AMPK activation induced by promethazine increases NOXA expression and Beclin-1 phosphorylation and drives autophagy-associated apoptosis in chronic myeloid leukemia

Medeiros, Hyllana C. D.; Colturato-Kido, Carina; Ferraz, Letícia Silva; Costa, Claudia A.; Moraes, Vivian W. R.; Paredes‐Gamero, Edgar Julian; Tersariol, Ivarne L.S.; Rodrigues, Tiago

doi:10.1016/j.cbi.2019.108888

Cited by 18 publications

(15 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AMPK played an important role in autophagy, serving as the upstream regulators of mTOR (Mihaylova and Shaw, 2011), and AMPK could be stimulated by ALCRA (Hunter et al, 2011). Similarly, recent studies showed that polysaccharide simultaneously increased AMPK and inhibited mTOR triggering autophagy-associated apoptosis (Medeiros et al, 2019;Liang et al, 2019). Our study showed that ethanol dramatically improved the expression level of p-mTOR and declined p-AMPK, but LDOP-1 upregulated p-AMPK and downregulated p-mTOR expression.…”

Section: Discussionsupporting

confidence: 57%

Polysaccharides of Dendrobium officinale Kimura & Migo Leaves Protect Against Ethanol-Induced Gastric Mucosal Injury via the AMPK/mTOR Signaling Pathway in Vitro and vivo

Zhan

Lü

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

Ethanol-induced gastric mucosal injury is a common gastrointestinal disorder. Polysaccharides separated from herbs have been shown to be effective for ethanol-induced gastric mucosal injury, but whether the polysaccharides from Dendrobium officinale Kimura & Migo leaves (LDOP-1) protected mucosa from ethanol-induced injury remains unknown. Thus, the present study carried out gastric mucosal protection and the mechanism of LDOP-1 in vivo and vitro . The chemical composition of LDOP-1 was a heteropolysaccharide comprising mannose, galacturonic acid, glucose, galactose, and arabinose at a molar ratio of 2.0:1.1:0.7:0.5:0.4. Pharmacological results showed that LDOP-1 significantly reduced gastric mucosal injury score and pathological injury, improved antioxidant capacity, reduced the level of reactive oxygen species, and reversed the apoptosis of GES-1 in vivo and vitro . Research showed that LDOP-1 pretreatment upregulated the expression level of p-AMPK, LC3β, HO-1, and Beclin-1; downregulated the expression level of p-mTOR and p62; and reversed the expression level of caspase3, Bax, and Bcl-2. This study was the first to demonstrate that LDOP-1 could protect against ethanol-induced gastric mucosal injury via the AMPK/mTOR signaling pathway in vitro and vivo .

show abstract

Section: Discussionsupporting

confidence: 57%

Polysaccharides of Dendrobium officinale Kimura & Migo Leaves Protect Against Ethanol-Induced Gastric Mucosal Injury via the AMPK/mTOR Signaling Pathway in Vitro and vivo

Zhan

Lü

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Furthermore, a nanostructure-based system containing chlorpromazine also exerted cytotoxicity against a vincristine-resistant CML model [ 16 ], and a phase 1 clinical trial evaluated the combination of TR and cytarabine and revealed a reduction in blast levels [ 43 ]. Promethazine, a phenothiazine derivative with anti-histamine activity, also presented cytotoxicity in K562 cells [ 44 ]. Most published studies on cytotoxicity of phenothiazines in cancer models in vitro have reported the ability of these drugs to inhibit cell proliferation, migration, and invasiveness, to interfere with cell cycle, and to induce apoptosis in a variety of tumor cells [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting Ca2+ and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells

Moraes

Santos

Suarez

et al. 2022

Life

View full text Add to dashboard Cite

Mitochondria have pivotal roles in cellular physiology including energy metabolism, reactive oxygen species production, Ca2+ homeostasis, and apoptosis. Altered mitochondrial morphology and function is a common feature of cancer cells and the regulation of mitochondrial homeostasis has been identified as a key to the response to chemotherapeutic agents in human leukemias. Here, we explore the mechanistic aspects of cytotoxicity produced by thioridazine (TR), an antipsychotic drug that has been investigated for its anticancer potential in human leukemia cellular models. TR exerts selective cytotoxicity against human leukemia cells in vitro. A PCR array provided a general view of the expression of genes involved in cell death pathways. TR immediately produced a pulse of cytosolic Ca2+, followed by mitochondrial uptake, resulting in mitochondrial permeabilization, caspase 9/3 activation, endoplasmic reticulum stress, and apoptosis. Ca2+ chelators, thiol reducer dithiothreitol, or CHOP knockdown prevented TR-induced cell death. TR also exhibited potent cytotoxicity against BCL-2/BCL-xL-overexpressing leukemia cells. Additionally, previous studies have shown that TR exhibits potent antitumor activity in vivo in different solid tumor models. These findings show that TR induces a Ca2+-mediated apoptosis with involvement of mitochondrial permeabilization and ER stress in leukemia and it emphasizes the pharmacological potential of TR as an adjuvant in antitumor chemotherapy.

show abstract

“…AMPK regulates multiple cellular processes, including autophagy, since active AMPK inhibits mTOR, a protein kinase that negatively regulates autophagy [53]. Although TR triggered a protective autophagic response in T-ALL cells, an antihistamine phenothiazine derivative promethazine induced autophagy-associated cell death in a Philadelphia chromosome-positive chronic myeloid leukemia model (K562) mediated by activation of AMPK [54], i.e., promethazine-induced autophagy in CML contributed to cell death. Thus, it is not clear yet whether these differences are due to the type of leukemia cell or the type and intensity of phenothiazine derivative promoting cell death.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

Colturato-Kido

Lopes

Medeiros

et al. 2021

Life

Self Cite

View full text Add to dashboard Cite

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a “double-edged sword” contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL.

show abstract

AMPK activation induced by promethazine increases NOXA expression and Beclin-1 phosphorylation and drives autophagy-associated apoptosis in chronic myeloid leukemia

Cited by 18 publications

References 53 publications

Polysaccharides of Dendrobium officinale Kimura & Migo Leaves Protect Against Ethanol-Induced Gastric Mucosal Injury via the AMPK/mTOR Signaling Pathway in Vitro and vivo

Polysaccharides of Dendrobium officinale Kimura & Migo Leaves Protect Against Ethanol-Induced Gastric Mucosal Injury via the AMPK/mTOR Signaling Pathway in Vitro and vivo

Targeting Ca2+ and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells

Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

Contact Info

Product

Resources

About