HIF-1α inhibition by 2-methoxyestradiol induces cell death via activation of the mitochondrial apoptotic pathway in acute myeloid leukemia

Zhe, Nana; Chen, Shuya; Zhou, Zhen; Liu, Ping; Lin, Xiaojing; Yu, Meisheng; Cheng, Bingqing; Zhang, Yaming; Wang, Jishi

doi:10.1080/15384047.2016.1177679

Cited by 40 publications

(39 citation statements)

References 33 publications

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“…A synergy was observed between metformin, which inhibits Complex I in mitochondria, and the broad‐spectrum metabolic inhibitor 6‐benzylthioinosine (6‐BT), with reduced glycolysis, ROS suppression and increased apoptosis (Sabnis et al , ). Inhibition of HIF1α by 2‐methoxyestradiol was found to activate the mitochondrial apoptotic pathway in AML (Zhe et al , ). Inhibitors for histone deacetylases as well as protein deacetylase SIRT1 have been evaluated in clinical trials in the US and European Union.…”

Section: Discussionmentioning

confidence: 99%

SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation

Liu

et al. 2019

Br J Haematol

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Summary Acute myeloid leukaemia (AML) cells possess metabolism profiles, such as higher rates of oxidative phosphorylation and dependence on fatty acid oxidation for survival, and are dependent on the sophisticated regulation of reactive oxygen species (ROS) generation for survival, drug resistance and stemness maintenance. We found that sensitivity of primary AML cells to cytarabine correlated with SOD2 acetylation and the ability of the drug to induce mitochondrial ROS. The SOD2 deacetylase, SIRT3, protected AML cells from chemotherapy as shown by inhibited apoptosis via inhibited drug‐induced production of mitochondrial ROS. SIRT3 significantly decreased nicotinamide adenine dinucleotide phosphate (NADP)/reduced NADP ratio and increased reduced glutathione/oxidized glutathione ratio. Furthermore, SIRT3 enhanced oxidative phosphorylation (OxPhos) in AML cells under both basic and cytarabine‐treated conditions. A xenograft mouse model showed that SIRT3 overexpressing AML cells and patient‐derived xenograft mice bearing high SIRT3 deacetylase activity were more resistant to chemotherapy in vivo. SIRT3 inhibitor displayed synergy with cytarabine to ablate AML cells in vitro and in mouse models. Taken together, our study showed that SIRT3 is capable of reprograming mitochondrial metabolism towards OxPhos and downregulating ROS generation, which contribute to the chemoresistance of AML cells. SIRT3 can be utilized as a potential therapeutic target to improve the anti‐leukaemic efficacy of standard chemotherapeutic agents for AML.

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Section: Discussionmentioning

confidence: 99%

SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation

Liu

et al. 2019

Br J Haematol

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“…The latest reports about the mechanism of action of 2-ME2 offer further insight into the importance of its influence on HIF-1α function, supported by the observations that when 2-ME2 is combined with other conventional chemotherapeutics or radiation therapy, it can increase the anticancer activity of the concomitant agent(s) or that of the irradiation [35][36][37]. Moreover, based on its inhibitory effect on HIF-1α acute myeloid leukemia has also been identified as a possible novel therapeutic target for 2-ME2 [38].…”

Section: -Methoxyestradiolmentioning

confidence: 85%

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

Minorics

Zupkó

2018

ACAMC

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Research of steroidal compounds as anticancer agents started almost 50 years ago. During the past decades, several innovative new steroids, like cyproterone, finasteride, estramustin, exemestane and fulvestrant have successfully become a part of routine clinical practice. Meanwhile, a vast amount of new information have accumulated about the functions of the endogenous steroid system (including the characterization of enzymes, receptors, transcription pathways, etc.) and about the role of steroids in carcinogenesis. Therefore, it is regularly required to review the latest published results, focusing on a well-defined part within this research field that has definitely developed into a highly diversified speciality by now. Herein, we make an attempt to summarize the most recent results reported about anticancer agents of estrane backbone, focusing on their mechanisms of action and their structure-activity relationships. Due to the vast number and various accessibilities of scientific publications, neither other reviews nor this one can be considered as absolutely exhaustive. In spite of these restrictive factors, the current review makes a good opportunity to define the recent scientific trends in the field of estradiol-related anticancer agents.

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“…2-ME-mediated mitochondrial apoptotic pathway activation is mediated by reactive oxygen species (ROS) in acute myeloid leukemia cells. 37 Furthermore, Foster et al 38 indicated that 1 µM 2-MeE2bi-sMATE caused loss of mitochondrial membrane potential followed by increased caspase-3 and caspase-7 activation in ovarian carcinoma (A2780), LNCaP and MCF-7 cells.…”

Section: Discussionmentioning

confidence: 99%

Modes of cell death induced by tetrahydroisoquinoline-based analogs in MDA-MB-231 breast and A549 lung cancer cell lines

Nel

Joubert

Döhle

et al. 2018

DDDT

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BackgroundA and B rings of the steroidal microtubule disruptor, 2-methoxyestradiol, and its analogs can be mimicked with a tetrahydroisoquinoline (THIQ) core. THIQs are cytotoxic agents with potential anticancer activities. The aim of this in vitro study was to investigate the modes of cell death induced by four nonsteroidal THIQ-based analogs, such as STX 2895, STX 3329, STX 3451 and STX 3450, on MDA-MB-231 metastatic breast and A549 epithelial lung carcinoma cells.Materials and methodsCytotoxicity studies determined the half-maximal growth inhibitory concentration of the analogs to be at nanomolar concentrations without the induction of necrosis. Light and fluorescent microscopy determined that compounds caused microtubule depolymerization and displayed morphological hallmarks of apoptosis.ResultsFlow cytometric analyses confirmed apoptosis induction as well as an increased G2/M phase on cell cycle analysis. Furthermore, intrinsic pathway signaling was implicated due to increased cytochrome c release and a decrease in mitochondrial transmembrane potential. Potential involvement of autophagy was observed due to increased acidic vacuole formation and increased aggresome activation factor.ConclusionThus, it can be concluded that these four THIQ-based analogs exert anti-proliferative and antimitotic effects, induce apoptosis and involve autophagic processes. Further investigation into the efficacy of these potential anticancer drugs will be conducted in vitro and in vivo.

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HIF-1α inhibition by 2-methoxyestradiol induces cell death via activation of the mitochondrial apoptotic pathway in acute myeloid leukemia

Cited by 40 publications

References 33 publications

SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation

SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

Modes of cell death induced by tetrahydroisoquinoline-based analogs in MDA-MB-231 breast and A549 lung cancer cell lines

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