β-Elemene Reverses the Resistance of p53-Deficient Colorectal Cancer Cells to 5-Fluorouracil by Inducing Pro-death Autophagy and Cyclin D3-Dependent Cycle Arrest

Abstract

Objective: Colorectal cancer is a malignant tumor of the digestive system with high morbidity and mortality. 5-fluorouracil remains a widely used chemotherapeutic drug in the treatment of advanced colorectal cancer, but chemotherapy drugs are prone to develop drug resistance, p53 deletion or mutation is an important reason for the resistance of colorectal cancer cells to 5-fluorouracil. β-elemene has been proved to have the potential of reverse chemotherapy drug resistance, but the mechanism is unknown. This study aimed to investigate the effect of β-elemene to 5-fluorouracil in drug-resistant p53-deficient colorectal cancer cells HCT116p53 −/− , and determine the possible molecular mechanism of β-elemene to reverse 5-fluorouracil resistance. Methods: The effect of β-elemene on HCT116p53 −/− cell activity was detected by Cell counting Kit-8. Cell proliferation was detected by monoclonal plate. The apoptosis was detected by flow cytometry and western blot. The autophagy was detected by western blot, immunofluorescence and transmission electron microscope. Determine the role of Cyclin-related protein Cyclin D3 in β-elemene reversing the resistance of HCT116p53 −/− to 5-fluorouracil was detected by overexpression of Cyclin D3. The effect of β-elemene on the tumorigenic ability of p53-deficient colorectal cancer cells was detected establishing HCT116p53 −/− all line xenograft model. Results: For p53 wildtype colorectal cancer cells, β-elemene could augment the sensitivity of 5-fluorouracil, for p53-deficient colorectal cancer cells, β-elemene significantly inhibited cell proliferation in a concentration-dependent manner, and

β-elemene enhances the antitumor activity of erlotinib by inducing apoptosis through AMPK and MAPK pathways in TKI-resistant H1975 lung cancer cells

“…In China, Chinese medicines and their active ingredients have been widely used to treat lung cancer including TKI-resistant NSCLC 18 , 41 - 45 , and some of them have shown a synergistic inhibitory effect and lower TKIs resistance in EGFR L858R+T790M-Mutated H1975 Cells 18 , 32 - 35 . β-elemene is one of these bioactive compounds and has been used to treat various cancers and has shown satisfactory efficacy with mild adverse effects 46 - 48 .…”

“…β-elemene, a bioactive compound extracted from Curcuma aromatica Salisb. ( Curcuma wenyujin Y.H.Chen & C.Ling) 16 , 17 , has been widely used as an antitumor agent to treat a variety of tumors including lung cancer, liver cancer, digestive tract cancer, and bladder cancer, etc., even the patients with TKI-resistant NSCLC can also benefit from the concurrent use of β-elemene with TKIs 18 - 21 , however, the effects of β-elemene on TKI-resistant lung cancer and the underlying mechanisms of action are largely unknown. To address these issues, we investigated the effects of β-elemene on EGFR L858R/T790M double mutation NCI-H1975 cells and the potential molecular mechanisms.…”

Anti-Tumor Drug Discovery Based on Natural Product β-Elemene: Anti-Tumor Mechanisms and Structural Modification

“…It has been reported that β-elemene could reverse chemoresistant human breast cancer cells (MCF-7/doxorubicin, MCF-7/adriacin, and MCF-7/docetaxel) associated with the inhibition of BCRP and P-gp transporter expression as well as the increased expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) [ 58 , 59 , 60 , 61 ]. Moreover, β-elemene was also found to reverse drug resistance through the mitochondrial apoptosis pathway in the cisplatin-resistant human lung adenocarcinoma A549/DDP cells and through inducing pro-death autophagy and arresting the cell cycle dependent on cyclin D3 in the 5-fluorouracil resistant human p53-deficient colorectal cancer lines HCT116p53 -/- [ 62 , 63 ].…”

Intraperitoneal Chemotherapy for Peritoneal Metastases: Technical Innovations, Preclinical and Clinical Advances and Future Perspectives

“…In 2020, Zhan et al demonstrated that β elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane), a natural product present in several plants, can reverse the resistance of the colorectal cancer cell line HCT116, which is deficient for p53 ( TP 53 mutated). More precisely, thanks to a HCT116p53 −/− xenograft model, intraperitoneal injections of β elemene plus 5-FU induced tumor volume inhibition, thus demonstrating thus reversion of the resistance of HCT116p53 −/− to 5-FU [ 85 ].…”