional chemotherapeutic regimens for the treatment of APL. The leukemic clone was reduced by RA-induced terminal differentiation and loss of proliferation capacity of leukemic cells. Relapse after CR in about 40% of patients was the major reason for the failure of the RA treatment. Patients who relapsed after a chemotherapy-maintained CR could be effectively reinduced to second CR by RA. However, if relapse occurred after a CR maintained by both RA and chemotherapy, the sensitivity of newly emerged leukemic clones to RA was greatly reduced. Therefore, it is suggested that RA should be replaced by conventional chemotherapy as soon as CR is achieved. Laboratory studies proved valuable in selecting cases for RA therapy and in predicting therapeutic effects and prognosis.

Hypercalcemia associated with the interaction between all trans retinoic acid and posaconazole in an acute promyelocytic leukemia case

2021 ◽  
pp. 107815522110078
Author(s):  
Hacer Berna Afacan Ozturk ◽  
Murat Albayrak ◽  
Senem Maral ◽  
Merih Reis Aras ◽  
Fatma Yilmaz ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Serum Calcium ◽  
Promyelocytic Leukemia ◽  
Cytochrome P450 Enzymes ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Normal Ranges ◽  
Rare Side Effect ◽  
High Level

Introduction All-trans retinoic acid (ATRA) is a physiological metabolite of vitamin A and it is used for the treatment of acute promyelocytic leukemia (APL). Hypercalcemia is a rare side effect of ATRA and it may be potentiated after interaction of ATRA with azole group antifungals. Herein, we have reported an APL case with hypercalcemia that is caused by the interaction of ATRA and posaconazole. Case Report A 49-year-old female patient was diagnosed as APL after the examinations performed upon the detection of pancytopenia when she had presented with the complaints of widespread bruising and fever. After the initiation of posaconazole and ATRA, her serum calcium levels begin to increase (10.3 to 11.1mg/dl). Her vitamin D level was 21.9 ng/ml and PTH 17.8 pg/ml, both were in the normal ranges. The Drug Interaction Probability Scale score of our case was calculated as 6, indicating that the probable adverse drug reaction. Therefore, the high level of serum calcium was attributed to the interaction between ATRA and posaconazole. Management & Outcome Although hypercalcemia with ATRA and other antifungal agents have been previously reported in the literature, this is the first report of hypercalcemia with the concomitant use of ATRA and posaconazole. Discussion This case highlights the importance of monitoring ATRA’s side effects when it is used in combination with drugs inhibiting the cytochrome P450 enzymes. In conclusion, the concomitant use of posaconazole and ATRA may lead to hypercalcemia and serum calcium levels return to normal ranges with the discontinuation of these drugs.

Hypercalcemia associated with all-trans-retinoic acid in the treatment of acute promyelocytic leukemia

1993 ◽  
Vol 17 (5) ◽  
pp. 441-443 ◽  
Author(s):  
Masae Sakakibara ◽  
Motoki Ichikawa ◽  
Yoshiro Amano ◽  
Shigeyuki Matsuzawa ◽  
Kazunaga Agematsu ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid
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