Repurposing Rafoxanide: From Parasite Killer to Cancer Fighter.

Rafoxanide, originally developed as a veterinary anthelmintic for the treatment of parasitic infections in livestock, has recently emerged as a promising therapeutic prospect in oncology. This compound has demonstrated notable antineoplastic effects against a variety of cancers, including skin, gastric, colorectal, and lung cancers, as well as hematological malignancies such as multiple myeloma. Rafoxanide exerts its anticancer activity through multiple complementary mechanisms, including the induction of endoplasmic reticulum stress, cell cycle arrest, apoptosis, and immunogenic cell death.

Defining CDK12 as a tumor suppressor and therapeutic target in mouse models of tubo-ovarian high-grade serous carcinoma.

Ovarian cancer is the sixth leading cause of cancer death among American women, with most fatalities attributable to tubo-ovarian high-grade serous carcinoma (HGSC). This malignancy usually develops resistance to conventional chemotherapy, underscoring the need for robust preclinical models to guide the development of novel therapies. Here, we introduce an HGSC mouse model generated via -driven Cre recombinase effecting CRISPR/Cas9-mediated deletion of , and tumor suppressors in mouse oviductal epithelium ( model).

Smad7 is a negative regulator of immunogenic cell death in colorectal cancer.

Induction of endoplasmic reticulum (ER) stress is followed by exposure of calreticulin (CRT) on the cancer cell plasma membrane and elicits an anticancer immune response, referred to as immunogenic cell death (ICD). Smad7 is highly expressed by colorectal cancer (CRC) cells, and its knockdown with a specific antisense oligonucleotide (AS) induces ER stress. We hypothesized that, by preventing ER stress, high Smad7 in CRC cells can contribute to limiting ICD.

High Smad7 marks inflammation in patients with chronic pouchitis.

Background And Aim: Patients with ulcerative colitis (UC) undergoing colectomy with ileal-anal pouch anastomosis can develop chronic pouchitis (CP). Since treatment options are very limited for patients with CP, identification of factors/mechanisms that amplify the CP-associated inflammatory response could help develop novel treatments. We here assessed the expression of Smad7, an inhibitor of TGF-β1 signaling and positive regulator of gut inflammation, in CP.

Editorial for the Special Issue "Gut Dysbiosis: Molecular Mechanisms and Therapies 2.0".

Gut homeostasis depends on maintaining a fine equilibrium between the intestinal epithelial barrier, the microbiota, and the host's immune system [...

Targeting hepcidin in colorectal cancer triggers a TNF-dependent-gasdermin E-driven immunogenic cell death response.

Interactions between colorectal cancer (CRC) cells and the noncancerous cells in the tumor microenvironment (TME) induce mechanisms for the escape of tumor cells from immune attack. Hepcidin, a peptide that controls immune cell functions, is overproduced by CRC cells. This study aimed to evaluate whether hepcidin acts as a regulator of anti-tumor immunity in CRC.

Rafoxanide negatively modulates STAT3 and NF-κB activity and inflammation-associated colon tumorigenesis.

In the colorectal cancer (CRC) niche, the transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are hyperactivated in both malignant cells and tumor-infiltrating leukocytes (TILs) and cooperate to maintain cancer cell proliferation/survival and drive protumor inflammation. Through drug repositioning studies, the anthelmintic drug rafoxanide has recently emerged as a potent and selective antitumor molecule for different types of cancer, including CRC. Here, we investigate whether rafoxanide could negatively modulate STAT3/NF-κB and inflammation-associated CRC.

Bromodomain-containing 4 is a positive regulator of the inflammatory cytokine response in the gut.

Background And Aim: Bromodomain-containing protein 4 (BRD4), one of the components of the bromodomain and extraterminal domain (BET) family, is a transcriptional and epigenetic regulator of cellular proliferation and cytokine production. In this study, we assessed whether BRD4 regulates the cytokine response in inflammatory bowel diseases (IBD).

Materials And Methods: BRD4 expression was analyzed in intestinal mucosal samples of patients with ulcerative colitis (UC), patients with Crohn's disease (CD), normal controls (CTRs), and mice with chemically-induced colitis by real-time PCR, Western blotting, and confocal microscopy.

Editorial for the Special Issue "Latest Review Papers in Molecular Oncology 2023".

Human cancers are products of multistep processes resulting in abnormal cell growth and differentiation, along with a loss of apoptotic function, leading to the uncontrolled expansion of neoplastic cells and their spread to surrounding tissues and, ultimately, distant parts of the body [...

Special Issue "Drug Treatments for Inflammatory Bowel Diseases".

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic idiopathic, relapsing and remitting inflammatory diseases that affect the gastrointestinal tract, causing significant morbidity and loss of quality of life in affected individuals [...

TRAIL-Sensitizing Effects of Flavonoids in Cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major hurdle, thus limiting the use of TRAIL as a single agent. Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated in resistant tumors by combined treatment with antitumor agents, ranging from synthetic molecules to natural products.

Insulin-like Growth Factor II mRNA-Binding Protein 1 Regulates Pancreatic Cancer Cell Growth through the Surveillance of mRNA.

A number of data indicate that the sources of different kinds of PDAC may be discovered at the transcription/transduction stage. RNA metabolism is manipulated at various steps by different RNA-binding proteins (RBPs), and the deregulation or irregular activity of RBPs is known to contribute to tumor promotion and progression. The insulin-like growth factor 2 mRNA-binding protein family (IMPs), and IMP1 in particular, has been linked with a poor prognosis in PDAC patients; however, little is known about its contribution in PDAC carcinogenesis.

TGF-β1 signaling and Smad7 control T-cell responses in health and immune-mediated disorders.

Transforming growth factor (TGF)-β1, a member of the TGF-β superfamily, is produced by many immune and nonimmune cells and has pleiotropic effects on both innate and adaptive immunity, especially in the control of T-cell differentiation and function. Consistently, loss of TGF-β1 function is associated with exacerbated T-cell-dependent inflammatory responses that culminate in pathological processes in allergic and immune-mediated diseases. In this review, we highlight the roles of TGF-β1 in immunity, focusing mainly on its ability to promote differentiation of regulatory T cells, T helper (Th)-17, and Th9 cells, thus contributing to amplifying or restricting T-cell responses in health and human diseases (e.

Impact of Western Diet and Ultra-Processed Food on the Intestinal Mucus Barrier.

The intestinal epithelial barrier plays a key role in the absorption of nutrients and water, in the regulation of the interactions between luminal contents and the underlying immune cells, and in the defense against enteric pathogens. Additionally, the intestinal mucus layer provides further protection due to mucin secretion and maturation by goblet cells, thus representing a crucial player in maintaining intestinal homeostasis. However, environmental factors, such as dietary products, can disrupt this equilibrium, leading to the development of inflammatory intestinal disorders.

Advances in Immunotherapy and Innovative Therapeutic Approaches for Cancer Treatment: Editorial to the Special Issue "State-of-the-Art Molecular Oncology in Italy".

Cancer remains one of the most common causes of death worldwide, mainly due to late diagnosis and the lack of efficient therapeutic options for patients with advanced diseases [...

Anthelmintic Drugs as Emerging Immune Modulators in Cancer.

Despite recent advances in treatment approaches, cancer is still one of the leading causes of death worldwide. Restoration of tumor immune surveillance represents a valid strategy to overcome the acquired resistance and cytotoxicity of conventional therapies in oncology and immunotherapeutic drugs, such as immune checkpoint inhibitors and immunogenic cell death inducers, and has substantially progressed the treatment of several malignancies and improved the clinical management of advanced disease. Unfortunately, because of tumor-intrinsic and/or -extrinsic mechanisms for escaping immune surveillance, only a fraction of patients clinically respond to and benefit from cancer immunotherapy.

A novel tumour enhancer function of Insulin-like growth factor II mRNA-binding protein 3 in colorectal cancer.

CRC cells evolve a variety of strategies to limit or circumvent apoptosis cell death. RNA binding proteins (RBPs) regulate many of the molecular mechanisms that underlie the development of cancer. The insulin-like growth factor II mRNA-binding proteins (IMP) family are oncofoetal RBPs, consisting of IMP1, IMP2 and IMP3, which have an important role in RNA metabolism.

and Gastric Cancer: Pathogenetic Mechanisms.

Gastric cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide. () is one of the main risk factors for this type of neoplasia. Carcinogenetic mechanisms associated with are based, on the one hand, on the onset of chronic inflammation and, on the other hand, on bacterial-specific virulence factors that can damage the DNA of gastric epithelial cells and promote genomic instability.

Targeted Therapy of Interleukin-34 as a Promising Approach to Overcome Cancer Therapy Resistance.

Chemotherapy and immunotherapy have markedly improved the management of several malignancies. However, not all cancer patients respond primarily to such therapies, and others can become resistant during treatment. Thus, identification of the factors/mechanisms underlying cancer resistance to such treatments could help develop novel effective therapeutic compounds.

Smad7 as a positive regulator of intestinal inflammatory diseases.

In physiological conditions, the human gut contains more immune cells than the rest of the body, but no overt tissue damage occurs, because several regulatory mechanisms control the activity of such cells thus preventing excessive and detrimental responses. One such mechanism relies on the action of transforming growth factor (TGF)-β1, a cytokine that targets both epithelial cells and many immune cell types. Loss of TGF-β1 function leads to intestinal pathology in both mice and humans.

Smad7 Antisense Oligonucleotide in Crohn's Disease: A Re-Evaluation and Explanation for the Discordant Results of Clinical Trials.

In Crohn's disease (CD) and ulcerative colitis (UC), the major inflammatory bowel diseases (IBD) in human beings, the tissue-damaging inflammatory response is characterized by elevated levels of Suppressor of Mothers Against Decapentaplegic (Smad)7, an inhibitor of the immunosuppressive cytokine Transforming Growth Factor (TGF)-β1. Consistently, preclinical work in mouse models of IBD-like colitis showed that the knockdown of Smad7 with an antisense oligonucleotide (AS) attenuated the mucosal inflammation, thus paving the way for the development of an AS-containing pharmaceutical compound, named mongersen, for clinical use. The initial phase 1 and phase 2 studies showed that oral administration of mongersen was safe and effective in inducing clinical remission in active CD patients.

Folate-Functionalization Enhances Cytotoxicity of Multivalent DNA Nanocages on Triple-Negative Breast Cancer Cells.

DNA is an excellent programmable polymer for the generation of self-assembled multivalent nanostructures useful for biomedical applications. Herein, we developed (i) folate-functionalized nanocages (Fol-NC), very efficiently internalized by tumor cells overexpressing the α isoform of the folate receptor; (ii) AS1411-linked nanocages (Apt-NC), internalized through nucleolin, a protein overexpressed in the cell surface of many types of cancers; and (iii) nanostructures that harbor both folate and AS1411 aptamer functionalization (Fol-Apt-NC). We analyzed the specific miRNA silencing activity of all types of nanostructures harboring miRNA sequestering sequences complementary to miR-21 and the cytotoxic effect when loaded with doxorubicin in a drug-resistant triple-negative breast cancer cell line.

CDT1 drives replication overlicensing and enhances tumorigenesis in the gut.

Colorectal carcinoma (CRC) is one of the most common forms of malignancy in the Western world. Recent decades have witnessed enormous progress in our understanding of the mechanisms that sustain CRC, even though the factors implicated in the initiation and progression of this neoplasia are not fully understood. A recent study published in The Journal of Pathology looked at the consequences of hyperactivity of chromatin licensing and DNA replication factor 1 (CDT1), a regulator of DNA replication that is produced in excess in CRC, on the course of intestinal tumorigenesis.

Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial-Mesenchymal Transition and Correlates with Progression of the Disease.

Advanced, metastatic colorectal cancer (CRC) is associated with high rate of mortality because of its poor responsiveness to chemotherapy/immunotherapy. Recent studies have shown that hepcidin, a peptide hormone produced mainly by hepatocytes, is expressed by and enhances the growth of tumor cells. We here assessed whether hepcidin expression helps identify subsets of CRC with advanced and aggressive course.