The combination of digoxin and GSK2606414 exerts synergistic anticancer activity against leukemia <i>in vitro</i> and <i>in vivo</i>

Zhang, Xue Hong; Wang, Xin Yu; Zhou, Zhi Wei; Bai, Hua; Shi, Lin; Yuan, Yin; Zhou, Shu Feng; Zhang, Xiao Chun

doi:10.1002/biof.1380

Cited by 20 publications

(15 citation statements)

References 22 publications

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“…In a P301L tau mouse frontotemporal dementia model, PERK inhibition allowed recovery of protein synthesis and prevented neuronal loss, reducing behavioral symptoms [132]. The PERK inhibitors were also effective in mouse models of prion disease [130], PD [131], TBI [135] and AD [133] and in models of bone cancer and leukemia [198,199]. However, the GSK compounds were reported to also have off-target effects [134].…”

Section: Perk Pathway Inhibitionmentioning

confidence: 99%

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

2021

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With the extension of life span in recent decades, there is an increasing burden of late-onset neurodegenerative diseases, for which effective treatments are lacking. Neurodegenerative diseases include the widespread Alzheimer’s disease (AD) and Parkinson’s disease (PD), the less frequent Huntington’s disease (HD) and Amyotrophic Lateral Sclerosis (ALS) and also rare early-onset diseases linked to mutations that cause protein aggregation or loss of function in genes that maintain protein homeostasis. The difficulties in applying gene therapy approaches to tackle these diseases is drawing increasing attention to strategies that aim to inhibit cellular toxicity and restore homeostasis by intervening in cellular pathways. These include the unfolded protein response (UPR), activated in response to endoplasmic reticulum (ER) stress, a cellular affliction that is shared by these diseases. Special focus is turned to the PKR-like ER kinase (PERK) pathway of the UPR as a target for intervention. However, the complexity of the pathway and its ability to promote cell survival or death, depending on ER stress resolution, has led to some confusion in conflicting studies. Both inhibition and activation of the PERK pathway have been reported to be beneficial in disease models, although there are also some reports where they are counterproductive. Although with the current knowledge a definitive answer cannot be given on whether it is better to activate or to inhibit the pathway, the most encouraging strategies appear to rely on boosting some steps without compromising downstream recovery.

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Section: Perk Pathway Inhibitionmentioning

confidence: 99%

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

2021

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“…Digoxin ( 133 ), isolated originally from Digitalis lanata Ehrh. (Plantaginaceae), has been long used to treat congestive heart failure through inhibition of the α subunits of Na + /K + -ATPase. , Recent studies showed that digoxin ( 133 ) is cytotoxic toward Raji and NAMALWA human Burkitt’s lymphoma and K562 and THP-1 human leukemia cells. , Tumor growth was inhibited when 4-week-old male BALB/c nude mice bearing Raji lymphoma xenografts were treated (i.p.) daily with digoxin ( 133 ) (2 mg/kg) for 3 weeks .…”

Section: Cardiac Glycosidesmentioning

confidence: 99%

“…Also, leukemia growth was suppressed synergistically by a combination treatment of digoxin ( 133 ) and the unfolded protein response signaling inhibitor GSK2606414 when 6-week-old female nude mice inoculated with K562 cells were treated (i.p.) with digoxin ( 133 ) (2 mg/kg), GSK2606414 (50 mg/kg), or digoxin (2 mg/kg) plus GSK2606414 (50 mg/kg) every 3 days for 4 weeks …”

Section: Cardiac Glycosidesmentioning

confidence: 99%

Potential Anticancer Agents Characterized from Selected Tropical Plants

et al. 2019

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Higher plants are well known for their value in affording clinically useful anticancer agents, with such compounds acting against cancer cells by a range of mechanisms of action. There remains a strong interest in the discovery and development of plant secondary metabolites as additional cancer chemotherapeutic lead compounds. In the present review, progress on the discovery of plant-derived compounds of the biflavonoid, lignan, sesquiterpene, steroid, and xanthone structural types is presented. Several potential anticancer leads of these types have been characterized from tropical plants collected in three countries as part of our ongoing collaborative multi-institutional project. Preliminary structure-activity relationships and work on in vivo testing and cellular mechanisms of action are also discussed. In addition, the relevant work reported by other groups on the same compound classes is included herein.

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“…Analyses of the FAERS and JMDC claims databases revealed significant inverse signals between digoxin and the four cancers. Previous basic research studies have supported the potential value of cardiac glycosides, such as digoxin, as chemotherapeutic candidates 25–28 . At the mechanistic level, several different pathways have been suggested to be responsible for mediating cytotoxic effects, including calcium-dependent activation of caspases and other hydrolytic enzymes 5,29 , generation of reactive oxygen species 30 , topoisomerase inhibition 31 and interference of signal transduction pathways, such as Src, epidermal growth factor receptor, p21 and hypoxia inducible factor-1α 2,4 .…”

Section: Discussionmentioning

confidence: 97%

Integrative analysis of clinical and bioinformatics databases to identify anticancer properties of digoxin

Yokoyama

Sugimoto

Nakagawa

et al. 2019

Sci Rep

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Cardiac glycosides, such as digoxin, inhibit Na+/K+-ATPases and cause secondary activation of Na+/Ca2+ exchangers. Preclinical investigations have suggested that digoxin may have anticancer properties. In order to clarify the functional mechanisms of digoxin in cancer, we performed an integrative analysis of clinical and bioinformatics databases. The US Food and Drug Administration Adverse Event Reporting System and the Japan Medical Data Center claims database were used as clinical databases to evaluate reporting odds ratios and adjusted sequence ratios, respectively. The BaseSpace Correlation Engine and Connectivity Map bioinformatics databases were used to investigate molecular pathways related to digoxin anticancer mechanisms. Clinical database analyses suggested an inverse association between digoxin and four cancers: gastric, colon, prostate and haematological malignancy. The bioinformatics database analysis suggested digoxin may exert an anticancer effect via peroxisome proliferator-activated receptor α and apoptotic caspase cascade pathways. Our integrative analysis revealed the possibility of digoxin as a drug repositioning candidate for cancers.

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The combination of digoxin and GSK2606414 exerts synergistic anticancer activity against leukemia in vitro and in vivo

Cited by 20 publications

References 22 publications

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

Potential Anticancer Agents Characterized from Selected Tropical Plants

Integrative analysis of clinical and bioinformatics databases to identify anticancer properties of digoxin

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