The cardiac glycoside oleandrin induces apoptosis in human colon cancer cells via the mitochondrial pathway

Li, Pan; Zhang, Yuming; Zhao, Wanlu; Zhou, Xia; Wang, Chunxia; Deng, Fan

doi:10.1007/s00280-017-3337-2

Cited by 38 publications

(25 citation statements)

References 38 publications

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“…We also found increased expressions of cleaved caspase-3 and PARP-1 in PSN-A treated prostate cancer cells which are the hallmarks of apoptotic cell death. Induction of mitochondrial apoptosis by PSN-A is in line with previous reports indicating that cardiac glycosides could effectively initiate mitochondrial apoptosis by modulating bcl-2 family protein in prostate cancer cells 19 , 20 , 21 . Although, PSN-A increased intracellular free Ca++ in prostate cancer cells, however, this Ca ++ release has not been found to be associated with anticancer activity of PSN-A.…”

Section: Discussionsupporting

confidence: 91%

Proscillaridin A induces apoptosis, inhibits STAT3 activation and augments doxorubicin toxicity in prostate cancer cells

He¹,

Khan²,

Yang³

et al. 2018

Int. J. Med. Sci.

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Cardiac glycosides are natural compounds used for the treatment of congestive heart failure and cardiac arrhythmias. Recently, they have been reported to exhibit anticancer activity. Proscillaridin A (PSN-A), a cardiac glycoside constituent of Urginea maritima has been shown to exhibit anticancer activity. However, the cellular targets and anticancer mechanism of PSN-A in various cancers including prostate cancer remain largely unexplored. In the present study, we have shown that PSN-A inhibits proliferation and induces apoptosis in prostate cancer cells in a dose-dependent manner. Further mechanistic study have shown that anticancer activity of PSN-A in prostate cancer cells is associated with ROS generation, Bcl-2 family proteins modulation, mitochondrial membrane potential disruption and ultimately activation of caspase-3 and cleavage of PARP. Moreover, we found that PSN-A inhibits JAK2/STAT3 signaling and augments doxorubicin toxicity in prostate cancer cells. Of note, LNCaP cells were found to be more sensitive to PSN-A treatment as compared to DU145 cells. Taken together, the data provided first evidence of the anticancer activity and possible molecular mechanism of PSN-A in prostate cancer. Further study is needed to develop PSN-A into a potential lead compound for the treatment of prostate cancer.

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Section: Discussionsupporting

confidence: 91%

Proscillaridin A induces apoptosis, inhibits STAT3 activation and augments doxorubicin toxicity in prostate cancer cells

He¹,

Khan²,

Yang³

et al. 2018

Int. J. Med. Sci.

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“…Apart from being a cardiac glycoside, oleandrin has been gathering attention due to its anti-tumoral [ 12 , 13 , 14 , 15 , 16 ] and antiviral potential [ 8 , 17 , 18 , 19 ], but its pharmacological use is held back by its variable toxicity. In this study, using the model S. cerevisiae , we detected oleandrin-induced fluctuations in cell Ca 2+ , which could be related to the Ca 2+ entry via the Cch1/Mid1 plasma membrane channel ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity of Oleandrin Is Mediated by Calcium Influx and by Increased Manganese Uptake in Saccharomyces cerevisiae Cells

2020

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Oleandrin, the main component of Nerium oleander L. extracts, is a cardiotoxic glycoside with multiple pharmacological implications, having potential anti-tumoral and antiviral characteristics. Although it is accepted that the main mechanism of oleandrin action is the inhibition of Na+/K+-ATPases and subsequent increase in cell calcium, many aspects which determine oleandrin cytotoxicity remain elusive. In this study, we used the model Saccharomyces cerevisiae to unravel new elements accounting for oleandrin toxicity. Using cells expressing the Ca2+-sensitive photoprotein aequorin, we found that oleandrin exposure resulted in Ca2+ influx into the cytosol and that failing to pump Ca2+ from the cytosol to the vacuole increased oleandrin toxicity. We also found that oleandrin exposure induced Mn2+ accumulation by yeast cells via the plasma membrane Smf1 and that mutants with defects in Mn2+ homeostasis are oleandrin-hypersensitive. Our data suggest that combining oleandrin with agents which alter Ca2+ or Mn2+ uptake may be a way of controlling oleandrin toxicity.

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“…Furthermore, Digitoxin and the other cardiac glycosides have been reported as cytotoxic agents, probably not exclusively due to their activity as Na + /K + ATPase inhibitors, with consequent membrane fluidity alterations, increasing Ca 2+ levels. Additionally, through mitochondrial Na + /Ca 2+ pump activity exacerbation and triggering cytoskeleton alterations, that lead to cell cycle dysregulation with possible Mcl-1 (induced myeloid leukemia cell differentiation protein Mcl-1) and Bcl-xl (B-cell lymphoma-extra large) down-regulation, it is a possible a mechanism involving a mitochondrial apoptosis-inducing pathway [ 71 , 72 ]. Other hypotheses involve an ampler signalosome [ 73 , 74 ] leading to a multitude of effects leading to cell death, namely topoisomerase inhibition [ 75 ], EGFR/Src/Akt signaling cross-talking [ 76 ], Na + /K + ATPase, and Src endosomal trafficking and immunogenic cell death [ 74 ], p21 up-regulation and JNKs (c-Jun N-terminal kinases) activation [ 77 ], and HIF1-α (hypoxia-inducible factor 1-alpha) inhibition [ 78 ].…”

Section: Yap/tead Interaction Modulation Through Direct Ligands Dementioning

confidence: 99%

Repurposing of Drugs Targeting YAP-TEAD Functions

Elisi

Santucci

D’Arca

et al. 2018

Cancers

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Drug repurposing is a fast and consolidated approach for the research of new active compounds bypassing the long streamline of the drug discovery process. Several drugs in clinical practice have been reported for modulating the major Hippo pathway’s terminal effectors, namely YAP (Yes1-associated protein), TAZ (transcriptional co-activator with PDZ-binding motif) and TEAD (transcriptional enhanced associate domains), which are directly involved in the regulation of cell growth and tissue homeostasis. Since this pathway is known to have many cross-talking phenomena with cell signaling pathways, many efforts have been made to understand its importance in oncology. Moreover, this could be relevant to obtain new molecular tools and potential therapeutic assets. In this review, we discuss the main mechanisms of action of the best-known compounds, clinically approved or investigational drugs, able to cross-talk and modulate the Hippo pathway, as an attractive strategy for the discovery of new potential lead compounds.

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The cardiac glycoside oleandrin induces apoptosis in human colon cancer cells via the mitochondrial pathway

Abstract: The present results suggest that oleandrin induces apoptosis in human colorectal cancer cells via the mitochondrial pathway. Our findings provide new insight into the mechanism of anti-cancer property of oleandrin.

Cited by 38 publications

References 38 publications

Proscillaridin A induces apoptosis, inhibits STAT3 activation and augments doxorubicin toxicity in prostate cancer cells

Proscillaridin A induces apoptosis, inhibits STAT3 activation and augments doxorubicin toxicity in prostate cancer cells

Cytotoxicity of Oleandrin Is Mediated by Calcium Influx and by Increased Manganese Uptake in Saccharomyces cerevisiae Cells

Repurposing of Drugs Targeting YAP-TEAD Functions

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