scholarly journals Novel therapeutic approach: organic arsenical (melarsoprol) alone or with all-trans-retinoic acid markedly inhibit growth of human breast and prostate cancer cells in vitro and in vivo

2000 ◽  
Vol 82 (2) ◽  
pp. 452-458 ◽  
Author(s):  
K Koshiuka ◽  
E Elstner ◽  
E Williamson ◽  
J W Said ◽  
Y Tada ◽  
...  
2013 ◽  
Vol 698 (1-3) ◽  
pp. 122-130 ◽  
Author(s):  
Dionissios Vourtsis ◽  
Margarita Lamprou ◽  
Eldem Sadikoglou ◽  
Anastassios Giannou ◽  
Olga Theodorakopoulou ◽  
...  

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1202
Author(s):  
Bojjibabu Chidipi ◽  
Syed Islamuddin Shah ◽  
Michelle Reiser ◽  
Manasa Kanithi ◽  
Amanda Garces ◽  
...  

In the heart, mitochondrial homeostasis is critical for sustaining normal function and optimal responses to metabolic and environmental stressors. Mitochondrial fusion and fission are thought to be necessary for maintaining a robust population of mitochondria, and disruptions in mitochondrial fission and/or fusion can lead to cellular dysfunction. The dynamin-related protein (DRP1) is an important mediator of mitochondrial fission. In this study, we investigated the direct effects of the micronutrient retinoid all-trans retinoic acid (ATRA) on the mitochondrial structure in vivo and in vitro using Western blot, confocal, and transmission electron microscopy, as well as mitochondrial network quantification using stochastic modeling. Our results showed that ATRA increases DRP1 protein levels, increases the localization of DRP1 to mitochondria in isolated mitochondrial preparations. Our results also suggested that ATRA remodels the mitochondrial ultrastructure where the mitochondrial area and perimeter were decreased and the circularity was increased. Microscopically, mitochondrial network remodeling is driven by an increased rate of fission over fusion events in ATRA, as suggested by our numerical modeling. In conclusion, ATRA results in a pharmacologically mediated increase in the DRP1 protein. It also results in the modulation of cardiac mitochondria by promoting fission events, altering the mitochondrial network, and modifying the ultrastructure of mitochondria in the heart.


2006 ◽  
Vol 99 (5) ◽  
pp. 1409-1419 ◽  
Author(s):  
Marc A. Thomas ◽  
Myles C. Hodgson ◽  
Susan D. Loermans ◽  
Joel Hooper ◽  
Raelene Endersby ◽  
...  

Oncotarget ◽  
2016 ◽  
Vol 7 (29) ◽  
pp. 46028-46041 ◽  
Author(s):  
Farzaneh Atashrazm ◽  
Ray M. Lowenthal ◽  
Joanne L. Dickinson ◽  
Adele F. Holloway ◽  
Gregory M. Woods

2015 ◽  
Vol 26 (7) ◽  
pp. 763-773
Author(s):  
Muhammad N. Aslam ◽  
Shannon McClintock ◽  
Shazli P. Khan ◽  
Patricia Perone ◽  
Ronald Allen ◽  
...  

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2980-2980
Author(s):  
Maaike Luesink ◽  
Jeroen Pennings ◽  
Willemijn Wissink ◽  
Peter Linssen ◽  
Petra Muus ◽  
...  

Abstract The most important complication of all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) is the retinoic acid syndrome (RAS), a life-threatening hyper-inflammatory reaction with a distinct capillary leak syndrome and multi-organ failure. Once established, the syndrome has proven very difficult to manage. Early recognition in combination with prompt corticosteroid treatment significantly reduces the mortality rate of patients with this syndrome. Nonetheless, still 15% of the induction deaths in APL is caused by RAS. The pathogenic mechanism of the hyper-inflammatory cascade in RAS is not fully understood yet. Infiltration of differentiating APL cells in the lung is important in the development of RAS. In addition, differentiation of APL cells by ATRA is associated with increased expression and release of pro-inflammatory cytokines, chemokines and adhesion molecules in vitro and it has been hypothesized that this is important for the triggering of the hyper-inflammatory cascade in RAS. We investigated the effect of ATRA on the expression and secretion of chemokines in APL cells in vitro and in vivo. Using microarray, quantitative PCR and ELISA we demonstrated significant induction (up to 16000-fold) of 8 CC-chemokines (CCLs) in the NB4 APL cell line after differentiation induction with ATRA in vitro. To demonstrate the significance of chemokine induction by ATRA in vivo, we measured plasma levels of CCLs in 3 APL patients, treated with a combination of ATRA, idarubicine and prednisone according to the AIDA-2000/P protocol. One of these patients developed an obvious retinoic acid syndrome. During therapy we observed increased plasma levels of 3 CCLs in all three patients. Induction of 5 other CCLs (CCL3, CCL4, CCL7, CCL8, CL11) was only observed during RAS, suggesting that upregulation of these 5 CC-chemokines is specific for RAS. To investigate whether the plasma levels of CC-chemokines are functionally relevant, we measured chemo-attraction of peripheral blood leukocytes towards plasma of an APL patient who developed RAS using a transwell system. Plasma from this patient during RAS showed significant more chemo-attraction than plasma from the same patient before treatment with ATRA, idarubicine and prednisone. Subsequently we investigated whether the therapeutic effect of dexamethasone in RAS can be ascribed to downregulation of chemokine expression in APL cells. Despite dexamethasone, the induction of chemokine expression in NB4 cells by ATRA sustained. We conclude that ATRA causes massive secretion of chemokines by APL cells, which might trigger the hyper-inflammatory cascade in RAS by continuous attraction of APL cells and other inflammatory cells towards tissues like the lung. Dexamethasone does not abrogate the production of CC-chemokines by APL cells, but rather seems to inhibit the hyper-inflammatory cascade at the level of the effector cells and target tissues like the lung. This might explain why dexamethasone is not able to sufficiently reverse a retinoic acid syndrome once it has been established. The application of neutralizing CC-chemokine receptor antibodies or other antagonists might be an alternative route to treat an established retinoic acid syndrome.


2019 ◽  
Vol 26 (4) ◽  
pp. 534-545 ◽  
Author(s):  
Shubha Priyamvada ◽  
Arivarasu N Anbazhagan ◽  
Anoop Kumar ◽  
Ishita Chatterjee ◽  
Alip Borthakur ◽  
...  

Abstract Background Intestinal epithelial apical membrane Cl-/HCO3- exchanger DRA (downregulated in adenoma, SLC26A3) has emerged as an important therapeutic target for diarrhea, emphasizing the potential therapeutic role of agents that upregulate DRA. All-trans retinoic acid (ATRA), a key vitamin A metabolite, was earlier shown by us to stimulate DRA expression in intestinal epithelial cells. However, its role in modulating DRA in gut inflammation has not been investigated. Aims Our aim was to analyze the efficacy of ATRA in counteracting inflammation-induced decrease in DRA in vitro and in vivo. Methods Interferon-γ (IFN-γ)-treated Caco-2 cells and dextran sulfate sodium (DSS)-treated C57BL/6J mice served as in vitro and in vivo models of gut inflammation, respectively. The effect of ATRA on IFN-γ-mediated inhibition of DRA function, expression, and promoter activity were elucidated. In the DSS colitis model, diarrheal phenotype, cytokine response, in vivo imaging, myeloperoxidase activity, and DRA expression were measured in the distal colon. Results All-trans retinoic acid (10 μM, 24 h) abrogated IFN-γ (30 ng/mL, 24 h)-induced decrease in DRA function, expression, and promoter activity in Caco-2 cells. All-trans retinoic acid altered IFN-γ signaling via blocking IFN-γ-induced tyrosine phosphorylation of STAT-1. All-trans retinoic acid cotreatment (1 mg/kg BW, i.p. daily) of DSS-treated mice (3% in drinking water for 7 days) alleviated colitis-associated weight loss, diarrheal phenotype, and induction of IL-1β and CXCL1 and a decrease in DRA mRNA and protein levels in the colon. Conclusion Our data showing upregulation of DRA under normal and inflammatory conditions by ATRA demonstrate a novel role of this micronutrient in alleviating IBD-associated diarrhea.


Blood ◽  
1990 ◽  
Vol 76 (9) ◽  
pp. 1704-1709 ◽  
Author(s):  
S Castaigne ◽  
C Chomienne ◽  
MT Daniel ◽  
P Ballerini ◽  
R Berger ◽  
...  

Abstract Twenty-two patients with acute promyelocytic leukemia were treated with all-trans retinoic acid (RA, 45 mg/m2 per day) for 90 days. Of the 22, four patients were previously untreated, two were resistant after conventional chemotherapy, and 16 were in first (n = 11), second (n = 4), or third (n = 1) relapse. We observed 14 complete response, four transient responses, one failure, and three early deaths. Length of hospitalization and number of transfusions were notably reduced in complete responders. Correction of coagulation disorders and an increase of WBCs were the first signs of all-trans RA efficacy. Morphologic analysis performed at days 0, 15, 30, 45, 60, and 90 showed that complete remissions were obtained without bone marrow (BM) hypoplasia. Presence of Auer rods in the maturing cells confirmed the differentiation effect of the treatment. At remission, the t(15;17) initially present in 20 patients was not found. The in vitro studies showed a differentiation in the presence of all-trans RA in 16 of the 18 tested cases. The single nonresponder to all trans RA in vitro did not respond in vivo. Adverse effects of RA therapy--skin and mucosa dryness, hypertriglyceridemia, and increase of hepatic transaminases-- were frequently noted. We also observed bone pain in 11 patients and hyperleukocytosis in four patients. Whether maintenance treatment consisted of low-dose chemotherapy or all-trans RA, early relapses were observed. Five patients are still in complete remission (CR) at 4 to 13 months. Our study confirms the major efficacy of all-trans RA in M3, even in relapsing patients. Remissions are obtained by a differentiation process.


Sign in / Sign up

Export Citation Format

Share Document