Search Results (5)

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. Furthermore, the drug has been reported to inhibit key oncogenic signaling pathways (e.g., STAT3, NF-κB, c-FLIP, survivin) that contribute to tumor growth and metastasis. Preclinical studies in murine models have demonstrated significant reductions in tumor volume of up to 50% and a tumor-free rate exceeding 80%, with effective doses ranging from 7.5 to 40 mg/kg. This multitargeted mode of action distinguishes rafoxanide from conventional therapies and may help overcome resistance mechanisms that often limit the efficacy of cancer treatments. In this review, we summarize and discuss the growing body of evidence supporting rafoxanide’s therapeutic potential in oncology, as well as its possible applications in cancer treatment. Full article

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. Accumulating evidence derived from studies of drug repositioning, that is, the strategy to identify new uses for approved or investigational drugs that are outside the scope of the original medical indication, has suggested that some anthelmintic drugs, in addition to their antineoplastic effects, exert important immunomodulatory actions on specific subsets of immune cell and related pathways. In this review, we report and discuss current knowledge on the impact of anthelmintic drugs on host immunity and their potential implication in cancer immunotherapy. Full article

Lysine-deficient protein kinase-1 (WNK1) is critical for both embryonic angiogenesis and tumor-induced angiogenesis. However, the downstream effectors of WNK1 during these processes remain ambiguous. In this study, we identified that oxidative stress responsive 1b (osr1b) is upregulated in endothelial cells in both embryonic and tumor-induced angiogenesis in zebrafish, accompanied by downregulation of protein phosphatase 2A (pp2a) subunit ppp2r1bb. In addition, wnk1a and osr1b are upregulated in two liver cancer transgenic fish models: [tert x p53^−/−] and [HBx,src,p53^−/−,RPIA], while ppp2r1bb is downregulated in [tert x p53^−/−]. Furthermore, using HUVEC endothelial cells co-cultured with HepG2 hepatoma cells, we confirmed that WNK1 plays a critical role in the induction of hepatoma cell migration in both endothelial cells and hepatoma cells. Moreover, overexpression of OSR1 can rescue the reduced cell migration caused by shWNK1 knockdown in HUVEC cells, indicating OSR1 is downstream of WNK1 in endothelial cells promoting hepatoma cell migration. Overexpression of PPP2R1A can rescue the increased cell migration caused by WNK1 overexpression in HepG2, indicating that PPP2R1A is a downstream effector in hepatoma. The combinatorial treatment with WNK1 inhibitor (WNK463) and OSR1 inhibitor (Rafoxanide) plus oligo-fucoidan via oral gavage to feed [HBx,src,p53^−/−,RPIA] transgenic fish exhibits much more significant anticancer efficacy than Regorafenib for advanced HCC. Importantly, oligo-fucoidan can reduce the cell senescence marker-IL-1β expression. Furthermore, oligo-fucoidan reduces the increased cell senescence-associated β-galactosidase activity in tert transgenic fish treated with WNK1-OSR1 inhibitors. Our results reveal the WNK1–OSR1–PPP2R1A axis plays a critical role in both endothelial and hepatoma cells during tumor-induced angiogenesis promoting cancer cell migration. By in vitro and in vivo experiments, we further uncover the molecular mechanisms of WNK1 and its downstream effectors during tumor-induced angiogenesis. Targeting WNK1–OSR1-mediated anti-angiogenesis and anti-cancer activity, the undesired inflammation response caused by inhibiting WNK1–OSR1 can be attenuated by the combination therapy with oligo-fucoidan and may improve the efficacy. Full article

Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their incidence continues to increase. Despite major efforts aimed at discovering and validating novel and effective drugs against these malignancies, the process of developing such drugs remains lengthy and costly, with high attrition rates. Drug repositioning (also known as drug repurposing), that is, the process of finding new uses for approved drugs, has been gaining popularity in oncological drug development as it provides the opportunity to expedite promising anti-cancer agents into clinical trials. Among the drugs considered for repurposing in oncology, compounds belonging to some classes of anthelmintics—a group of agents acting against infections caused by parasitic worms (helminths) that colonize the mammalian intestine—have shown pronounced anti-tumor activities and attracted particular attention due to their ability to target key oncogenic signal transduction pathways. In this review, we summarize and discuss the available experimental and clinical evidence about the use of anthelmintic drugs for the treatment of cancers of the digestive system. Full article

Colorectal cancer (CRC) is a major cause of cancer-related death in the world. Emerging evidence suggests that the clinical success of conventional chemotherapy does not merely rely on cell toxicity, but also results from the restoration of tumor immune surveillance. Anti-tumor immune response can be primed by immunogenic cell death (ICD), a form of apoptosis associated with endoplasmic reticulum stress (ERS) induction and the expression/release of specific damage-associated molecular patterns (DAMPs). Unfortunately, a limited number of ICD inducers have been identified so far. The anti-helmintic drug rafoxanide has recently showed anti-tumor activity in different cancer types, including CRC. As such latter effects relied on ERS activation, we here investigated whether rafoxanide could promote ICD of CRC cells. The potential of rafoxanide to induce ICD-related DAMPs in both human and mouse CRC cells was assessed by flow-cytometry, chemiluminescent assay and ELISA. In addition, the immunogenic potential of rafoxanide was assessed in vivo using a vaccination assay. Rafoxanide induced all the main DAMPs (ecto-calreticulin exposure, adenosine triphosphate (ATP)/high mobility group box 1 (HMGB1) release) required for ICD. We observed a marked increase of tumor-free survival among immunocompetent mice immunized with rafoxanide-treated dying tumor cells as compared with sham. Altogether, our data indicate rafoxanide as a bona fide ICD inducer. Full article