Harnessing Ferroptosis to Overcome Drug Resistance in Colorectal Cancer: Promising Therapeutic Approaches.

Drug resistance remains a significant challenge in the treatment of colorectal cancer (CRC). In recent years, the emerging field of ferroptosis, a unique form of regulated cell death characterized by iron-dependent lipid peroxidation, has offered new insights and potential therapeutic strategies for overcoming drug resistance in CRC. This review examines the role of ferroptosis in CRC and its impact on drug resistance. It highlights the distinctive features and advantages of ferroptosis compared to other cell death pathways, such as apoptosis and necrosis. Furthermore, the review discusses current research advances in the field, including novel treatment approaches that target ferroptosis. These approaches involve the use of ferroptosis inducers, interventions in iron metabolism and lipid peroxidation, and combination therapies to enhance the efficacy of ferroptosis. The review also explores the potential of immunotherapy in modulating ferroptosis as a therapeutic strategy. Additionally, it evaluates the strengths and limitations of targeting ferroptosis, such as its selectivity, low side effects, and potential to overcome resistance, as well as challenges related to treatment specificity and drug development. Looking to the future, this review discusses the prospects of ferroptosis-based therapies in CRC, emphasizing the importance of further research to elucidate the interaction between ferroptosis and drug resistance. It proposes future directions for more effective treatment strategies, including the development of new therapeutic approaches, combination therapies, and integration with emerging fields such as precision medicine. In conclusion, harnessing ferroptosis represents a promising avenue for overcoming drug resistance in CRC. Continued research efforts in this field are crucial for optimizing therapeutic outcomes and providing hope for CRC patients.

SETD8 promotes glycolysis in colorectal cancer via regulating HIF1α/HK2 axis.

Glycolysis is one of the factors influencing cancer cell growth and metastasis. Here, we aimed to investigate the role of SETD8 gene, which is a pro-oncogene. Using bioinformatics tools including Ualcan, Timer, GEPIA, and PrognoScan to study the expression of SETD8 in colorectal cancer, we found that SETD8 expression was higher in colon cancer tissues than that in normal tissues. Higher levels of SETD8 predicted poorer survival of patients. This piqued our interest, so we transfected SETD8 knockdown and overexpression plasmids into colorectal cancer cells and found that SETD8 overexpression enhanced proliferation and glycolysis in colon cancer cells, while SETD8 knockdown decreased cell proliferation and glycolysis. Mechanistically, we examined the expression of HIF1α and HK2 protein by western-blot assay and found that SETD8 activated the HIF1α/HK2 pathway. Then, we treated SETD8-overexpressed cells with HIF1α inhibitor and found that the pro-tumor growth and glycolytic effects of SETD8 were reversed, indicating that SETD8 promoted the growths of colorectal cancer cells by upregulating the HIF1α /HK2 pathway.

ALKBH2 inhibition alleviates malignancy in colorectal cancer by regulating BMI1-mediated activation of NF-κB pathway.

BACKGROUND: The alkB homolog 2, alpha-ketoglutarate-dependent dioxygenase (ALKBH2) gene is involved in DNA repair and is expressed in different types of malignancies. However, the role of ALKBH2 in colorectal carcinoma (CRC) remains unclear. This study aimed to explore the potential mechanism of ALKBH2 and its function in CRC. METHODS: The expression levels of ALKBH2 in CRC tissues and cells were determined by qRT-PCR. Following that, the role of ALKBH2 in cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) in CRC cells (Caco-2 and LOVO) were assessed by Cell Counting Kit-8 (CCK-8), transwell assays, and Western blotting, respectively. The effect of ALKBH2 on B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) and downstream NF-κB pathway was determined by Western blotting and luciferase reporter assay. RESULTS: The expression of ALKBH2 was significantly upregulated both in CRC tissues and cells. Further experiments demonstrated that reduction of ALKBH2 suppressed Caco-2 and LOVO cell proliferation and invasion. Moreover, ALKBH2 knockdown also suppressed EMT, which increased E-cadherin expression and reduced N-cadherin expression. Besides, ALKBH2 silencing inhibited BMI1 expression and reduced nuclear accumulation of the NF-κB p65 protein, as well as the luciferase activity of NF-κB p65. Upregulation of BMI1 reversed the effect of ALKBH2 knockdown on the proliferation and invasion in CRC cells. CONCLUSIONS: Our findings suggest that suppression of ALKBH2 alleviates malignancy in CRC by regulating BMI1-mediated activation of NF-κB pathway. ALKBH2 may serve as a potential treatment target for human CRC.

Application of spontaneously closing cannula ileostomy in laparoscopic anterior resection of rectal cancer.

An anastomotic leak (AL) is the most serious complication observed in laparoscopic anterior resection of rectal cancer (LARRC). In order to protect anastomosis from AL and avoid stoma reversal surgery in patients with ileostomy, spontaneously closing cannula ileostomy (SCCI) was used in LARRC and its safety and feasibility were assessed in the present study. To the best of our knowledge, this is the first time that SCCI has been used in such a case. A total of 41 patients who underwent LARRC with SCCI or ileostomy procedures between November 2013 and August 2014 were retrospectively analyzed. The patient demographics, clinical features and surgical data were evaluated using a Mann-Whitney U-test, Fisher's exact test or linear-by-linear association. Demographics, surgical data and the majority of clinical features of the two groups were consistently similar. In the SCCI group, the length of postoperative stay, total cost and stoma period were significantly improved compared with those in the ileostomy group. Additionally, the median protective period in the SCCI group was 22 days [interquartile range (IQR), 19-22 days], the median time to cannula removal was 23 days (IQR, 20-24 days) and the median time to cannula stoma closure was 12 days (IQR, 11-13 days). No SCCI-associated complications occurred. No significant differences in routine complications, including staple-line bleeding, anastomotic leak, anastomotic dehiscence, anastomotic stenosis and wound infection, were identified between the two groups. In LARRC, the SCCI procedure was demonstrated to be a safe and feasible diverting technique to protect anastomosis from AL. In contrast to ileostomy, the SCCI procedure obviated the requirement for stoma reversal surgery, which resulted in decreased lengths of postoperative hospital stay, hospitalization costs and stoma periods.

Application of a spontaneously closed protective stoma in an ileal pouch-anal anastomosis: a preliminary study.

BACKGROUND: To evaluate the application value of a spontaneously closed protective stoma (SCPS) in an ileal pouch-anal anastomosis, which is a novel procedure first performed in our hospital in 2008. MATERIALS AND METHODS: Two males cases with ulcerative colitis and one female with familial adenomatous polyposis were treated with colorectal surgery at the First Affiliated Hospital of Zhejiang University since March 2010. The surgery was designed as total proctocolectomy with an ileal pouch-anal anastomosis and SCPS. The surgical plan and procedure was determined with the patients after analyzing their hospitalized records and follow-up information. RESULTS: No operation-induced death or anastomotic leakage occurred. One patient had a persistent fever and another patient presented with postoperative urinary retention. The average time until flatulence occurred post-SCPS was 26 days, and the average time until the removal of the postoperative stomal tube was 46 days that healed well. CONCLUSIONS: An SCPS can effectively protect the anastomosis with a simple operation and avoid the second surgery. Patients with ulcerative colitis require a two-stage operation, those who were in poor health and had a long history of hormone treatment even requiring a three-stage operation. However, a one- or two-stage operation could help alleviate pain for patients who require multiple surgeries and reduce economic burden.