Roles of p38 and JNK protein kinase pathways activated by compound cantharidin capsules containing serum on proliferation inhibition and apoptosis of human gastric cancer cell line

Abstract

Abstract. The aim of the present study was to investigate the inhibitory effect of compound cantharides capsules (CCCs) on the viability and apoptosis of human gastric cancer cell lines, BGC-823 and SGC-7901, and to detect its regulation of gene expression levels, as well as its inhibition mechanisms. Each cell line was grouped into a control group, CCC serum group, 5-fluorouracil (5-FU) group, combination therapy group (CCC serum + 5-FU) and serum control group. Growth curves were measured and flow cytometry was used to detect cell apoptosis and cell viability. The mRNA expression level of proliferation-related C-MYC and p53 genes were assayed by reverse transcription-quantitative polymerase chain reaction. Protein phosphorylation levels of proliferating cell nuclear antigen, p38 mitogen-activated protein kinase, extracellular signal-related kinase 1/2, c-Jun N-terminal kinase (JNK) and IκB were assayed by western blotting. The combined CCC serum and 5-FU group exhibited a higher inhibition rate in both cell lines and CCC serum therapy demonstrated a similar effect to 5-FU treatment, as demonstrated in the MTT and cell growth assay. Combined therapy significantly decreased the C-MYC mRNA expression levels and increased p53 mRNA expression levels (P<0.05). Combined therapy of 5-FU and CCC was more significant compared with CCC serum or 5-FU only (P<0.05). P38 and JNK-related protein phosphorylation are involved in apoptosis initiated by CCC combined 5-FU therapy. Combined therapy was able to significantly inhibit human gastric cancer cell growth (P<0.05), and advance cell apoptosis compared with CCC serum only. CCC serum resulted in downregulation of the c-Myc gene and upregulation of the p53 gene. p38 and JNK-related protein phosphorylation is involved in the inhibition of cell viability and apoptosis of human gastric cancer cell lines. IntroductionIn the last 5 years, gastric cancer has become the most frequent cause of cancer-related fatality, making it the fifth most common cancer in the world, with approximately 952,000 new cases diagnosed in 2012 (1,2). In China, gastric cancer is one of the most common cancers and the incidence ranks third among all malignant tumors, after lung and liver cancer in men and after breast and lung cancer in women (3). Despite the fact that diagnostic and therapeutic approaches have advanced in the past decade, the prognosis is still unclear due to the high recurrence (4).5-fluorouracil (5-FU) is a chemotherapeutic agent that is currently the most widely used drug choice for the treatment of solid tumors, such as metastatic colorectal cancer and gastric cancer (5-8). Alternatively, Traditional Chinese Medicine (TCM) is a multi-channel, multi-layer and multi-target method for treating cancer as an alternative to surgery, radiotherapy, chemotherapy and biological therapy (9). TCM involves the use of complicated ingredients that may promote the inhibition and apoptosis of cancer cells (9). Compound cantharides capsules (CCC) are one of the most common TCMs that contain cantharidi...

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