Anti-cancer effect of Rumex obtusifolius in combination with arginase/nitric oxide synthase inhibitors via downregulation of oxidative stress, inflammation, and polyamine synthesis

• Published in: The international journal of biochemistry & cell biology Vol. 158; p. 106396
• Main Authors: Ginovyan, Mikayel, Javrushyan, Hayarpi, Petrosyan, Gayane, Kusznierewicz, Barbara, Koss-Mikołajczyk, Izabela, Koziara, Zuzanna, Kuczyńska, Monika, Jakubek, Patrycja, Karapetyan, Anna, Sahakyan, Naira, Maloyan, Alina, Bartoszek, Agnieszka, Avtandilyan, Nikolay
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-05-2023
• Subjects: Animals; Antioxidant properties; Antioxidants - metabolism; Antioxidants - pharmacology; Arginase - metabolism; Arginine - metabolism; Breast cancer; Breast Neoplasms - drug therapy; Cancer treatment; Combination therapy; Down-Regulation; Female; Humans; Inflammation - drug therapy; L-arginine metabolic pathway; NG-Nitroarginine Methyl Ester - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase - metabolism; Oxidative Stress; Polyamines; Rats; Rumex - chemistry; Rumex - metabolism; Rumex obtusifolius; DRN; ILC; NO; eNOS; DMSO; Rumex obtusifolius; cGMP; IDC; nor-NOHA; TLC; MDA; MTT; Combination therapy; DR; SC; IDP; PC- G1; PLBC; iNOS; Antioxidant properties; CAA; L-NAME; DPPH; Cancer treatment; VEGF; L-arginine metabolic pathway; IP; DMBA; ADMA; AKT; IL-2; Breast cancer; TC; MMP; SCC; NOS; nNOS; ROS; RO; ABTS; DRL; TIMP
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2023.106396

Cancer continues to be a leading cause of death worldwide, making the development of new treatment methods crucial in the fight against it. With cancer incidence rates increasing worldwide, ongoing research must focus on identifying new and effective ways to prevent and treat the disease. The combination of herbal extracts with chemotherapeutic agents has gained much interest as a novel strategy to combat cancer. Rumex obtusifolius L. is a wild plant known for its medicinal properties and is widely distributed worldwide. Our preclinical evaluations suggested that R. obtusifolius seed extracts possessed cancer-inhibiting properties and we also evaluated the beneficial effects of the arginase inhibitor NG-hydroxy-nor-L-arginine and nitric oxide inhibitor NG-nitro-L-arginine methyl ester in the treatment of breast cancer. The current study aimed to combine these observations and evaluate the antioxidant and antitumor properties of R. obtusifolius extracts alone and in combination with the arginase and nitric oxide synthase inhibitors. Metabolic characterization of the plant extract using a liquid chromatography/high-resolution mass spectrometry advanced system revealed the presence of 240 phenolic compounds many of which possess anticancer properties, according to the literature. In vitro studies revealed a significant cytotoxic effect of the R. obtusifolius extracts on the human colon (HT29) and breast cancer (MCF-7) cell lines. Thus, a new treatment approach of combining R. obtusifolius bioactive phytochemicals with the arginase and nitric oxide synthase inhibitors NG-nitro-L-arginine methyl ester and/or NG-hydroxy-nor-L-arginine, respectively, was proposed and could potentially be an effective way to treat breast cancer. Indeed, these combinations showed immunostimulatory, antiproliferative, antioxidant, anti-inflammatory, and antiangiogenic properties in a rat breast cancer model.
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•The extract of Rumex obtusifolius possessed high antioxidant properties.•Based on the HPLC/MS data, R. obtusifolius seeds contain a variety and abundance of natural antioxidants and antitumor compounds.•R. obtusifolius possessed a remarkable cytotoxic effect on HT29 and MCF-7 cancer cell cultures and an antioxidant effect on HT29 cell culture.•The combination of R. obtusifolius extract with inhibitors of the L-arginine metabolic pathway presents anti-cancer effects in vivo.•Synergistic interactions have been found between R. obtusifolius extract and chemotherapeutic agents against the induced mammary tumor.