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1.
Introduction
Betulinic acid (BA) is a lupane-type pentacyclic triterpenoid saponin (3β-hydroxy-lup-20 (29)-en-28-oic acid; MW, 456.71; Fig. 1), which exists in the bark of a variety of natural plants, principally in Betula. It has been investigated extensively in previous decades due to its beneficial properties, including anticancer, anti-inflammatory, anti-angiogenic, and immunomodulatory effects, its anthelmintic activity and its anti-human immunodeficiency virus effects. Its antitumor effects are higher at a reduced pH (<6.8), a characteristic of several types of tumor (1–3).
In previous decades, BA has been shown to have a marked antitumor therapeutic effect in melanoma cells and several types of solid tumor, including glioblastoma (4), lung carcinoma (5), breast carcinoma (6), colorectal carcinoma (7) and prostate carcinoma (8). In addition, the antitumor effects on hematological malignancies have been investigated in our previous studies and in those of others in previous years (1,9–11).
The reported primary mechanisms of the anticancer effects of BA treatment are shown in Fig. 2 and described below.
Promotion of apoptosis by activation of the mitochondrial pathway
BA improves the level of reactive oxygen species (ROS) production and alters the mitochondrial membrane potential gradient, followed by the release of cytochrome c (Cyt c), which causes the mitochondrial-mediated apoptosis of tumor cells via a caspase-dependent mechanism and apoptosis inducing factor (1,12,13). It has been demonstrated that there is a link between ROS and the p38 and stress-activated protein (SAP) kinase/c-Jun N-terminal kinase (JNK) in melanoma cells. This indicates that ROS act upstream of the mitogen-activated protein kinases (MAPKs) in the signaling pathway of BA (14). In addition, autophagy has been shown to occur downstream of the mitochondrial damage induced by BA (15).
Regulation of cell cycle and the angiogenic pathway via specificity protein (Sp) transcription factors, cyclin D1 and epidermal growth factor receptor (EGFR)
BA can inhibit cancer cell growth and proliferation via cell cycle arrest. Drugs, including BA, can inhibit the protein expression of Sp1, Sp2 and Sp4 through the microRNA (miR)-27a-ZBTB10-Sp1 axis and slow down the aggressiveness of the tumor (16–19).
Inhibition of the signal transducer and activator of transcription 3 (STAT3) and nuclear factor (NF)-κB signaling pathways
BA can downregulate the activation of STAT3 through the upregulation of Src homology 2 domain-containing phosphatase 1 (SHP-1), and affect the...