Hedyotis diffusa Willd. extract suppresses proliferation and induces apoptosis via IL-6-inducible STAT3 pathway inactivation in human colorectal cancer cells

Abstract

Recent studies have indicated that the inflammatory microenvironment plays a significant role in colorectal cancer (CRC). The interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway mediates the proliferative and anti-apoptotic activities required for oncogenesis under inflammatory conditions; thus, suppressing tumor growth by targeting the IL-6/STAT3 pathway is a promising therapeutic strategy for CRC. Our previous study reported that the ethanol extract obtained from Hedyotis diffusa Willd. (EEHDW) can induce apoptosis, and inhibit the proliferation of colon cancer cells and tumor angiogenesis by modulating various signaling pathways; however, less is known regarding the activity of EEHDW in a cancer-promoting inflammatory environment. Therefore, the present study investigated whether EEHDW inhibits the growth of the CRC HT-29 cell line via the IL-6/STAT3 signaling pathway. Pretreatment of HT-29 cells with IL-6 led to an increase in cell viability, colony formation and phosphorylated STAT3 (p-STAT3) expression. Treatment of these cells with EEHDW prior to IL-6 stimulation resulted in a significant reduction in the IL-6-induced phosphorylation of STAT3. In addition, EEHDW treatment significantly reduced the mRNA expression levels of cyclin D1, cyclin-dependent kinase 4 and B-cell lymphoma-2 (Bcl-2), and upregulated the expression levels of Bcl-2-associated X protein (P<0.05), which are important target genes of the IL-6/STAT3 pathway. These findings strongly indicated that EEHDW suppresses tumor cell growth and induces the apoptosis of human CRC cells via inactivation of the IL-6/STAT3 signaling pathway.

The Hedyotis diffusa Willd. (Rubiaceae): A Review on Phytochemistry, Pharmacology, Quality Control and Pharmacokinetics

“…In vitro, ethanol extract of H. diffusa treatment significantly suppresses proliferation and induced apoptosis of HT-29 cells, resulting in DNA fragmentation, loss of plasma membrane asymmetry, collapse of mitochondrial membrane potential, activation of caspase-9 and caspase-3, increase of the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2, reduction of the mRNA expression levels of cyclin D1, cyclin-dependent kinase 4 and B-cell lymphoma-2 (Bcl-2), upregulation of the expression levels of Bcl-2-associated X protein, prevention of G1-S progression, and reduction of mRNA expression of pro-proliferative PCNA, Cyclin D1 and CDK4. These results indicated that the anti-colorectal cancer cells effect of H. diffusa might be carried out via multiple approaches, such as the mitochondria-dependent pathway, IL-6/STAT3 pathway and cell cycle arrest [2,[55][56][57][58]. The mechanism was also confirmed by animal experiments [58,59].…”

“…In our previous studies, the water extract of H. diffusa has been proved to have an obvious protective effect in lipopolysaccharide-induced renal inflammation in mice. Recently, H. diffusa has gained increasing attention for its properties of anti-proliferative activity in cancer cells and anti-tumor activity in tumor-bearing animals [2][3][4][5]. It has been proved as the most commonly prescribed single Chinese herb used for colon cancer and breast cancer patients [6,7], according to the statistics from the National Health Insurance Research Database of Taiwan.…”

Fuzheng Qingjie granules potentiate the anticancer effect of cyclophosphamide by regulating cellular immune function and inducing apoptosis in Hepatoma 22 tumor-bearing mice

“…IL-2 is able to enhance the antitumor efficacy of TNF-α, despite being less cytotoxic itself (32). In addition, Hedyotis diffusa Willd and Prunella vulgaris in FZQJ granules were reported to induce cell apoptosis via modulation of the IL-6/signal transducer and activator of transcription 3, MAPK and mitochondria-dependent signaling pathways (33,34). The present and previous studies indicated that FZQJ granules were able to induce H22 cell apoptosis via IL-6/stat 3, MAPK and mitochondria-dependent pathway as well as stimulating IL-2 and TNF-α production.…”

Selective Cytotoxicity and Apoptosis-Induction of Cyrtopodion scabrum Extract Against Digestive Cancer Cell Lines

“…Nowadays the use of traditional medicine (TM) for achieving useful drugs to treat variable diseases has become the focus of attention (8)(9)(10)(11). Two most powerful branches of TM are herbal therapy (12)(13)(14) and zoo therapy; the latter uses different parts of the animals' body and their products as drugs.…”