Overcome Apoptosis Resistance Research Articles

Unveiling the Potential of Hyptis Capitata and Hyptis Brevipes Compounds in Overcoming Apoptosis Resistance and Inducing Targeted Cell Cycle Arrest in Breast Cancer Stem Cells

Breast cancer stem cells (CSC), as a kind of tumor cells, are able to regenerate themselves, leading to apoptosis resistance and cancer relapse. In this study, we investigated the potential of Hyptis Capitata and Hyptis Brevipes compounds in preventing apoptosis resistance and inducing targeted cell cycle arrest in CSC. The cytotoxic effects of the compounds were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and the cell cycle distribution and apoptosis induction were assessed through flow cytometry analysis. The phytochemical characterization of Hyptis bravipes extract (HBE) and Hyptis capitata extract (HCE) conducted under thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) analysis. The results revealed that Hyptis Brevipes extract (HBE) exhibited strong cytotoxicity towards CSCs, with an IC50 value of 89 µg/mL. In contrast, Hyptis Capitata extract (HCE) showed weak growth inhibition, with an IC50 value greater than 500 µg/mL. Subsequent analysis demonstrated that HBE induced cell cycle arrest in the G2/M and S phases and significantly increased apoptosis in the CSC population. Furthermore, phytochemical characterization using TLC and HPLC revealed that HBE and HCE share similar constituent compounds, with HBE exhibiting a more diverse compound content and stronger cytotoxic effects. These findings provide valuable insights into the potential of Hyptis Capitata and Hyptis Brevipes compounds as targeted agents against breast cancer stem cells and contribute to understanding their chemical profiles and pharmacological properties. HIGHLIGHTS Hyptis brevipes extract induced cell cycle arrest in G2/M and S phases. Cytotoxicity of Hyptis brevipes leading to apoptosis induction on CSC Hyptis brevipes significantly targeted Breast Cancer Stem Cells GRAPHICAL ABSTRACT

Sphaeropsidin A C15-C16 Cross-Metathesis Analogues with Potent Anticancer Activity.

We recently discovered that sphaeropsidin A (SphA), a fungal metabolite from Diplodia cupressi, overcomes apoptosis resistance in cancer cells by inducing cellular shrinkage by impairing regulatory volume increase. Previously, we prepared a pyrene-conjugated derivative of SphA by a cross-metathesis reaction involving the phytotoxin's C15,C16-alkene. This derivative's evaluation in a cancer cell panel revealed a significant increase in potency, with the IC50 values 5-10× lower than those displayed by the original natural product. Herein, we describe the preparation and anticancer evaluation of fifteen novel C15,C16-alkene cross-metathesis analogues in which the pyrene moiety was replaced with other aromatic or non-aromatic hydrophobic groups. The idea for this replacement was to prepare a family of compounds that would not be predicted to be mutagenic compared with the original pyrene analogue. We predict several of our new compounds to be non-mutagenic, while retaining the high potency of the original pyrene-containing analogues. Examples of these potential lead compounds included those containing pentamethylphenyl and triphenylethylene pendant groups. As an additional feature of the current investigation, we prepared several deuterated pyrene-containing compounds to overcome intellectual property issues associated with non-patentability of the original pyrene derivative.

MLKL regulates radiation-induced death in breast cancer cells: an interplay between apoptotic and necroptotic signals.

Resistance to caspase-dependent apoptosis is often responsible for treatments failure in cancer. Necroptosis is a type of programmed necrosis that occurs under caspase-deficient conditions that could overcome apoptosis resistance. Our purpose was to investigate the interrelationship between apoptotic and necroptotic death pathways and their influence on the response of breast cancer cells to radiotherapy in vitro. Human BC cell lines MCF-7 and MDA-MB-231 were treated with ionizing radiation, and then several markers of apoptosis, necroptosis, and survival were assessed in the presence and absence of necroptosis inhibition. MLKL knockdown was achieved by siRNA transfection. Our main findings emphasize the role of necroptosis in cellular response to radiation represented in the dose- and time-dependent elevated expression of necroptotic markers RIPK1, RIPK3, and MLKL. Knockdown of necroptotic marker MLKL by siRNA led to a significant elevation in MDA-MB-231 and MCF-7 survival with a dose modifying factor (DMF) of 1.23 and 1.61, respectively. Apoptotic markers Caspase 8 and TRADD showed transitory or delayed upregulation, indicating that apoptosis was not the main mechanism by which cells respond to radiation exposure. Apoptotic markers also showed a significant elevation following MLKL knockdown, suggesting its role either as a secondary or death alternative pathway. The result of our study emphasizes the critical role of the necroptotic pathway in regulating breast cancer cells responses to radiotherapy and suggests a promising utilization of its key modulator, MLKL, as a treatment strategy to improve the response to radiotherapy.

Nanotechnology Utilizing Ferroptosis Inducers in Cancer Treatment.

Current cancer treatment options have presented numerous challenges in terms of reaching high efficacy. As a result, an immediate step must be taken to create novel therapies that can achieve more than satisfying outcomes in the fight against tumors. Ferroptosis, an emerging form of regulated cell death (RCD) that is reliant on iron and reactive oxygen species, has garnered significant attention in the field of cancer therapy. Ferroptosis has been reported to be induced by a variety of small molecule compounds known as ferroptosis inducers (FINs), as well as several licensed chemotherapy medicines. These compounds' low solubility, systemic toxicity, and limited capacity to target tumors are some of the significant limitations that have hindered their clinical effectiveness. A novel cancer therapy paradigm has been created by the hypothesis that ferroptosis induced by nanoparticles has superior preclinical properties to that induced by small drugs and can overcome apoptosis resistance. Knowing the different ideas behind the preparation of nanomaterials that target ferroptosis can be very helpful in generating new ideas. Simultaneously, more improvement in nanomaterial design is needed to make them appropriate for therapeutic treatment. This paper first discusses the fundamentals of nanomedicine-based ferroptosis to highlight the potential and characteristics of ferroptosis in the context of cancer treatment. The latest study on nanomedicine applications for ferroptosis-based anticancer therapy is then highlighted.

Abstract LB083: Near-infrared light-triggered tumor pyroptosis potentiates PD-1 immunotherapy in esophageal cancer

Abstract Background: Esophageal cancer remains a lethal malignancy accounting for 604,000 new cases and 544,000 cancer-related modalities worldwide. To date, the clinical outcomes for patient with esophageal cancer are severely limited by the lack of effective treatment modalities. Moreover, the intrinsic and acquired resistances to chemotherapy and radiotherapy, stemming from DNA damage responses, inevitably exacerbates the disease progression. Pyroptosis is a proinflammatory programmed cell death (PCD) that is causally linked to anti-tumor immune responses, but the development of pyroptosis-based therapy has been limited by the lack of effective inducers to mediate pyroptotic cell death in a tumor-specific and controllable manner. Herein, we establishes that near-infrared light-triggered tumor pyroptosis (NIR-pyroptosis) is a novel non-apoptotic anticancer modality, providing a promising opportunity to overcome apoptosis resistance in current esophageal cancer therapies. Method: In this study, a novel esophageal cancer-targeted, NIR-pyroptosis antibody-drug conjugates (ADC) was established by covalently conjugating IRDye700, a photosensitizer, with ICAM1 antibody using thiol-maleimide click chemistry. This antibody-photosensitizer conjugate (ICAM1-IRDye700) functions as a potent NIR-pyroptosis inducer in multiple preclinical models of esophageal squamous cell carcinoma (ESCC). The in vitro potency of ICAM1-IRDye700 was determined by flow cytometry, immunofluorescent co-localization, and high-content imaging. Transmission electron microscopy (TEM) further characterized pyroptosis-related morphological changes in ICAM1-IRDye700-treated ESCC cells. To elucidate its underlying mechanism, transcriptomic and immune-blot analyses were performed to identify the molecular signaling cascades of NIR-pyroptosis ignited by ICAM1-IRDye700. Results: Under minimal doses (2ug/ml) of near-infrared light stimulation, ICAM1-IRDye700 rapidly triggered pyroptosis in ESCC cells, achieving approximately 95% cell death within 2 hours. Importantly, the potency of NIR-pyroptosis predominantly depends on the spatio. At different stages of drug accumulation on the cell membrane, in endosomes, and lysosomes, the time of pyroptosis induction varied. Transmission electron microscopy further observed pyroptosis-related morphological changes, and immunoblot analysis and sequencing results also provided supporting evidence, demonstrating the activation of the subcellular depositing locations of ICAM1-IRDye700 upon NIR irradiation. Further biomechanistic studies reveal that ICAM1-IRDye700 potently activates NLRP1-CASP1-GSDMD signaling axis, leading to a boosted antitumor immunity in vivo. This antitumor immunity activation was independent from reactive oxygen species (ROS). Furthermore, NIR-pyroptosis works in synergy with PD-1 immunotherapy by improving adaptive antitumor immunity in immunocompetent tumor models. Conclusion: Collectively, we established ICAM1-IRDye700 as a concept-of-proof ADC for NIR-pyroptosis therapy. Mechanistically, we explored the biomechanism of how ICAM1-IRDye700 igniting NIR-pyroptosis in ESCC tumors. This novel ADC boosts innate and adaptive immunity, resulting in potent and sustained tumor attenuations in combination with PD-1 checkpoint immunotherapy. Citation Format: Xue-Fei Tian, Fan Chen, Xi-Ru Xue, Yang Yang, Peng Guo. Near-infrared light-triggered tumor pyroptosis potentiates PD-1 immunotherapy in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB083.

Employing Piezoelectric Mg2+-Doped Hydroxyapatite to Target Death Receptor-Mediated Necroptosis: A Strategy for Amplifying Immune Activation.

Although immunogenic cell death (ICD) inducers evidently enhance the effectiveness of immunotherapy, their potential is increasingly restricted by the development of apoptosis resistance in tumor cells, poor immunogenicity, and low T-cell immune responsiveness. In this study, for the first time, piezoelectrically catalyzed Mg2+-doped hydroxyapatite (Mg-HAP) nanoparticles, which are coated with a mesoporous silica layer and loaded with ONC201 as an agonist to specifically target the death receptor DR5 on tumor cells, ultimately developing an Mg-HAP@MS/ONC201 nanoparticle (MHMO NP) system, are engineered. Owing to its excellent piezoelectric properties, MHMO facilitates the release of a significant amount of reactive oxygen species and Ca2+ within tumor cells, effectively promoting the upregulation of DR5 expression and inducing tumor cell necroptosis to ultimately overcome apoptosis resistance. Concurrently, Mg2+ released in the tumor microenvironment promotes CD8+ T receptor activation in response to the antitumor immune reaction induced by ICD. Using RNA-seq analysis, it is elucidated that MHMO can activate the NF-κB pathway under piezoelectric catalysis, thus inducing M1-type macrophage polarization. In summary, a dual-targeting therapy system that targets both tumor cells and the tumor microenvironment under piezoelectric catalysis is designed. This system holds substantial potential for advancements in tumor immunotherapy.

Enhanced photodynamic therapy through multienzyme-like MOF for cancer treatment.

Overcoming resistance to apoptosis is a major challenge in cancer therapy. Recent research has shown that manipulating mitochondria, the organelles critical for energy metabolism in tumor cells, can increase the effectiveness of photodynamic therapy and trigger apoptosis in tumor cells. However, there is currently insufficient research and effective methods to exploit mitochondrial damage to induce apoptosis in tumor cells and improve the effectiveness of photodynamic therapy. In this study, we present a novel nanomedicine delivery and therapeutic system called PyroFPSH, which utilizes a nanozymes-modified metal-organic framework as a carrier. PyroFPSH exhibits remarkable multienzyme-like activities, including glutathione peroxidase (GPx) and catalase (CAT) mimicry, allowing it to overcome apoptosis resistance, reduce endogenous glutathione levels, and continuously generate reactive oxygen species (ROS). In addition, PyroFPSH can serve as a carrier for the targeted delivery of sulfasalazine, a drug that can induce mitochondrial depolarization in tumor cells, thereby reducing oxygen consumption and energy supply in the mitochondria of tumor cells and weakening resistance to other synergistic treatment approaches. Our experimental results highlight the potential of PyroFPSH as a versatile nanoplatform in cancer treatment. This study expands the biomedical applications of nanomaterials as platforms and enables the integration of various novel therapeutic strategies to synergistically improve tumor therapy. It deepens our understanding of multienzyme-mimicking active nanocarriers and mitochondrial damage through photodynamic therapy. Future research can further explore the potential of PyroFPSH in clinical cancer treatment and improve its drug loading capacity, biocompatibility and targeting specificity. In summary, PyroFPSH represents a promising therapeutic approach that can provide new insights and possibilities for cancer treatment.

Clinically used drug arsenic trioxide targets XIAP and overcomes apoptosis resistance in an organoid-based preclinical cancer model

Drug resistance in tumor cells remains a persistent clinical challenge in the pursuit of effective anticancer therapy. Herein, we repurpose clinically used drug arsenic trioxide to target XIAP and overcome cisplatin drug resistance in tumors.

Sonosensitizer Nanoplatforms Augmented Sonodynamic Therapy-Sensitizing Shikonin-Induced Necroptosis Against Hepatocellular Carcinoma.

Apoptosis resistance of hepatocellular carcinoma (HCC) often leads to treatment failure. Nonetheless, overcoming the resistance of HCC to apoptosis by inducing necroptosis of tumor cells to bypass the apoptotic pathway may be a promising treatment strategy. Sonodynamic therapy (SDT) has broad prospects in disease treatment because of its noninvasive characteristic and spatiotemporal control. The combination of SDT and shikonin in the treatment of HCC is expected to be a new tumor treatment method that can overcome apoptosis resistance. In this study, the antitumor effect was evaluated using normal liver cell line WRL68, HCC cell line HepG2 and HepG2 xenograft mouse models. Indocyanine green (ICG) was loaded on nanobubbles (NBs) to construct ICG-loaded nanobubbles (ICG-NBs). Combined sonosensitizer nanoplatforms with ultrasound (US) to achieve efficient SDT, the combination of SDT and shikonin in treating HCC can activate shikonin-induced necroptosis. As a result, tumor cells that produced apoptosis resistance were destroyed by necroptosis. The results indicated a successful preparation of ICG-NBs with a uniform particle size of 273.0 ± 118.9 nm spherical structures. ICG-NB-mediated SDT, in combination with shikonin treatment, inhibited the viability, invasion, and migration of tumor cells. SDT + shikonin treatment group caused a substantial increase in necroptotic cells. The increased degree of tumor necrosis and the upregulated expression of receptor-interacting protein 3 kinase were observed in vivo studies, which indicated that the antitumor effect was accompanied by enhanced necroptosis in the SDT + shikonin treatment group. ICG-NB-mediated SDT combined with shikonin inhibits the growth of HCC by increasing the necroptosis of tumor cells. Therefore, this combination therapy is a promising treatment strategy against the specific cancer.

Genome, Metabolism, or Immunity: Which Is the Primary Decider of Pancreatic Cancer Fate through Non-Apoptotic Cell Death?

Pancreatic ductal adenocarcinoma (PDAC) is a solid tumor characterized by poor prognosis and resistance to treatment. Resistance to apoptosis, a cell death process, and anti-apoptotic mechanisms, are some of the hallmarks of cancer. Exploring non-apoptotic cell death mechanisms provides an opportunity to overcome apoptosis resistance in PDAC. Several recent studies evaluated ferroptosis, necroptosis, and pyroptosis as the non-apoptotic cell death processes in PDAC that play a crucial role in the prognosis and treatment of this disease. Ferroptosis, necroptosis, and pyroptosis play a crucial role in PDAC development via several signaling pathways, gene expression, and immunity regulation. This review summarizes the current understanding of how ferroptosis, necroptosis, and pyroptosis interact with signaling pathways, the genome, the immune system, the metabolism, and other factors in the prognosis and treatment of PDAC.

P10.22.B COMBINATION OF ARTS MIMETICS WITH AUTOPHAGY INHIBITORS AS A NOVEL THERAPEUTIC STRATEGY TO OVERCOME APOPTOSIS RESISTANCE IN GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most common malignant brain tumour in adults. The current standard of care for GBM patients consists of maximal surgical resection followed by chemotherapy and radiation. Despite such an aggressive treatment approach, the average 5-year survival rate for GBM patients is approximately 5%. One of the main reasons for poor therapy response in the GBM is resistance to programmed cell death, otherwise known as apoptosis. One of the mechanisms behind apoptosis resistance relies on the upregulation of inhibitor of apoptosis proteins (IAPs) which are known to hinder pro-apoptotic proteins and allow cell survival under abnormal conditions such as severe DNA damage. However, there are natural IAP antagonists such as ARTS which are capable of stimulating cell death by promoting the degradation of IAPs. To harness the pro-apoptotic function of IAP antagonists, small peptide mimetics of ARTS have been developed. This project investigates the efficacy of utilizing ARTS mimetics as a novel strategy to overcome apoptosis resistance in the GBM treatment. MATERIAL AND METHODS This study utilizes patient-derived cells with exogenous gain-of-function (GOF) overexpression to introduce full-length ARTS protein as well as pharmacological small peptide mimetics of ARTS to evaluate the response of GBM cells following the promotion of ARTS activity. We also employ a patient-derived orthotopic xenograft mouse model to test novel combinatorial strategies in vivo, where we used a nanoparticle drug delivery system to ensure treatment delivery across the blood-brain barrier (BBB). RESULTS We found that patient-derived GBM cells were highly resistant to ARTS-induced apoptosis. Further molecular investigation unveiled a novel role of ARTS in the upregulation of autophagy as a resistance mechanism. A combination of ARTS GOF or mimetic peptides with autophagy inhibitors mitigated resistance to ARTS-mediated apoptosis and drastically decreased GBM cell proliferation. This combination was further tested in the patient-derived xenograft mouse model, which demonstrated the successful delivery of ARTS mimetic peptides and autophagy inhibitors through the BBB via nanoparticle lipid carriers. Animals treated with a combination of the autophagy inhibitor Spautin-1 and ARTS mimetic peptides demonstrated significantly prolonged survival, confirming the therapeutic potential of such combinatorial approach for GBM treatment. CONCLUSION Altogether, these findings uncover a previously unknown role of ARTS in autophagy regulation and provide evidence that the combination of IAP-antagonist mimetics with autophagy inhibitors can be an effective strategy against highly aggressive GBM brain tumours. This work was supported by the Health Sciences Centre Foundation (HSCF).

Perspectives and mechanisms for targeting mitotic catastrophe in cancer treatment.

Mitotic catastrophe is distinct from other cell death modes due to unique nuclear alterations characterized as multi and/or micronucleation. Mitotic catastrophe is a common and virtually unavoidable consequence during cancer therapy. However, a comprehensive understanding of mitotic catastrophe remains lacking. Herein, we summarize the anticancer drugs that induce mitotic catastrophe, including microtubule-targeting agents, spindle assembly checkpoint kinase inhibitors, DNA damage agents and DNA damage response inhibitors. Based on the relationships between mitotic catastrophe and other cell death modes, we thoroughly evaluated the roles played by mitotic catastrophe in cancer treatment as well as its advantages and disadvantages. Some strategies for overcoming its shortcomings while fully utilizing its advantages are summarized and proposed in this review. We also review how mitotic catastrophe regulates cancer immunotherapy. These summarized findings suggest that the induction of mitotic catastrophe can serve as a promising new therapeutic approach for overcoming apoptosis resistance and strengthening cancer immunotherapy.

Necroptosis in human cancers with special emphasis on oral squamous cell carcinoma

Necroptosis is a type of caspase independent ‘programmed or regulated’ necrotic cell death that has a morphological resemblance to necrosis and mechanistic analogy to apoptosis. This type of cell death requires RIPK1, RIPK3, MLKL, death receptors, toll like receptors, interferons, and various other proteins. Necroptosis is implicated in plethora of diseases like rheumatoid arthritis, Alzheimer's disease, Crohn's disease, and head and neck cancers including oral squamous cell carcinoma. Oral carcinomas show dysregulation or mutation of necroptotic proteins, mediate antitumoral immunity, activate immune response and control tumor progression. Necroptosis is known to play a dual role (pro tumorigenic and anti-tumorigenic) in cancer progression and targeting this pathway could be an effective approach in cancer therapy. Necroptosis based chemotherapy has been proposed in malignancies, highlighting the importance of necroptotic pathway to overcome apoptosis resistance and serve as a “fail-safe” pathway to modulate cancer initiation, progression, and metastasis. However, there is dearth of information regarding the use of necroptotic cell death mechanism in the treatment of oral squamous cell carcinoma. In this review, we summarise molecular mechanism of necroptosis, and its protumorigenic and antitumorigenic role in cancers to shed light on the possible therapeutic significance of necroptosis in oral squamous cell carcinoma.

Engineering 2D Multienzyme-Mimicking Pyroptosis Inducers for Ultrasound-Augmented Catalytic Tumor Nanotherapy.

Overcoming apoptosis resistance is necessary to ensure an effective cancer treatment; however, it is currently very difficult to achieve. A desirable alternative for cancer treatment is the targeted activation of pyroptosis, a unique type of programmed cell death. However, the pyroptosis inducers that are efficient for cancer therapy are limited. This work reports the engineering of 2D NiCoOx nanosheets as inducers of the production of harmful reactive oxygen species (ROS), which promote intense cell pyroptosis, and that can be applied to ultrasound (US)-augmented catalytic tumor nanotherapy. The main therapeutic task is carried out by the 2D NiCoOx nanosheets, which have four multienzyme-mimicking activities: peroxidase- (POD), oxidase- (OXD), glutathione peroxidase- (GPx), and catalase- (CAT) mimicking activities. These activities induce the reversal of the hypoxic microenvironment, endogenous glutathione depletion, and a continuous ROS output. The ROS-induced pyroptosis process is carried out via the ROS-NLRP3-GSDMD pathway, and the exogenous US activation boosts the multienzyme-mimicking activities and favors the incremental ROS generation, thus inducing mitochondrial dysfunction. The anti-cancer experimental results support the dominance of NiCoOx nanosheet-induced pyroptosis. This work expands on the biomedical applications of engineering 2D materials for US-augmented catalytic breast cancer nanotherapy and deepens the understanding of the multienzyme activities of nanomaterials.

Ultrasound-Amplified Enzyodynamic Tumor Therapy by Perovskite Nanoenzyme-Enabled Cell Pyroptosis and Cascade Catalysis.

Overcoming apoptosis resistance to achieve efficient breast cancer treatment remains a challenge. The precise induction of another form of programmed cell death, pyroptosis, is an excellent alternative for treating cancer. Ultrasound (US)-enhanced enzyme dynamic (enzyodynamic) therapy is developed by employing LaFeO3 (LFO) perovskite nanocrystals as a substrate to increase the rate of deleterious reactive oxygen species (ROS) generation for intensive cell pyroptosis. LFO nanocrystals possess quadruple enzyme-mimicking activities, including oxidase-, peroxidase-, glutathione peroxidase-, and catalase-mimicking activities, which undertake the dominant therapeutic task through cascade catalytic reactions, including the reversal of hypoxic microenvironment, depletion of endogenous glutathione, and continuous output of ROS. US exogenous stimulation increases the transition rate of the intermediate complex to Fe (II) and favors incremental ROS production, by which the ROS burst-induced pyroptosis process is accomplished through the ROS-TXNIP-NLRP3-GSDMD pathway. Both in vitro and in vivo antineoplastic outcomes affirm the ascendancy of LFO nanozyme-induced pyroptosis. This work highlights the critical role of US coupled with nanocatalytic reactors in pyroptosis-dominant breast cancer treatment with the apoptosis resistance circumvention feature.

Unsaturated Fatty Acid Liposomes Selectively Regulate Glutathione Peroxidase 4 to Exacerbate Lipid Peroxidation as an Adaptable Liposome Platform for Anti-Tumor Therapy.

Regulating non-apoptotic cell death of cancer cells provides a promising strategy to overcome apoptosis resistance during cancer treatment. Lipids are essential components to exacerbate several non-apoptotic cell death pathways. In the present study, unsaturated fatty acid (UFA) liposomes prepared with linoleic acid, oleic acid, or α-linolenic acid have the potential to affect lipid metabolism. Notably, UFA liposomes markedly increased cellular reactive oxygen species (ROS) and down-regulated the expression of glutathione peroxidase 4 (GPX4) in tumor cells, resulting in lipid peroxidation, which in turn caused rapid membrane rupture and induced non-apoptotic cell death of tumor cells. Concomitantly, UFA liposomes induced ROS-mediated tumor-associated macrophages toward a tumoricidal phenotype to reverse the immunosuppressive tumor microenvironment. Consequently, UFA liposomes substantially inhibited tumor growth in a melanoma model by promoting lipid peroxidation, inducing non-apoptotic cell death of tumor cells, and increasing infiltration of anti-tumor immune cells at tumor sites. Therefore, UFA liposomes regulate GXP4 to exacerbate lipid peroxidation and provide a versatile liposome platform for enhancing anti-tumor therapy which could be readily extended to the delivery of anticancer agents.

Multi-omics analysis reveals the panoramic picture of necroptosis-related regulators in pan-cancer.

Background: Unlike apoptosis, necroptosis is a tightly regulated form of programmed cell death (PCD) that occurs in a caspase-independent manner and is mainly triggered by receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 and the RIPK3 substrate mixed-lineage kinase domain-like protein (MLKL). A growing body of evidence has documented that necroptosis, as a novel therapeutic strategy to overcome apoptosis resistance, has potential pro- or anti-tumoral effects in tumorigenesis, metastasis, and immunosurveillance. However, comprehensive multi-omics studies on regulators of necroptosis from a pan-cancer perspective are lacking.Methods: In the present study, a pan-cancer multi-omics analysis of necroptosis-related regulators was performed by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from TCGA, 481 small-molecule drug response data from CTRP, and normal tissue data from GTEx. Pan-cancer pathway-level analyses of necroptosis were conducted by gene set variation analysis (GSVA), including differential expression, clinical relevance, immune cell infiltration, and regulation of cancer-related pathways.Results: Genomic alterations and abnormal epigenetic modifications were associated with dysregulated gene expression levels of necroptosis-related regulators. Changes in the gene expression levels of necroptosis-related regulators significantly influenced cancer progression, intratumoral heterogeneity, alterations in the immunological condition, and regulation of cancer marker-related pathways. These changes, in turn, caused differences in potential drug sensitivity and the prognosis of patients.Conclusion: Necroptosis-related regulators are expected to become novel biomarkers of prognosis and provide a fresh perspective on cancer diagnosis and treatment.

Comprehensive Analysis of Necroptosis in Pancreatic Cancer for Appealing its Implications in Prognosis, Immunotherapy, and Chemotherapy Responses

Objective: Necroptosis represents a new target for cancer immunotherapy and is considered a form of cell death that overcomes apoptosis resistance and enhances tumor immunogenicity. Herein, we aimed to determine necroptosis subtypes and investigate the roles of necroptosis in pancreatic cancer therapy. Methods: Based on the expression of prognostic necroptosis genes in pancreatic cancer samples from TCGA and ICGC cohorts, a consensus clustering approach was implemented for robustly identifying necroptosis subtypes. Immunogenic features were evaluated according to immune cell infiltrations, immune checkpoints, HLA molecules, and cancer–immunity cycle. The sensitivity to chemotherapy agents was estimated using the pRRophetic package. A necroptosis-relevant risk model was developed with a multivariate Cox regression analysis. Results: Five necroptosis subtypes were determined for pancreatic cancer (C1∼C5) with diverse prognosis, immunogenic features, and chemosensitivity. In particular, C4 and C5 presented favorable prognosis and weakened immunogenicity; C2 had high immunogenicity; C1 had undesirable prognosis and high genetic mutations. C5 was the most sensitive to known chemotherapy agents (cisplatin, gemcitabine, docetaxel, and paclitaxel), while C4 displayed resistance to aforementioned agents. The necroptosis-relevant risk model could accurately predict prognosis, immunogenicity, and chemosensitivity. Conclusion: Our findings provided a conceptual framework for comprehending necroptosis in pancreatic cancer biology. Future work is required for evaluating its relevance in the design of combined therapeutic regimens and guiding the best choice for immuno- and chemotherapy.

Nobiletin Induces Ferroptosis in Human Skin Melanoma Cells Through the GSK3β-Mediated Keap1/Nrf2/HO-1 Signalling Pathway.

Melanoma is an aggressive malignant skin tumour with an increasing global incidence. However, current treatments have limitations owing to the acquired tumour drug resistance. Ferroptosis is a recently discovered form of programmed cell death characterised by iron accumulation and lipid peroxidation and plays a critical role in tumour growth inhibition. Recently, ferroptosis inducers have been regarded as a promising therapeutic strategy to overcome apoptosis resistance in tumour cells. In this study, we reported that nobiletin, a natural product isolated from citrus peel, and exhibited antitumour activity by inducing ferroptosis in melanoma cells. Subsequently, we further explored the potential mechanism of nobiletin-induced ferroptosis, and found that the expression level of glycogen synthase kinase 3β (GSK3β) in the skin tissue of patients with melanoma was significantly reduced compared to that in the skin of normal tissue. Additionally, nobiletin increased GSK3β expression in melanoma cells. Moreover, the level of Kelch-like Ech-associated protein-1 (Keap1) was increased, while the level of nuclear factor erythroid 2-related factor 2 (Nrf2), and haem oxygenase-1 (HO-1) was decreased in nobiletin-treated melanoma cells, suggesting that the antioxidant defence system was downregulated. Furthermore, knockdown of GSK3β significantly reduced nobiletin-induced ferroptosis and upregulated the Keap1/Nrf2/HO-1 signalling pathway, while the opposite was observed in cells overexpressing GSK3β. In addition, molecular docking assay results indicated that nobiletin showed strong binding affinities for GSK3β, Keap1, Nrf2, and HO-1. Taken together, our results demonstrated that nobiletin could induce ferroptosis by regulating the GSK3β-mediated Keap1/Nrf2/HO-1 signalling pathway in human melanoma cells. Hence, nobiletin stands as a promising drug candidate for melanoma treatment with development prospects.

Targeting the translational machinery to overcome apoptosis resistance in pancreatic cancer

Targeting the translational machinery to overcome apoptosis resistance in pancreatic cancer