Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, and approximately one-third of CRC patients present with metastatic disease. Periplocymarin (PPM), a cardiac glycoside isolated from Periploca sepium, is a latent anticancer compound. The purpose of this study was to explore the effect of PPM on CRC cells. CRC cells were treated with PPM and cell viability was evaluated by CCK-8 assay. Flow cytometry and TUNEL staining were performed to assess cell cycle and apoptosis. Quantitative proteomics has been used to check the proteins differentially expressed by using tandem mass tag (TMT) labeling and liquid chromatography–tandem mass spectrometry. Bioinformatic analysis was undertaken to identify the biological processes that these differentially expressed proteins are involved in. Gene expression was analyzed by western blotting. The effect of PPM in vivo was primarily checked in a subcutaneous xenograft mouse model of CRC, and the gene expression of tumor was checked by histochemistry staining. PPM could inhibit the proliferation of CRC cells in a dose-dependent manner, induce cell apoptosis and promote G0/G1 cell cycle arrest. A total of 539 proteins were identified differentially expressed following PPM treatment, where among those there were 286 genes upregulated and 293 downregulated. PPM treatment caused a pro-apoptosis gene expression profile both in vivo and in vitro, and impaired PI3K/AKT signaling pathway might be involved. In addition, PPM treatment caused less detrimental effects on blood cell, hepatic and renal function in mice, and the anti-cancer effect was found exaggerated by PPM+5-FU combination treatment. PPM may perform anti-CRC effects by promoting cell apoptosis and this might be achieved by targeting PI3K/AKT pathway. PPM might be a safe and promising anti-cancer drug that needs to be further studied.
Highlights
Global cancer statistics for 2020 showed that colorectal cancer (CRC) ranks third in terms of cancer incidence, but second in terms of cancer mortality, where more than 1.9 million new Colorectal cancer (CRC) cases and 935,000 deaths were estimated to occur worldwide [1]
The results showed that, the viability of HCT 116, RKO, HT-29, and SW480 cells were inhibited by PPM in a dose- and time-dependent manner (P
To clarify the effect of PPM on the apoptosis of CRC cells, HCT 116 and RKO cells were treated with different concentration of PPM for 24 h, and the number of apoptotic cells was detected by flow cytometry
Summary
Global cancer statistics for 2020 showed that colorectal cancer (CRC) ranks third in terms of cancer incidence, but second in terms of cancer mortality, where more than 1.9 million new CRC cases and 935,000 deaths were estimated to occur worldwide [1]. The prognosis for patients with metastatic CRC remains poor, with a median five-year survival of CRC in 2012–2015 just 56.9% in China [4]. Chemotherapeutic agents such as FOLFOX, the main therapy strategy for CRC patients, are effective but combined with unwanted toxicity and side effects [5]. Previous studies have indicated that, PPM performed antitumor effects in various of cancer [8, 9]. We have investigated the effect of PPM on CRC, to provide more candidate drugs for CRC patients and prolong their lives
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