Promising Modulatory Effects of Cenicriviroc on the Progression of Mouse Colorectal Cancer through Inhibition of CCR2_CCL2 Signaling Pathway.

The study was designed to assay the efficacy of cenicriviroc (CVC) on the progression of mouse colorectal cancer by downregulation of CCR2_CCL2. In this study, CVC was used to inhibit the CCR2 receptor. Next, an MTT assay was performed to evaluate the cytotoxic effects of CVC on the CT26 cell line. CT26 cells were implanted subcutaneously in BALB/c mice. After tumor implantation, one group of animals received 20 mg/kg of CVC several times. The mRNA levels of CCR2, CCL2, VEGF, NF-κB, c-Myc, vimentin, and IL33 were determined in the CT26 cell line and then tumor tissues (after 21 days), by qRT-PCR. Protein levels of the above-mentioned targets were determined by western blot and ELISA. Flow cytometry was performed to assess the changes in apoptosis. Tumor growth inhibition was measured on the 1st, 7th, and 21st days after the first treatment. In both cell line and tumor cells treated with CVC, expression levels of the markers of our interest in mRNA and protein levels were significantly reduced compared to controls. A significantly higher apoptotic index was observed in CVC-treated groups. The rates of tumor growth were significantly decreased on the 7th and 21st days after the first injection. To our knowledge, this was the first time that we demonstrated the promising effect of CVC on the development of CRC through inhibition of the CCR2_CCL2 signaling and its downstream biomarkers.

The Combination of Zerumbone with 5-Fluorouracil for Sensitizing Colorectal Cancer-Associated Fibroblasts to Treatment.

The present study aimed to evaluate the synergic effects of combination therapy on 5-fluorouracil (5-FU) resistance-cancer-associated fibroblasts (CAFs) to treatment. Chemotherapy resistance is an important challenge in colorectal cancer (CRC) eradication attention to the tumor microenvironment (TME) is very important. CAFs in the TME play an essential role in cancer chemoresistance and relapse. Additionally, many patients with advanced CRC show resistance to 5-FU therapy. Anti-tumorigenic activities of ZER, a chemopreventive compound derived from the rhizomes of the wild ginger, have been demonstrated. Synergistic and potentiating effects of combination therapy, using herbal and chemical drugs, can improve patients' response. At the first, CAFs were isolated from a CRC patient and sorted by fluorescent-activated cell sorting (FACS), then, confirmed by flow cytometry, and immunocytochemistry (ICC). The effect of 5-FU and ZER on the cell viability was investigated by MTT assay in a dose and time-dependent manner, after that, the expression of vimentin, ß-catenin, and survivin was quantified. Apoptosis, cell cycle, and invasion were analyzed by flow cytometry and scratch test, respectively. ZER could significantly sensitize CAFs cells to 5-FU. A combination of 5-FU + ZER revealed a marked decrease in the marker of interest in both mRNA and protein levels compared to control groups, including 5-FU, ZER treated, and untreated cells. Functional evaluation of cells in different groups presented significant suppression in migration of CAFs and an apparent increase in cell arrest and apoptosis by 5-FU + ZER treatment.

Aerial Parts of Peucedanum chenur Have Anti-Cancer Properties through the Induction of Apoptosis and Inhibition of Invasion in Human Colorectal Cancer Cells.

Background: The Peucedanum species have many pharmacological effects due to the presence of coumarins, flavonoids, phenolic compounds, and essential fatty acids in these species. In this study, for the first time, the anticancer activity of Peucedanum chenur methanolic extract via the induction of apoptosis and inhibition of invasion in HCT-116 human colon cancer cells was investigated. Methods: P. chenur methanolic extract effect on HCT-116 cells viability and antioxidant activity were evaluated using MTT assay, 1,1-Diphenyl-2-picrylhydrazyl, and iron chelating tests, respectively. Changes in mRNA expression level in a panel of relevant genes were assessed by the quantitative real-time PCR. Also, apoptosis was assessed by cell cycle analysis and Annexin V/PI (propidium iodide) method, and the effect on cell migration was tested using scratch test. Results: P. chenur methanolic extract increased significantly the expression of BAX while decreased the expression of BCL-2, AKT1, FAK, RhoA, and matrix metalloproteinase (MMP) genes compared to the control group. BAX/BCL-2 ratio and apoptosis elevated, whereas cell migration reduced significantly. Besides, our extract showed an appropriate antioxidant activity. Conclusion: P. chenur may be introduced as a new chemopreventive agent in medicine due to its notable power in terms of induction of apoptosis and inhibition of invasion.