Salvianolic acid B suppresses cell proliferation and induces apoptosis in osteosarcoma through p38-mediated reactive oxygen species generation

Abstract

Abstract. The present study aimed to investigate the potential anticancer effect and mechanisms of salvianolic acid B on osteosarcoma. Salvianolic acid B suppressed osteosarcoma cell proliferation and induced apoptosis in the osteosarcoma MG63 cell line, and activated the expressions of cleaved caspase-3, phosphorylated-tumor protein (p)38 mitogen-activated protein kinase (p-p38 MAPK) and phosphorylated-p53 (p-p53) proteins in the MG63 cells. Additionally, Salvianolic acid B also increased the level of reactive oxygen species (ROS) generation in the MG63 cells. The silencing of p38 expression inhibited the anticancer effect of salvianolic acid B on the levels of cell proliferation, p-p53 protein expression and ROS generation level in the MG63 cells. All these data supported the hypothesis that the anticancer effect of salvianolic acid B includes the suppression of cell proliferation and induces apoptosis in MG63 cells, and that p38 is important in the anticancer effect of salvianolic acid B on osteosarcoma cells due to the direct regulation of ROS generation. These data suggest that salvianolic acid B is important in the proliferation of osteosarcoma cells due to the direct regulation of p38-mediated ROS signaling. IntroductionOsteosarcoma is a type of primary malignant tumor that exhibits the highest morbidity of all neoplasms in the human skeletal system, and often presents in the metaphysis of the long tubal bones (1). Osteosarcoma often affects young people between the age of 20 and 30 years old. The mortality rate is high (2) and ~20% of patients exhibit pulmonary metastasis prior to diagnosis. Subsequent to diagnosis, the majority of patients succumb to the disease within 2 years (2). At present, there are no effective therapeutic treatments for early osteosarcoma (3). Therefore, it is important to investigate the causes of osteosarcoma occurrence, development and invasion, the mechanisms of osteosarcoma oncogenesis, and to identify effective diagnostic and therapeutic techniques. The development of gene therapy has created novel research targets in oncotherapy, including the identification of a target gene (4).Mitogen-activated protein kinase (MAPK) is the one of the most important types of signal conduction pathway in humans, and interacts with multiple signaling pathways (5). The tumor protein (p)38 MAPK pathway is activated through phosphotyrosine and threonine and inflammatory and growth factors, and activates downstream transcription factors on target genes, increases the initiation of cancer cell development, promotes protein synthesis, regulates cell surface receptors and regulates the invasion and transfer of tumor cells (6).Reactive oxygen species (ROS) are secondary products in the process of aerobic metabolism and include oxygen ions, peroxide and oxygen radical molecules (7). The increase in the level of intracellular ROS may promote cellular proliferation and differentiation to some extent. However, excessive levels of ROS results in damage to lipids, proteins and DNA, destroying numerous nor...

JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models

“…www.science.org/doi/10.1126/scitranslmed.abb3312 Materials and Methods Figs. S1 to S10 Tables S1 to S3 Data file S1 References (56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67) View/request a protocol for this paper from Bio-protocol.…”

Pharmacological Effects of Salvianolic Acid B Against Oxidative Damage

“…For cancer cells, Sal B has the opposite effect on regulating cell apoptosis. Previous studies in vitro have shown that Sal B can not only inhibit the proliferation and induce apoptosis of osteosarcoma cells by promoting the p38-MAPK pathway to mediate ROS production (Zeng et al, 2018), but also promote the autophagy of colorectal cancer cells and hepatocellular carcinoma cells by inhibiting the Akt/mTOR signaling pathway (Gong et al, 2016;Jing et al, 2016). Since mitochondria are both the main source of ROS and the site of cellular energy metabolism, cell types with abnormal energy metabolism such as cancer cells may have higher levels of ROS to maintain a high proliferation rate.…”

“…Therefore, the anti-inflammatory effect of Sal B may be mediated by its regulation of Nrf2/Keap1. Several studies have shown that Sal B can inhibit the expressions of TNF-α, IL-1β, IL-6 and other pro-inflammatory factors in a variety of diseases to exert a good anti-inflammatory effect, and its mechanisms mainly involve the TNF-α/NF-κB signaling pathway and TLR pathway ( Zeng et al, 2015 ; Zhang et al, 2015 ; Xu et al, 2017 ) ( Table 1 ; Figure 5 ). Most studies involve the protective effect of Sal B in neuroinflammation, and middle cerebral artery occlusion (MCAO) is obviously a commonly used model for rat brain I/R injury, which may be more suitable for the pathological state of human cerebral ischemia.…”

Salvianolic Acid B Improves Postresuscitation Myocardial and Cerebral Outcomes in a Murine Model of Cardiac Arrest: Involvement of Nrf2 Signaling Pathway

“…Previous studies have suggested that mitigating ROS production by administration of antioxidants such as vitamin C following ROSC was able to reduce myocardial injury, resulting in improved postresuscitation myocardial function [43,44]. Because oxidative stress is causatively [48][49][50]. Thus, the role of Sal B in inhibiting or promoting oxidative stress may be dependent on cell and tissue type.…”

“…The involvement of Sal B in regulating oxidative stress has been reported in several cell types; interestingly, Sal B had antioxidant effects in several cell types, but oxidative effects in others. For example, Sal B inhibited oxidative stress in endothelial cells, smooth muscle cells, and Schwann cells [ 45 – 47 ], but facilitated oxidative stress in some tumor cells, such as glioma, osteosarcoma, and colorectal carcinomas [ 48 – 50 ]. Thus, the role of Sal B in inhibiting or promoting oxidative stress may be dependent on cell and tissue type.…”