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Background
Sorafenib, a kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC) but provides only a limited survival benefit. Disulfiram (DSF), a drug for treating alcoholism and a chelator of copper (Cu), forms a complex with Cu (DSF/Cu). DSF/Cu is a potent inducer of autophagic apoptosis of cancer stem cells, which c...
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Context 1
... were seeded in 6-well plates at a density of 2×10 5 cells/well in 2 mL appropriate complete medium and incubated overnight. Cells were then treated with DMSO, DSF/Cu, sorafenib, or DSF/ Cu + sorafenib for 12 h, and IC 50 values ( Table 1) of DSF/Cu and sorafenib for each cell line were used for experiments. For the detection of ALDH + activity in each cell line, flow cytometry was performed as previously described (18). ...Context 2
... were plated in 24-well plates at a density of 1000 cells/well in 0.5 mL appropriate complete medium followed immediately by treatment with DMSO, DSF, Cu, DSF/Cu, sorafenib, or DSF/ Cu + sorafenib for an additional 24 h. IC 50 values ( Table 1) of DSF and sorafenib in each cell line were used for experiments. Sphere formation procedures were performed as previously described (18). ...Similar publications
mRNA‐based gene therapy has emerged as an advanced strategy for hepatocellular carcinoma (HCC) treatment. However, one of its main limitations is lacking delivery precision in vivo. Distinguishing HCC cells from other tissues is crucial for maintaining the high stability, positive therapeutic outcomes, and safety of mRNA therapeutics. Here, a novel...
Citations
... This mechanism of inhibiting proteasome activity may be achieved by targeting nuclear protein localization protein 4 homolog (NPL4), which is the adapter factor for the p97 (also known as VCP) segregase, involved in the conversion of proteins involved in multiple regulatory and stress response pathways (198). Studies have also shown that disulfiram-copper (DSF-Cu) can inhibit aldehyde dehydrogenase (ALDH), targeting cancer stem cells, and therefore has a synergistic effect on the chemoresistance of tumor stem cells that affect sorafenib treatment outcomes (199). HCC cells treated with DSF/Cu show immunogenic cell death (ICD) characteristics in vitro and can enhance the effect of CD47 blockade therapy by immune activation (200). ...
... (190,(196)(197)(198) Target Cancer Stem Cells DSF and Elesclomol can target cancer stem cells, enhancing the sensitivity and anti-tumor effects of anti-cancer drugs. (195,199) Promote Immune Activation DSF can enhance the effect of CD47 blockade therapy by inducing ICD. ...
As an essential nutrient, copper’s redox properties are both beneficial and toxic to cells. Therefore, leveraging the characteristics of copper-dependent diseases or using copper toxicity to treat copper-sensitive diseases may offer new strategies for specific disease treatments. In particular, copper concentration is typically higher in cancer cells, making copper a critical limiting nutrient for cancer cell growth and proliferation. Hence, intervening in copper metabolism specific to cancer cells may become a potential tumor treatment strategy, directly impacting tumor growth and metastasis. In this review, we discuss the metabolism of copper in the body and summarize research progress on the role of copper in promoting tumor cell growth or inducing programmed cell death in tumor cells. Additionally, we elucidate the role of copper-related drugs in cancer treatment, intending to provide new perspectives for cancer treatment.
... Most recently, Zhang et al [157] reported that disulfiram plus copper in combination with sorafenib resulted in increased anticancer activity against HCC under in vitro and in vivo conditions. Moreover, this combination synergistically inhibited the proliferation of human HCC cell lines and significantly increased autophagy and apoptosis compared to sorafenib alone. ...
... Moreover, this combination synergistically inhibited the proliferation of human HCC cell lines and significantly increased autophagy and apoptosis compared to sorafenib alone. In addition, in a mouse orthotopic HCC xenograft model, the combination effectively inhibited tumour growth compared to the effect of sorafenib alone [157]. ...
Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumours worldwide. The mortality-to-incidence ratio is up to 91.6% in many countries, representing the third leading cause of cancer-related deaths. Systemic drugs, including the multikinase inhibitors sorafenib and lenvatinib, are first-line drugs used in HCC treatment. Unfortunately, these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance. Thus, novel pharmacological alternatives are urgently needed. For instance, immune checkpoint inhibitors have provided new approaches targeting cells of the immune system. Furthermore, monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients. In addition, drug combinations, including first-line treatment and immunotherapy, as well as drug repurposing, are promising novel therapeutic alternatives. Here, we review the current and novel pharmacological approaches to fight HCC. Preclinical studies, as well as approved and ongoing clinical trials for liver cancer treatment, are discussed. The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.
... Performed as described 38 . ...
The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumor is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach massively reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquired early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogrammed and reversed immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells (PBMC) of healthy or metastatic breast cancer patients, induced robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a novel therapy for solid tumor.
Background
Cancer stem cells (CSCs) have emerged as pivotal players in tumorigenesis, disease progression, and resistance to therapies.
Objective
This comprehensive review delves into the intricate relationship between CSCs and the cell-of-origin in diverse cancer types.
Design
Comprehensive review of thematically-relevant literature.
Methods
We explore the underlying molecular mechanisms that drive the conversion of normal cells into CSCs and the impact of the cell-of-origin on CSC properties, tumor initiation, and therapeutic responses. Moreover, we discuss potential therapeutic interventions targeting CSCs based on their distinct cell-of-origin characteristics.
Results
Accruing evidence suggest that the cell-of-origin, the cell type from which the tumor originates, plays a crucial role in determining the properties of CSCs and their contribution to tumor heterogeneity.
Conclusion
By providing critical insights into the complex interplay between CSCs and their cellular origins, this article aims to enhance our understanding of cancer biology and pave the way for more effective and personalized cancer treatments.
Copper, like iron, is an essential trace metal element for human cells. The role of iron overload and ferroptosis has been gradually clarified in tumors, but the role of copper overload and cuproptosis is still being explored. Cuproptosis is a novel mode of cell death, secondary to impaired mitochondrial function induced by copper overload, and characterized by copper-dependent and programmed. The excessive copper leads to protein toxicity stress by binding to sulfhydryl proteins in the tricarboxylic acid (TCA) cycle of mitochondria, disrupting cellular homeostasis and triggering cuproptosis. Copper accumulation has carcinogenic effects on normal cells, dual effects on tumor cells. Liver cancer is one of the most common malignant tumors in China and even globally, with hepatocellular carcinoma (HCC) being the most common histological subtype. Copper exhibits dualism in HCC, as it both contributes to the growth and invasion of HCC cells, and exerts anticancer effects by inducing cuproptosis. Also, cuproptosis-related genes can be the evaluation of immunotherapy effect and the construction of prognostic models. Clarifying the role of copper death in liver cancer can help explore new methods for liver cancer screening, treatment, and prognosis evaluation.
In the present study, we investigated the antitumor effect and associated molecular mechanisms of the copper (II) complex of salicylate phenanthroline [Cu(sal)(phen)] against hepatocellular carcinoma (HCC). Cu(sal)(phen) inhibited the proliferation of HCC cells (HepG2 and HCC-LM9) and induced apoptosis of HCC cells in a dose-dependent manner by upregulating mitochondrial reactive oxygen species (ROS) production. The expression of the antiapoptotic proteins survivin and Bcl-2 was decreased, while the expression of the DNA damage marker γ-H2 AX and the apoptotic marker cleaved PARP was upregulated with Cu(sal)(phen) treatment. In vivo, the growth of HepG2 subcutaneous xenograft tumors was greatly attenuated by Cu(sal)(phen) treatment. Immunohistochemistry staining showed that the expression of survivin, Bcl-2, and Ki67 in the tumor was downregulated by Cu(sal)(phen). Toxicity experiments with BALB/c mice revealed that Cu(sal)(phen) is a relatively safe drug. Our results indicate that Cu(sal)(phen) possesses great potential as a therapeutic drug for HCC.
Modern cancer chemotherapy originated in the 1940s, and since then, many chemotherapeutic agents have been developed. However, most of these agents show limited response in patients due to innate and acquired resistance to therapy, which leads to the development of multi-drug resistance to different treatment modalities, leading to cancer recurrence and, eventually, patient death. One of the crucial players in inducing chemotherapy resistance is the aldehyde dehydrogenase (ALDH) enzyme. ALDH is overexpressed in chemotherapy-resistant cancer cells, which detoxifies the generated toxic aldehydes from chemotherapy, preventing the formation of reactive oxygen species and, thus, inhibiting the induction of oxidative stress and the stimulation of DNA damage and cell death. This review discusses the mechanisms of chemotherapy resistance in cancer cells promoted by ALDH. In addition, we provide detailed insight into the role of ALDH in cancer stemness, metastasis, metabolism, and cell death. Several studies investigated targeting ALDH in combination with other treatments as a potential therapeutic regimen to overcome resistance. We also highlight novel approaches in ALDH inhibition, including the potential synergistic employment of ALDH inhibitors in combination with chemotherapy or immunotherapy against different cancers, including head and neck, colorectal, breast, lung, and liver.
