The Notch Inhibitors Isolated from <i>Nerium indicum</i>

Arai, Midori A.; Akamine, Ryuta; Hayashi, Narumi; Koyano, Takashi; Kowithayakorn, Thaworn; Ishibashi, Masami

doi:10.1021/acs.jnatprod.7b01031

Cited by 15 publications

(5 citation statements)

References 29 publications

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“…Cardenolides (including oleandrin) are well characterized for their inhibitory activity towards Na + /K + -ATPase [ 34 , 35 , 36 , 37 , 38 ]. N. indicum (which can be considered as a synonym for N. oleander) was described as a Notch inhibitor [ 39 ], and N. oleander was found to target fibroblast growth factor 2, Wnt/β-catenin signaling, and the AKT/PI3K/mTOR pathway [ 40 , 41 , 42 , 43 ]. N. oleander and oleandrin were found to be inhibitors of the multidrug-resistance-conferring efflux pump P-glycoprotein in most, but not all, investigations [ 11 , 44 , 45 , 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Modes of Action of an Aqueous Nerium oleander Extract in Cancer Cells In Vitro and In Vivo

et al. 2023

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Cancer drug resistance remains a major obstacle in clinical oncology. As most anticancer drugs are of natural origin, we investigated the anticancer potential of a standardized cold-water leaf extract from Nerium oleander L., termed Breastin. The phytochemical characterization by nuclear magnetic resonance spectroscopy (NMR) and low- and high-resolution mass spectrometry revealed several monoglycosidic cardenolides as major constituents (adynerin, neritaloside, odoroside A, odoroside H, oleandrin, and vanderoside). Breastin inhibited the growth of 14 cell lines from hematopoietic tumors and 5 of 6 carcinomas. Remarkably, the cellular responsiveness of odoroside H and neritaloside was not correlated with all other classical drug resistance mechanisms, i.e., ATP-binding cassette transporters (ABCB1, ABCB5, ABCC1, ABCG2), oncogenes (EGFR, RAS), tumor suppressors (TP53, WT1), and others (GSTP1, HSP90, proliferation rate), in 59 tumor cell lines of the National Cancer Institute (NCI, USA), indicating that Breastin may indeed bypass drug resistance. COMPARE analyses with 153 anticancer agents in 74 tumor cell lines of the Oncotest panel revealed frequent correlations of Breastin with mitosis-inhibiting drugs. Using tubulin-GFP-transfected U2OS cells and confocal microscopy, it was found that the microtubule-disturbing effect of Breastin was comparable to that of the tubulin-depolymerizing drug paclitaxel. This result was verified by a tubulin polymerization assay in vitro and molecular docking in silico. Proteome profiling of 3171 proteins in the NCI panel revealed protein subsets whose expression significantly correlated with cellular responsiveness to odoroside H and neritaloside, indicating that protein expression profiles can be identified to predict the sensitivity or resistance of tumor cells to Breastin constituents. Breastin moderately inhibited breast cancer xenograft tumors in vivo. Remarkably, in contrast to what was observed with paclitaxel monotherapy, the combination of paclitaxel and Breastin prevented tumor relapse, indicating Breastin’s potential for drug combination regimens.

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Section: Discussionmentioning

confidence: 99%

Molecular Modes of Action of an Aqueous Nerium oleander Extract in Cancer Cells In Vitro and In Vivo

et al. 2023

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“…160 In a recent study, oleandrin (135) was found to inhibit the proliferation and invasion of human U2OS bone and SaOS-2 sapiens osteosarcoma cells by suppressing the Wnt/β-catenin signaling pathway, 161 and its cytotoxicity against HPB-ALL human T-cell leukemia cells was mediated by inhibition of the Notch signaling pathway. 162 Based on its potent antitumor efficacy, a standardized Nerium oleander plant-based botanical preparation, Anvirzel, containing the main cardiac glycoside oleandrin (135), polysaccharides, and proteins, has reached a cancer clinical trial, but this was withdrawn later in 2015, without any new trials on this formulation being reported thus far. 163 A major challenge for the development of cardiac glycosidelike anticancer drugs is their narrow therapeutic index.…”

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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“…Compounds 4 – 6 were isolated from leaves of Nerium indicum as Notch signaling inhibitors [16] . Oleandrin ( 4 ) was reported as a HIF‐1 inhibitor [17] .…”

Section: Resultsmentioning

confidence: 99%

Evaluation of Naturally Occurring HIF‐1 Inhibitors for Pulmonary Arterial Hypertension

et al. 2021

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Pulmonary arterial hypertension (PAH) is a rare and severe progressive disorder characterized by high pulmonary artery pressure. Chronic hypoxia causes a metabolic disorder and the Warburg effect in pulmonary arterial smooth muscle cells (PASMCs). Pyruvate dehydrogenase kinase 1 (PDK1) is a key enzyme in Warburg effect increased by hypoxia‐inducible factor (HIF‐1). We constructed a cell‐based luciferase assay system for HIF‐1 inhibitors. Using this system, six HIF‐1 inhibitors were identified. Among these inhibitors, the effect of tagitinin C (1) on PASMC was investigated. Tagitinin C (1) clearly decreased the amount of HIF‐1β and the HIF‐1 target PDK1. This result indicates that HIF‐1 inhibitors effectively decrease PDK1 activity, which is a cause of the metabolic disorder and Warburg effect observed in PASMCs. Identifying naturally occurring HIF‐1 inhibitors could provide novel insights into the development of PAH medications.

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The Notch Inhibitors Isolated from Nerium indicum

Cited by 15 publications

References 29 publications

Molecular Modes of Action of an Aqueous Nerium oleander Extract in Cancer Cells In Vitro and In Vivo

Molecular Modes of Action of an Aqueous Nerium oleander Extract in Cancer Cells In Vitro and In Vivo

Potential Anticancer Agents Characterized from Selected Tropical Plants

Evaluation of Naturally Occurring HIF‐1 Inhibitors for Pulmonary Arterial Hypertension

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