Silibinin induces G1 arrest, apoptosis and JNK/SAPK upregulation in SW1990 human pancreatic cancer cells

Abstract

The aim of the present study was to investigate the inhibitory effect of silibinin on SW1990 pancreatic cancer cells. An MTT assay following silibinin treatment demonstrated an inhibitory effect on AsPC-1 and SW1990 cells in a dose- and time-dependent manner. Propidium iodide staining analysis identified the cell cycle arrest of G1 phase and western blotting analysis demonstrated that the expression levels of cyclin D1, cyclin E2, cyclin A and cyclin B1 were decreased. The expression of G1-associated cell cycle-dependent kinases, cyclin-dependent kinase (CDK)4 and CDK6, were also decreased, whereas the expression of p15 (p15INK4B) was increased. In addition, after SW1990 cells were incubated with various concentrations of silibinin, early and late apoptotic cells were detected using flow cytometry. Silibinin increased the activities of caspase-9 and caspase-3, and subsequent cleavage of poly (ADP-ribose) polymerase (PARP) was also observed. The expression levels of B-cell lymphoma (Bcl)-2, Bcl-2-like 1 and myeloid cell leukemia 1 were decreased, whereas the expression of Bcl-like protein 4 did not alter and the expression levels of Bcl-2-like 1 small and Bcl-2-like protein 11 were increased. The expression levels of c-Jun N-terminal kinase (JNK) and phospho-JNK were also increased. In conclusion, silibinin inhibited cell proliferation, induced cell cycle G1 arrest via upregulating p15INK4B and induced mitochondrial apoptosis via upregulating JNK/stress-activated protein kinase (SAPK) signaling pathway in human pancreatic cancer SW1990 cells.

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Silibinin exhibits anti-cancer activities mainly due to the cell cycle arrest [330,[338][339][340][341]. It induces G1 phase arrest in human pancreatic cancer SW1990 and AsPC-1, and breast cancer MCF-7 and MCF-10A cells [330,339,340], whilst it causes G2 phase arrest in human cervical cancer HeLa, and gastric cancer MGC-803 and SGC-7901 cells [338,341]. It also decreases the expressions of CDKs such as CDK1, CDK2, CDK4 and CDK6 that are involved in G1 and G2 progression [338,339].…”

“…It induces G1 phase arrest in human pancreatic cancer SW1990 and AsPC-1, and breast cancer MCF-7 and MCF-10A cells [330,339,340], whilst it causes G2 phase arrest in human cervical cancer HeLa, and gastric cancer MGC-803 and SGC-7901 cells [338,341]. It also decreases the expressions of CDKs such as CDK1, CDK2, CDK4 and CDK6 that are involved in G1 and G2 progression [338,339]. Besides, silibinin suppresses metastasis through ERK1/2 and MMP-9 down-regulation in human thyroid cancer TPC-1, breast cancer MCF-7, renal carcinoma ACHN, OS-RC-2 and SW-839, and epidermoid carcinoma A-431 cells [342][343][344].…”

Natural Compounds and Derivatives as Ser/Thr Protein Kinase Modulators and Inhibitors

“…Silymarin, which is extracted from the seeds and fruits of the milk thistle Silybum marianum is a mixture of three structural isomers, silibinin, silidianin and silichristin. Silibinin induces cell cycle arrest in G1 phase, apoptosis and JNK/SAPK upregulation in SW1990 human pancreatic cancer cells [52]. Moreover, it was shown that combined treatment with sorafenib and silibinin synergistically targets both hepatocellular carcinoma cells and cancer stem cells by enhanced inhibition of the phosphorylation of STAT3/ERK/AKT [53].…”

Dual Effects of Silibinin on Human Pancreatic Cancer Cells

“…Firstly, silibinin induces apoptosis of pancreatic cancer cells through a multi-signal pathway. Silibinin induces apoptosis by activating c-Jun N-terminal kinases /Stress-activated protein kinases (JNK/SAPK) signaling in SW1990, a human pancreatic cancer cell line [15,16]. Furthermore, silibinin induces apoptosis by downregulating the glucagon-like peptide-1 receptor and protein kinase A (GLP-1R/PKA) signal pathway in cells of INS-1, a rat insulinoma cell line, with amylin [17].…”