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Colorectal cancer (CRC) is the second most common gastrointestinal cancer globally. Prevention of tumor cell proliferation and metastasis is vital for prolonging patient survival. Polyphenols provide a wide range of health benefits and prevention from cancer. In the gut, urolithins are the major metabolites of polyphenols. The objective of our study was to elucidate the molecular mechanism of the anticancer effect of urolithin A (UA) on colorectal cancer cells. UA was found to inhibit the cell proliferation of CRC cell lines in a dose-dependent and time-dependent manner in HT29, SW480, and SW620 cells. Exposure to UA resulted in cell cycle arrest in a dose-dependent manner along with alteration in the expression of cell cycle–related protein. Treatment of CRC cell lines with UA resulted in the induction of apoptosis. Treatment of HT29, SW480, and SW620 with UA resulted in increased expression of the pro-apoptotic proteins, p53 and p21. Similarly, UA treatment inhibited the anti-apoptotic protein expression of Bcl-2. Moreover, exposure of UA induced cytochrome c release and caspase activation. Furthermore, UA was found to generate reactive oxygen species (ROS) production in CRC cells. These findings indicate that UA possesses anticancer potential and may be used therapeutically for the treatment of CRC.

Background Malignant colonic obstruction (MCO) occurs in 10–18% of colorectal cancers. Traditionally, emergency surgery has been the standard treatment modality. However, it is associated with higher morbidity and mortality rates compared to patients undergoing elective surgery. With the advancement of endoscopic techniques, the self-expandable metal stent has been advocated as an alternative management that provides relief of obstructive symptoms, allowing the patient’s general condition to be restored and enabling elective surgery. Furthermore, the ability to complete staging allowed identification and avoidance of unnecessary surgery in patients with advanced disease who need palliative measures. However, various stent-related complications have been reported in the literature, including perforation, migration, and obstruction. In this study, we aimed to evaluate the success and complication rates of stent placement in MCO and compare short-term outcomes to those of upfront surgical management. Methods We conducted a retrospective cohort study that included all patients with MCO between March 2015 and September 2021. Patients who had colon perforation at the time of the diagnosis, benign colonic obstruction, tumors of the rectum, or peritoneal metastasis that underwent cytoreductive surgery were all excluded. Patients were divided into groups according to the initial treatment, stent versus surgery, and the intent of therapy, curative versus palliative. Data was collected from medical records. Results Among 112 patients, 24 had stenting as a bridge to surgery (SBTS), and 16 underwent palliative stenting. The technical success rate was 95%, with failure in two patients due to complete obstruction and perforation in one patient each. Two patients (5%) who underwent stenting had clinical failure with persistent symptomatic obstruction beyond 48 h. The early complication rate following stent insertion was 8%, primarily due to perforation, obstruction from fecal impaction, and stent kinking. SBTS did not affect the laparoscopic approach or stoma creation rate among curative patients. However, it was associated with a more extended hospital stay. Half the patients who received stenting in the palliative group required re-stenting due to re-obstruction, with a mean stent patency time of 7 months. Conclusions Management of MCO varies based on the patient’s clinical presentation, tumor site, and surgeon’s preference. Stent placement, whether as a bridge to surgery or as a palliative measure, is a safe, less invasive, and effective management option with success and low complication rates.

Introduction: There is a steady increase in colorectal cancer (CRC) incidences worldwide; at diagnosis, about 20 percent of cases show metastases. The transforming growth factor-beta (TGF-β) signaling pathway is one of the critical pathways that influence the expression of cadherins allowing the epithelial-to-mesenchymal transition (EMT), which is involved in the progression of the normal colorectal epithelium to adenoma and metastatic carcinoma. The current study aimed to investigate the impact of a novel coordination complex of platinum (salicylaldiminato) PT(II) complex with dimethyl propylene linkage (PT-complex) on TGF-β and EMT markers involved in the invasion and migration of the human HT-29 and SW620 CRC cell lines. Methods: Functional study and wound healing assay showed PT-complex significantly reduced cell motility and the migration and invasion of CRC cell lines compared to the untreated control. Western blot performed in the presence and absence of TGF-β demonstrated that PT-complex significantly regulated the TGF-β-mediated altered expressions of EMT markers. Results and Discussion: PT-complex attenuated the migration and invasion by upregulating the protein expression of EMT-suppressing factor E-cadherin and suppressing EMT-inducing factors such as N-Cadherin and Vimentin. Moreover, PT-complex significantly suppressed the activation of SMAD3 in both CRC cell lines. Further, the microarray data analysis revealed differential expression of genes related to invasion and migration. In conclusion, besides displaying antiproliferative activity, the PT complex can decrease the metastasis of CRC cell lines by modulating TGF-β-regulated EMT markers. These findings provide new insight into TGF-β/SMAD signaling as the molecular mechanism involved in the antitumoral properties of novel PT-complex.

Liver cancer is a leading cause of cancer death globally. Marine mollusc-derived drugs have gained attention as potential natural-based anti-cancer agents to overcome the side effects caused by conventional chemotherapeutic drugs during cancer therapy. Using liquid chromatography-mass spectrometry, the main biomolecules in the purple ink secretion released by the sea hare, named Bursatella leachii (B. leachii), were identified as hectochlorin, malyngamide X, malyngolide S, bursatellin and lyngbyatoxin A. The cytotoxic effects of B. leachii ink concentrate against human hepatocarcinoma (HepG2) cells were determined to be dose- and time-dependent, and further exploration of the underlying mechanisms causing the programmed cell death (apoptosis) were performed. The expression of cleaved-caspase-8 and cleaved-caspase-3, key cysteine-aspartic proteases involved in the initiation and completion of the apoptosis process, appeared after HepG2 cell exposure to the B. leachii ink concentrate. The gene expression levels of pro-apoptotic BAX, TP53 and Cyclin D1 were increased after treatment with the B. leachii ink concentrate. Applying in silico approaches, the high scores predicted that bioactivities for the five compounds were protease and kinase inhibitors. The ADME and cytochrome profiles for the compounds were also predicted. Altogether, the B. leachii ink concentrate has high pro-apoptotic potentials, suggesting it as a promising safe natural product-based drug for the treatment of liver cancer.

Schistosomiasis is a chronic, debilitating parasitic disease infecting more than 200 million people and is second only to malaria in terms of public health importance. Due to the lack of a vaccine, patient therapy is heavily reliant on chemotherapy with praziquantel as the World Health Organization-recommended drug, but concerns over drug resistance encourage the search for new drug leads. The efficacy of the vinyl sulfone cysteine protease inhibitor K11777 was tested in the murine model of schistosomiasis mansoni. Disease parameters measured were worm and egg burdens, and organ pathology including hepato- and splenomegaly, presence of parasite egg-induced granulomas in the liver, and levels of circulating alanine aminotransferase activity as a marker of hepatocellular function. K11777 (25 mg/kg twice daily [BID]), administered intraperitoneally at the time of parasite migration through the skin and lungs (days 1-14 postinfection [p.i.]), resulted in parasitologic cure (elimination of parasite eggs) in five of seven cases and a resolution of other disease parameters. K11777 (50 mg/kg BID), administered at the commencement of egg-laying by mature parasites (days 30-37 p.i.), reduced worm and egg burdens, and ameliorated organ pathology. Using protease class-specific substrates and active-site labeling, one molecular target of K11777 was identified as the gut-associated cathepsin B1 cysteine protease, although other cysteine protease targets are not excluded. In rodents, dogs, and primates, K11777 is nonmutagenic with satisfactory safety and pharmacokinetic profiles. The significant reduction in parasite burden and pathology by this vinyl sulfone cysteine protease inhibitor validates schistosome cysteine proteases as drug targets and offers the potential of a new direction for chemotherapy of human schistosomiasis.

Allium cepa L (A. cepa) extract is frequently used as an adjuvant food in cancer treatment. We hypothesized that it contains a source of anticancer activity. There is a need to synthesize the silver nanoparticles (AgNPs) using an environment-friendly green synthesis reduction method using an aqueous extract of A. cepa. The AgNPs-CEPA were prepared by reduction method using the aqueous extract of A. cepa. The formed AgNPs-CEPA were characterized for their sizes and charge distribution. The AgNP-CEPA was investigated for its antioxidant and anticancer properties. Cell viability was evaluated by MTT assay. Gene expression was evaluated by real-time polymerase chain reaction (RT-PCR), and apoptosis measurement was carried out by flow cytometry in AgNP-CEPA-treated cells. The results showed a uniform size for AgNPs-CEPA of 155±2.1 nm with a zeta potential of −37.3±−2.92 mv. The produced AgNPs-CEPA are biocompatible with anticancer action and a moderate level of antioxidant reactivity. AgNPs-CEPA showed better reducing activity for A. cepa extract compared to the AgNPs-CEPA. AgNP-CEPA treatment of human colorectal cancer cell lines (HT-29 and SW620) inhibited cell proliferation and altered Bcl2 family gene expression. Moreover, exposure of cell lines to AgNPs-CEPA resulted in the significant induction of apoptosis compared to A. cepa and AgNO3. These findings indicate that AgNP-CEPA induces apoptosis by inhibiting Bcl2 family gene expression, suggesting that this formula is a promising anticancer agent for treating colorectal cancer.

Cytotoxic T lymphocyte antigen-4 (CTLA-4) has been identified as an immunosuppressive molecule involved in the negative regulation of T cells. It is highly expressed in several types of autoimmune diseases and cancers including colorectal cancer (CRC). (1) Objective: To explore the association between CTLA-4 single nucleotide polymorphisms (SNP) and risk to (CRC) in the Saudi population. (2) Methods: In this case-control study, 100 patients with CRC and 100 matched healthy controls were genotyped for three CTLA-4 SNPs: rs11571317 (−658C > T), rs231775 (+49A > G) and rs3087243 (CT60 G > A), using TaqMan assay method. Associations were evaluated using odds ratios (ORs) and 95% confidence intervals (95% CIs) for five inheritance models (co-dominant, dominant, recessive, over-dominant and log-additive). Furthermore, CTLA-4 expression levels were evaluated using quantitative real-time PCR (Q-RT-PCR) in colon cancer and adjacent colon tissues. (3) Results: Our result showed a significant association of the G allele (OR = 2.337, p < 0.0001) and GG genotype of the missense SNP +49A > G with increased risk of developing CRC in codominant (OR = 8.93, p < 0.0001) and recessive (OR = 16.32, p < 0.0001) models. Inversely, the AG genotype was significantly associated with decreased risk to CRC in the codominant model (OR = 0.23, p < 0.0001). In addition, the CT60 G > A polymorphism exhibited a strong association with a high risk of developing CRC for the AA genotype in codominant (OR = 3.323, p = 0.0053) and in allele models (OR = 1.816, p = 0.005). No significant association was found between −658C > T and CRC. The haplotype analysis showed that the G-A-G haplotype of the rs11571317, rs231775 and rs3087243 was associated with high risk for CRC (OR = 57.66; p < 0.001). The CTLA-4 mRNA gene expression was found significantly higher in tumors compared to normal adjacent colon samples (p < 0.001). (4) Conclusions: Our findings support an association between the CTLA-4 rs231775 (+49A > G) and rs3087243 (CT60 G > A) polymorphisms and CRC risk in the Saudi population. Further validation in a larger cohort size is needed prior to utilizing these SNPs as a potential screening marker in the Saudi population.

Abstract Background: In this study, we aimed to identify the oncological outcomes in colon cancer patients who underwent elective versus emergency curative resection. Methods: All patients who underwent curative resection for colon cancer between July 2015 and December 2019 were retrospectively reviewed and analyzed. Patients were divided into two groups based on the presentation into elective and emergency groups. Results: A total of 215 patients with colon cancer were admitted and underwent curative surgical resection. Of those, 145 patients (67.4%) were elective cases, and 70 (32.5%) were emergency cases. Family history of malignancy was positive in 44 patients (20.5%) and significantly more common in the emergency group (P = 0.016). The emergency group had higher T and TNM stages (P = 0.001). The 3-year survival rate was 60.9% and significantly less in the emergency group (P = 0.026). The mean duration from surgery to recurrence, 3-year disease-free survival, and overall survival were 1.19, 2.81, and 3.11, respectively. Conclusion: Elective group was associated with better 3-year survival, longer overall, and 3-year disease-free survival compared to the emergency group. The disease recurrence rate was comparable in both groups, mainly in the first two years after curative resection.

Background Colorectal carcinoma is one of the most deadly cancers that requests effective and safe chemotherapy. Evaluation of natural product-based anticancer drugs as adjuvant treatment with fewer side effects is largely unexplored research fields. Herbal melanin (HM) is an extract of the seed coats of Nigella sativa that modulates an inflammatory response through toll-like receptor 4 (TLR4). This TLR4 receptor is also involved in the modulation of apoptosis. We therefore explored the anticancer potential of HM and specifically its effect on the molecular mechanisms underlying adenocarcinoma and metastatic colorectal cancer (mCRC) cell death in vitro. Methods Cell viability was evaluated using the MTT assay. Cellular reactive oxygen species (ROS), glutathione levels, and apoptotic status were assessed using fluorometric and colorimetric detection methods. HM-induced apoptotic and other signaling pathways were investigated using Western blot technology and mitochondrial transition pore assay kit. TLR4 receptor downregulation and blockade were performed using siRNA technology and neutralizing antibody, respectively. Results Our results showed that HM inhibited the proliferation of the colorectal adenocarcinoma HT29 and mCRC SW620 cell lines. Furthermore, HM enhanced ROS production and decreased glutathione levels. HM-induced apoptosis was associated with mitochondrial outer membrane permeability and cytochrome c release, inhibition of the Bcl2 family proteins, and activation of caspase-3/-7. In addition, HM modulated MAPK pathways by activating the JNK pathway and by inhibiting ERK phosphorylation. TLR4 receptor downregulation enhanced HM-induced apoptosis while TLR4 receptor blockade partially alleviated HM-inhibited ERK phosphorylation. Conclusion Altogether, these findings indicate that HM exerts pro-apoptotic effects and inhibits MAPK pathway through TLR4 in mCRC and colorectal adenocarcinoma cells, suggesting HM as a promising natural-based drug for the treatment of colorectal cancer.

Vitamin D, causally implicated in bone diseases and human malignancies, exerts its effects through binding to the vitamin D receptor (VDR). VDR is a transcription factor modulating the expression of several genes in different pathways. Genetic variants in the VDR gene have been associated with several cancers in different population including colorectal cancer. To assess the association of VDR gene polymorphisms in relation with colorectal cancer (CRC) in a Saudi population. The polymorphisms of VDR gene (BsmI, FokI, ApaI and TaqI) were analyzed by the polymerase chain reaction amplification of segments of interest followed by Sanger sequencing. One hundred diagnosed CRC patients and 100 healthy control subjects that were age and gender matched were recruited. We did not observe significant association of any of the four VDR polymorphisms with colorectal cancer risk in the overall analysis. Although not statistically significant, the AA genotype of BsmI conferred about two-fold protection against CRCs compared to the GG genotype. Stratification of the study subjects based on age and gender suggests statistically significant association of CRC with the 'C' allele of ApaI in patients >57 years of age at disease diagnosis and BsmI polymorphism in females. In addition, statistically significant differences were observed for the genotypic distributions of VDR-BsmI, ApaI and TaqI SNPs between Saudi Arabian population and several of the International HapMap project populations. Despite the absence of correlation of the examined VDR polymorphisms with CRCs in the combined analysis, ApaI and BsmI loci are statistically significantly associated with CRC in elderly and female patients, respectively. These findings need further validation in larger cohorts prior to utilizing these SNPs as potential screening markers for colorectal cancers in Saudi population.