A novel protoapigenone analog RY10-4 induces apoptosis of breast cancer cells by exacerbating mitochondrial Ca2+ influx through mitochondrial calcium uniporter

3区 · 医学

Article

作者: Ren, Xiuhua ; Xue, Pingping ; Liu, Dong ; Chen, Qian ; Yang, Xiaofan

RY10-4, a novel protoapigenone analog with a specific nonaromatic B-ring, displayed enhanced cytotoxicity in various tumor cells, especially for breast cancer cells, but the underlying mechanism remains unclear. In the present study, we confirmed the pro-apoptotic effect of RY10-4 on breast cancer cells. Furthermore, mitochondrial calcium uniporter (MCU) was proved to be up-regulated in RY10-4-treated MDA-MB-231 cells, which resulted in the overload of mitochondrial calcium ([Ca²⁺]m) and subsequently disrupted mitochondrial functions (characterized by mitochondrial reactive oxygen species (mtROS) accumulation, membrane potential (ΔΨm) depolarization and permeability transition pore (mPTP) opening). And finally, the mitochondrial apoptosis was activated by the release of cytochrome C. Interestingly, knockdown of MCU attenuated the overload of [Ca²⁺]m and blocked the apoptosis of MDA-MB-231 cells induced by RY10-4, which was consistent with the in vivo results. Taken together, this study proved that RY10-4 could induce apoptosis of breast cancer cells by elevating [Ca²⁺]m through MCU. Our work contributed previously unknown insights into the mechanisms involving in the clinical efficacy of RY10-4 on breast cancer cells, which also advanced calcium homeostasis as a potential target for chemotherapeutic drugs.

2017-12-01·Chemico-Biological Interactions2区 · 医学

Anti-tumor compound RY10-4 suppresses multidrug resistance in MCF-7/ADR cells by inhibiting PI3K/Akt/NF-κB signaling

2区 · 医学

Article

作者: Xiao, Miao ; Xue, Pingping ; Ruan, Jinlan ; Yang, Xiaofan ; Ding, Yufeng ; Liu, Xin

RY10-4, an anti-tumor agent, exerts cytotoxicity to various human cancer cell lines. However, few studies reported the effect of combined application of RY10-4 and chemotherapeutic drugs against cancer cells with multidrug resistance (MDR). In this study, P-glycoprotein (P-gp), which is reported to mediate MDR to anti-cancer drugs, was proved to be overexpressed in the adriamycin (ADR)-resistant human breast cancer cells, namely MCF-7/ADR cells. Furthermore, RY10-4 application resulted in a downregulation of P-gp in MCF-7/ADR cells, thus leading to higher chemosensitivity to ADR. Our study further demonstrated that the MDR phenomenon was under the control of the PI3K/Akt/NF-κB pathway, which was suppressed by RY10-4, leading to MDR reversal effects in MCF-7/ADR cells. In vivo, MCF-7/ADR cells were effectively suppressed by the combined ADR/RY10-4 treatment compared with the ADR-alone treatment. Taken together, these results demonstrated that RY10-4 reverses the MDR phenotype in MCF-7/ADR cells by suppressing the PI3K/Akt/NF-κB pathway.

2016-01-26·Oncotarget

Combination therapy of RY10-4 with the γ-secretase inhibitor DAPT shows promise in treating HER2-amplified breast cancer

Article

作者: Yuan, Qianying ; Zhu, Shilin ; Muftuoglu, Yagmur ; Su, Feng ; Ruan, Jinlan ; Zhang, Longbo

RY10-4, a novel protoapigenone analog, shows potent cytotoxicity against human breast cancer cells. However, breast cancer cell lines overexpressing human epidermal growth factor receptor 2 (HER2), SKBR3 and BT474, showed less sensitivity to RY10-4 when compared to breast cancer cells lines expressing lower levels of HER2, such as MDA-MB-231 and MCF-7 cells. This was associated with aberrant hyperactivity in Notch signaling in cells treated with RY10-4, since treatment with RY10-4 causes an increase in Notch activity by 2-to3.5-fold in SKBR3 and BT474 cell lines. The increase in activity was abrogated with a γ-secretase inhibitor, DAPT, or with Notch1 small-interfering RNA (si-Notch1). Cell proliferation was inhibited more effectively by RY10-4 plus DAPT or si-Notch1 than either agent alone. RY10-4 plus DAPT increases apoptosis in both HER2-overexpressing cell lines by two-fold compared to RY10-4 alone, while DAPT alone has no significant effects on apoptosis. In addition, we previously found RY10-4 could inhibit tumor growth through the PI3K/AKT pathway. Here we report that the combination of RY10-4 and DAPT exhibit additive suppression on AKT phosphorylation, contributing to the anti-cancer effects. In an animal model, this combination therapy inhibits the growth of SKBR3 tumor xenografts in nude mice to a greater extent than treatment with either reagent alone. These results indicate that the aberrant activation of Notch signaling impedes the inhibitory effect of RY10-4 on HER2-amplified cell proliferation. Furthermore, these adverse effects can be prevented by treatment combining RY10-4 with a Notch pathway inhibitor.

项与 NG-101(Reyonpharm) 相关的新闻（医药）

2024-10-16

·GlobeNewswire-Health Care

Neurogastrx Announces Positive Proof-of-Concept Data for Investigational Drug NG101 in Reducing Nausea and Vomiting Associated with the Administration of GLP-1 Agonist Medication

NG101 Significantly Reduced Incidence of Nausea by 40% and Frequency of Vomiting by 56% without Changing the Safety Profile of the GLP-1 AgonistWOBURN, Mass., Oct. 16, 2024 (GLOBE NEWSWIRE) -- Neurogastrx, Inc. today announced positive topline results from a new study of NG101 (metopimazine mesylate) showing significant reduction of nausea and vomiting side effects caused by a glucagon-like peptide 1 (GLP-1) agonist medication. NG101 is an oral, peripherally restricted dopamine D2 receptor antagonist. “The randomized, double-blind, placebo-controlled proof-of-concept (POC) safety and efficacy study showed positive effects of NG101 in participants who received double the starting dose of the GLP-1 agonist semaglutide,” said Cyril De Colle, Ph.D., Chief Scientific Officer, Neurogastrx. “Findings from this study suggest NG101 could be an important addition to GLP-1 agonist therapy, helping more patients adhere to treatment as they transition to the higher doses needed to reach weight loss and broader health goals.” Key efficacy endpoints showed NG101 significantly: Reduced the incidence of nausea by 40% (p=0.0343)Reduced the frequency of vomiting by 56% (p=0.0412) NG101 also significantly reduced both the duration of nausea (p=0.0101) and the participant-reported severity of nausea (p=0.0225). The addition of NG101 to semaglutide dosing was not associated with any new safety findings, including the incidence of other common adverse events (AEs) such as diarrhea or constipation. There were no serious AEs and no discontinuations due to treatment emergent adverse events (TEAEs) in the study. Gastrointestinal (GI) adverse events, especially nausea and vomiting, are the primary challenge to titration and adherence of GLP-1 therapy. A recent real-world adherence study utilizing an IQVIA database followed over 160,000 new semaglutide weight loss patients and showed a 50% discontinuation rate at six months and 70% at one year. “Our POC study offers hope to patients who cannot tolerate these medicines long enough to realize their benefits,” said James O’Mara, President and Chief Executive Officer, Neurogastrx. “We look forward to discussions with the FDA to initiate a larger Phase 2/3 study in 2025, with the goal to bring this product to patients.” Study Design A total of 90 participants aged 18-55 received a single subcutaneous dose of semaglutide (0.5 mg) along with five days of NG101 20 mg twice per day (BID) or placebo. The study evaluated the efficacy of NG101 in reducing the incidence, duration and severity of nausea and vomiting. Efficacy endpoints included: Number of days with TEAEs of nausea and/or vomiting within four days (96 hours) following a single subcutaneous GLP-1 agonist injection.Moderate and/or severe TEAEs of nausea and/or vomiting within four days (96 hours) following a single subcutaneous GLP-1 agonist injection (as graded by the principal investigator or designee).TEAEs of nausea and/or vomiting within four days (96 hours) following a single subcutaneous GLP-1 agonist injection. The study also evaluated the safety of NG101 (20 mg BID) in participants receiving a single subcutaneous injection of the GLP-1 agonist. Primary safety endpoints included incidence and severity of TEAEs (other than nausea and vomiting), and standard laboratory assessments. For more details, go to www.clinicaltrials.gov, NCT006500429. About Neurogastrx, Inc. Neurogastrx, Inc. is a privately held specialty pharmaceutical company developing transformative therapies to advance the treatment of GI disorders for which meaningful therapeutic innovation is required to satisfy unmet patient need and disease burden. Media ContactAmanda BreedingScient PRamanda@scientpr.com

临床结果

2024-10-16

·EndPoints

Seeking to treat obesity drug side effect, Neurogastrx releases data on drug for GLP-1-associated nausea, vomiting

Neurogastrx believes its drug could treat one of the most troublesome side effects of one of the industry’s biggest blockbusters. On Wednesday, the Boston-area biotech said that its experimental drug, NG101, reduced the incidence of nausea by 40% and cut vomiting by 56% in adults taking Novo Nordisk’s semaglutide, which is marketed as Wegovy for obesity and Ozempic for type 2 diabetes. In the Phase 2 trial, about 90 adults received a single subcutaneous dose of semaglutide, at 0.5 mg, and then for five days, they took two capsules of NG101 or placebo each day. The results were statistically significant. Neurogastrx sees a market opportunity worth “billions of dollars,” CEO James O’Mara told Endpoints News. “The GLP-1s are miracle drugs,” O’Mara said. But many patients stop taking the medicines within a year, and a lot of them cite the gastrointestinal side effects as a key reason, he said. The news is Neurogastrx’s first major step since 2021, when it outlined a $60 million Series B and unveiled a partnership with Daewoong Pharmaceutical, which it then terminated in mid-2023. NG101 is a dopamine D2 antagonist, and it affects the area postrema, or the “nausea center of the brain,” O’Mara said. That region is outside the blood-brain barrier, meaning it might allow the medicine to avoid CNS side effects that come with some other dopamine modulators, the CEO said. Neurogastrx will have to test NG101 in larger studies and for a longer duration before seeking regulatory approval, and the company aims to start either a Phase 2 or a Phase 2/3 trial next year, the CEO said. “Whether it’s registrational, we’ll have to see,” O’Mara said. A Phase 3 would likely involve both semaglutide and Eli Lilly’s related drug tirzepatide. “I think you would have to include both eventually in order to get them in the label,” O’Mara said. The company thinks it can raise the money it needs to get into later-stage testing, O’Mara said, noting Neurogastrx is starting discussions with potential partners and funding sources. In February 2023, Neurogastrx completed a Phase 2 of NG101 in patients with gastroparesis, in which the body struggles to empty food, but the company has yet to announce the results. O’Mara said the results have been submitted for publication and described the data as “interesting.” “We had endpoints which looked good and others which we were disappointed in,” he said. In May, another biotech in the space, CinDome Pharma, announced a $40 million funding extension to finish its Phase 2 in diabetic gastroparesis. It anticipates results next year and will likely seek a pharma partner or acquirer to bring it into Phase 3, CinDome creator CinRx CEO Jon Isaacsohn told Endpoints in May . O’Mara also gave more details of the company’s terminated pact with South Korea’s Daewoong. Under the deal, Neurogastrx was to have developed Daewoong’s investigational acid blocker fexuprazan for GERD and other acid-related conditions. The US and Canada-focused agreement was terminated last year. “We did a deal for fexuprazan when there was a lot of money flowing into biotech, and very shortly, frankly, after we closed that deal, it was just harder to raise capital,” O’Mara said. “We wanted to be fair with our collaborator and give them the opportunity to find another company that could better escort the drug forward.”

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