The Antioxidant from Ethanolic Extract of Rosa cymosa Fruits Activates Phosphatase and Tensin Homolog In Vitro and In Vivo: A New Insight on Its Antileukemic Effect

Abstract

Rosa cymosa Tratt is a Chinese herbal remedy that is used in the treatment of diarrhea, burns, rheumatoid arthritis, and hemorrhage. Despite its use in Asian folk medicine, there are limited reports on the biological activity of R. cymosa fruits. This study focused on the investigation of the antitumor effect of the antioxidative ethanolic extract of R. cymosa fruits (RCE) along with its underlying mechanism of action. RCE showed a potent cytotoxic effect against Sup-T1 and Molt-4 lymphoblastic leukemia cells. In the xenograft animal model, the tumor size was significantly reduced to about 59.42% in the RCE-treated group in comparison with the control group. The use of RCE (37.5, 75, or 150 μg/mL) triggered apoptosis by 26.52–83.49%, disrupted mitochondrial membrane potential (MMP) by 10.44–58.60%, and promoted calcium release by 1.29-, 1.44-, and 1.71-fold compared with the control group. The extract induced redox oxygen species (ROS) generation through the elimination of Nrf2/Keap1/P62-mediated oxidative stress response. The loss of phosphatase and tensin homolog (PTEN) activation by RCE impaired PI3K/Akt/Foxo and Jak/Stat activation pathways, which contributed to tumorigenesis. These multiple targets of R. cymosa against hematologic cancer cells suggested its potential application as an antileukemic dietary supplement.

Targeting Nrf2-Mediated Oxidative Stress Response Signaling Pathways as New Therapeutic Strategy for Pituitary Adenomas

“…Multiple in vivo and in vitro environmental factors, including inflammatory cytokines, prostaglandins, growth factors, low-density lipoproteins, bacterial and viral infection, heavy metals, ultraviolet (UV) radiation, ionizing radiation, drugs, xenobiotics, antioxidants, oxidants, and chemopreventive agents, cause the increased upload of free radicals ROS/RNS and electrophiles to result in oxidative stress ( Hetland et al, 2020 ; Mehnati et al, 2020 ). The increased ROS or electrophiles will activate the Nrf2/Keap1 complex in the cytoplasm through ERK1/2, ERK5, JNK1/2, p38 MAPK, PKC, and PI3K-AKT signaling pathways, and these signaling pathways will communicate with each other ( Roy Chowdhury et al, 2014 ; Tian et al, 2014 ; Wang K.-C. et al, 2019 ). The activated Nrf2 is phosphorylated and separated from Keap1 ( Hambright et al, 2015 ; Sánchez-Martín et al, 2020 ).…”

Regulatory function of peroxiredoxin I on 4‑(methylnitrosamino)‑1‑(3‑pyridyl)‑1‑butanone‑induced lung cancer development (Review)

“…Additionally, Prdx1 inhibits the oxidative stress-induced PI3K/AKT signaling pathway by eliminating ROS. It is known that the ROS-induced activation of PI3K/AKT is due to the oxidative inactivation of phosphatase and tensin homolog (PTEN) protein ( 99 ). Furthermore, Prdx1 protects PTEN lipid phosphatase activity from oxidative inactivation, thereby preventing AKT from driving tumor cell proliferation and inducing apoptosis ( 26 ).…”

The Tumor Suppressor PTEN as Molecular Switch Node Regulating Cell Metabolism and Autophagy: Implications in Immune System and Tumor Microenvironment

“…Since PTEN overexpression is associated with cancer protection, this increase in ROS levels is not sufficient to exert relevant effects on DNA. Besides, it should be evidenced that PTEN induces the transcription of genes mediating antioxidant activity through the Forkhead box O (FOXO)3 transcription factors [60].…”