The Notch inhibitor cowanin accelerates nicastrin degradation

Arai, Midori A.; Akamine, Ryuta; Tsuchiya, Anna; Yoneyama, Tatsuro; Koyano, Takashi; Kowithayakorn, Thaworn; Ishibashi, Masami

doi:10.1038/s41598-018-23698-4

Cited by 20 publications

(10 citation statements)

References 34 publications

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“…Cardenolides, together with the bufadienolides, which contain an α-pyrone ring, compose the group of so-called cardiac glycosides. Arai et al [46] compared the anticancer activity of various compounds isolated from Nerium oleander and reported that the sugar moiety at C3 is important for anticancer activity. In addition, when a double bond at C16 and C17 was introduced, the activity decreased, and the OH group at C8 also reduced the activity.…”

Section: Discussionmentioning

confidence: 99%

Oleandrin and Its Derivative Odoroside A, Both Cardiac Glycosides, Exhibit Anticancer Effects by Inhibiting Invasion via Suppressing the STAT-3 Signaling Pathway

Trojan

Jin

et al. 2018

IJMS

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The cardiac glycosides oleandrin and odoroside A, polyphenolic monomer compounds extracted from Nerium oleander, have been found to have antitumor effects on various tumors at low doses. However, the mechanisms of anticancer effects of oleandrin and odoroside A are not well known. Therefore, in this study, we aimed to investigate the anticancer effects of oleandrin and odoroside A and their associated mechanisms in highly metastatic MDA-MB-231 breast cancer cells and radiotherapy-resistant (RT-R) MDA-MB-231 cells. Our results showed that oleandrin and odoroside A dose-dependently decreased the colony formation and the invasion of both cell lines at nanomolar ranges. Furthermore, oleandrin (50 nM) and odoroside A (100 nM) reduced octamer-binding transcription factor 3/4 (OCT3/4) and β-catenin levels and matrix metalloproteinase-9 (MMP-9) activity. Finally, we found that phospho-STAT-3 levels were increased in MDA-MB-231 and RT-R-MDA-MB-231, but not in endothelial cells (ECs), and that the levels were significantly decreased by oleandrin (50 nM) and odoroside A (100 nM). Inhibition of phospho-signal transducer and activator of transcription (STAT)-3 significantly reduced OCT3/4 and β-catenin levels and MMP-9 activity, ultimately resulting in reduced invasion. These results suggest that the anticancer effects of oleandrin and odoroside A might be due to the inhibition of invasion through of phospho-STAT-3-mediated pathways that are involved in the regulation of invasion-related molecules.

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Section: Discussionmentioning

confidence: 99%

Oleandrin and Its Derivative Odoroside A, Both Cardiac Glycosides, Exhibit Anticancer Effects by Inhibiting Invasion via Suppressing the STAT-3 Signaling Pathway

Trojan

Jin

et al. 2018

IJMS

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“…Similarly, in an orthotopic model of breast cancer treated with the monoclonal antibodies 10C11 and 2H6 targeting NCSTN, no histological evidence of goblet cell hyperplasia was detected, while these effects were evident in a GSI-treated arm [ 222 ]. Unfortunately, the therapeutic index of emerging NCSTN small molecule inhibitors, such as cowanin, for wild-type vs. mutant has not been tested yet [ 223 ]. Nevertheless, these encouraging results suggest that the selective disruption of members of the γ-secretase complex may preferentially affect mutated proteins, overcoming the innate limitations associated with pan γ-secretase inhibition.…”

Section: Discussionmentioning

confidence: 99%

Targeting Notch Trafficking and Processing in Cancers

Pagliaro

Sissi

Roti

2020

Cells

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The Notch family comprises a group of four ligand-dependent receptors that control evolutionarily conserved developmental and homeostatic processes and transmit signals to the microenvironment. NOTCH undergoes remodeling, maturation, and trafficking in a series of post-translational events, including glycosylation, ubiquitination, and endocytosis. The regulatory modifications occurring in the endoplasmic reticulum/Golgi precede the intramembrane γ-secretase proteolysis and the transfer of active NOTCH to the nucleus. Hence, NOTCH proteins coexist in different subcellular compartments and undergo continuous relocation. Various factors, including ion concentration, enzymatic activity, and co-regulatory elements control Notch trafficking. Interfering with these regulatory mechanisms represents an innovative therapeutic way to bar oncogenic Notch signaling. In this review, we briefly summarize the role of Notch signaling in cancer and describe the protein modifications required for NOTCH to relocate across different subcellular compartments. We focus on the functional relationship between these modifications and the corresponding therapeutic options, and our findings could support the development of trafficking modulators as a potential alternative to the well-known γ-secretase inhibitors.

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“…Although many studies have considered the viability effects of secondary metabolites from Garcinia cowa on cancer cell lines [ 40 , 41 , 80 , 83 , 84 ], none has investigated the biological activity from the endophytes isolated from Garcinia cowa leaves. Few reports reveal the biological activity of Phyllosticta ampelicida/Guignardia bidwellii metabolites from other host plants [ 85 ].…”

Section: Discussionmentioning

confidence: 99%

DNA Repair Biosensor-Identified DNA Damage Activities of Endophyte Extracts from Garcinia cowa

et al. 2020

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Recent developments in chemotherapy focus on target-specific mechanisms, which occur only in cancer cells and minimize the effects on normal cells. DNA damage and repair pathways are a promising target in the treatment of cancer. In order to identify novel compounds targeting DNA repair pathways, two key proteins, 53BP1 and RAD54L, were tagged with fluorescent proteins as indicators for two major double strand break (DSB) repair pathways: non-homologous end-joining (NHEJ) and homologous recombination (HR). The engineered biosensor cells exhibited the same DNA repair properties as the wild type. The biosensor cells were further used to investigate the DNA repair activities of natural biological compounds. An extract from Phyllosticta sp., the endophyte isolated from the medicinal plant Garcinia cowa Roxb. ex Choisy, was tested. The results showed that the crude extract induced DSB, as demonstrated by the increase in the DNA DSB marker γH2AX. The damaged DNA appeared to be repaired through NHEJ, as the 53BP1 focus formation in the treated fraction was higher than in the control group. In conclusion, DNA repair-based biosensors are useful for the preliminary screening of crude extracts and biological compounds for the identification of potential targeted therapeutic drugs.

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The Notch inhibitor cowanin accelerates nicastrin degradation

Cited by 20 publications

References 34 publications

Oleandrin and Its Derivative Odoroside A, Both Cardiac Glycosides, Exhibit Anticancer Effects by Inhibiting Invasion via Suppressing the STAT-3 Signaling Pathway

Oleandrin and Its Derivative Odoroside A, Both Cardiac Glycosides, Exhibit Anticancer Effects by Inhibiting Invasion via Suppressing the STAT-3 Signaling Pathway

Targeting Notch Trafficking and Processing in Cancers

DNA Repair Biosensor-Identified DNA Damage Activities of Endophyte Extracts from Garcinia cowa

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