Induce Cancer Cell Death Research Articles

Evaluating STING Agonist Impact on Kaposi’s Sarcoma-Associated Virus-related Cancers

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an etiological agent of multiple malignancies associated with compromised immunity, such as Kaposi’s sarcoma (KS) and Primary Effusion Lymphoma (PEL). KSHV infection is lifelong with no available treatment or vaccines and poses a high risk to immunocompromised individuals. The virus is transmitted via the oral and sexual route, and has a biphasic life cycle with a short lytic replication cycle followed by long-term latency, with the expression of few genes making detection difficult. Reactivation from latency results in a cascade of viral gene expression and pathogenesis. Critical to controlling KSHV infection is the cGAS-STING DNA-sensing pathway (STING), known to activate the type I interferon response and induce cancer cell death or growth inhibition. STING exhibits both anti-viral and anti-tumor responses, showing promise as a protein of interest to study for the development of a therapeutic treatment. By examining the in vitro effectiveness of STING agonists in inhibiting KSHV oncogenesis in PEL, the study aimed to provide the foundation for a potential novel therapeutic approach. Six patient-derived PEL cell lines were treated with the STING agonist diaminobenzamidazole (diABZI) in a dose-dependent manner. Four of the PEL cell lines exhibited decreased cell growth, viability, and colony formation, while two PEL cell lines were resistant to treatment, correlating with the presence or absence of STING expression. RNA-sequencing was performed and discovered upregulation of multiple interferon-stimulated genes (ISG) in responsive cell lines. Further investigations will explore STING agonists’ inhibition of PEL oncogenesis in vitro via colony formation and in vivo using a PEL xenograft model with NSG mice. Successful completion of this project will offer insight into potential clinical treatments for targeting KSHV infection and reactivation.

Tumor integrin-targeted glucose oxidase enzyme promotes ROS-mediated cell death that combines with interferon alpha therapy for tumor control.

While heightened intratumoral levels of reactive oxygen species (ROS) are typically associated with a suppressive tumor microenvironment, under certain conditions ROS contribute to tumor elimination. Treatment approaches, including some chemotherapy and radiation protocols, increase cancer cell ROS levels that influence their mechanism of cell death and subsequent recognition by the immune system. Furthermore, activated myeloid cells rapidly generate ROS upon encounter with pathogens or infected cells to eliminate disease, and recently, this effector function has been noted in cancer contexts as well. Collectively, ROS-induced cancer cell death may help initiate adaptive anti-tumor immune responses that could synergize with current approved immunotherapies, for improved control of solid tumors. In this work, we explore the use of glucose oxidase, an enzyme which produces hydrogen peroxide, a type of ROS, to therapeutically mimic the endogenous oxidative burst from myeloid cells to promote antigen generation within the tumor microenvironment. We engineer the enzyme to target pan-tumor expressed integrins both as a tumor-agnostic therapeutic approach, but also as a strategy to prolong local enzyme activity following intratumoral administration. We found the targeted enzyme potently induced cancer cell death and enhanced cross-presentation by dendritic cells in vitro, and further combined with interferon alpha for long-term tumor control in murine MC38 tumors in vivo. Optimizing the single-dose administration of this enzyme overcomes limitations with immunogenicity noted for other pro-oxidant enzyme approaches. Overall, our results suggest ROS-induced cell death can be harnessed for tumor control, and highlight the potential use of designed enzyme therapies alongside immunotherapy against cancer.

Synergistic Inhibition of Colorectal Cancer Cells by Autocrine Motility Factor Peptide and Glycyrrhetinic Acid.

Anti-cancer peptides are a powerful drug concept that induces cancer cell death through growth inhibition and membrane disruption, providing broad efficacy. The autocrine motility factor (AMF) interacts with the AMF receptor, regulating cancer cell motility, proliferation, metastasis, and angiogenesis through autocrine and paracrine pathways. However, studies verifying the synergistic effect of the combined use of anti-cancer drugs extracted from plants and AMF treatment are insufficient. The effects of AMF-derived peptide sequences were evaluated in HT29 and SW620 colorectal cancer (CRC) cell lines. The study assessed the impact of AMF peptides on cell proliferation, colony formation, the Nicotinamide Adenine Dinucleotide Phosphate/Reduced Nicotinamide Adenine Dinucleotide Phosphate (NADP+/NADPH) ratio, and reactive oxygen species (ROS) generation in these CRC cells. Additionally, the combined effect of AMF peptides and glycyrrhetinic acid (GA), a compound derived from licorice plants, was investigated by analyzing cell proliferation, colony formation, ROS production, and cell cycle progression in CRC cells. AMF peptides significantly inhibited CRC cell growth (p < 0.05), decreased colony formation (p < 0.05), and increased the NADP+/NADPH ratio (p < 0.05) and ROS production (p < 0.001). When combined with GA, AMF peptides enhanced GA's effects on CRC cells, further suppressing cell growth (p < 0.05) and colony formation (p < 0.05) while increasing ROS generation (p < 0.05). The synergy between AMF peptides and GA, derived from licorice plants, suggests the potential for combined peptide-phytochemical therapy for treating CRC.

Integrated stress response plasticity governs normal cell adaptation to chronic stress via the PP2A-TFE3-ATF4 pathway.

The integrated stress response (ISR) regulates cell fate during conditions of stress by leveraging the cell's capacity to endure sustainable and efficient adaptive stress responses. Protein phosphatase 2A (PP2A) activity modulation has been shown to be successful in achieving both therapeutic efficacy and safety across various cancer models. However, the molecular mechanisms driving its selective antitumor effects remain unclear. Here, we show for the first time that ISR plasticity relies on PP2A activation to regulate drug response and dictate cellular survival under conditions of chronic stress. We demonstrate that genetic and chemical modulation of the PP2A leads to chronic proteolytic stress and triggers an ISR to dictate whether the cell lives or dies. More specifically, we uncovered that the PP2A-TFE3-ATF4 pathway governs ISR cell plasticity during endoplasmic reticular and cellular stress independent of the unfolded protein response. We further show that normal cells reprogram their genetic signatures to undergo ISR-mediated adaptation and homeostatic recovery thereby avoiding toxicity following PP2A-mediated stress. Conversely, oncogenic specific cytotoxicity induced by chemical modulation of PP2A is achieved by activating chronic and irreversible ISR in cancer cells. Our findings propose that a differential response to chemical modulation of PP2A is determined by intrinsic ISR plasticity, providing a novel biological vulnerability to selectively induce cancer cell death and improve targeted therapeutic efficacy.

Tumor Microenvironment-Activated In Situ Synthesis of Peroxynitrite for Enhanced Chemodynamic Therapy.

Chemodynamic therapy (CDT) can induce cancer cell death through hydroxyl radicals (·OH) generated from Fenton or Fenton-like reactions. Compared with traditional therapies, CDT effectively overcomes inevitable drug resistance and exhibits low side effects. However, clinical application still faces challenges, primarily due to insufficient ·OH generation and the short-lifetime of ·OH in vivo. To address these challenges, we developed a peroxynitrite (ONOO-)-based CDT nanodrug (DOX@PMOF) composed of MOF-199, NO donor (PArg), and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) activator (doxorubicin, DOX). In DOX@PMOF, MOF-199 serves as both a carrier for loading DOX and a source of Cu+ for triggering CDT. Upon uptake by cancer cells, the high concentration of glutathione (GSH) reduces MOF-199 to Cu+, which then reacts with H2O2 to generate ·OH. Moreover, the released DOX upregulates NOX4 expression, leading to the elevated H2O2 level and thereby promoting a high-efficiency Fenton-like reaction for sufficient ·OH generation. Subsequently, PArg generates abundant NO in response to the tumor microenvironment, leading to a cascade of NO and ·OH for the in situ synthesis of ONOO-. ONOO- is more toxic and has a longer lifetime and diffusion distance than ·OH, resulting in a more effective CDT treatment. To further enhance the in vivo therapeutic effect, we coated DOX@PMOF with a homologous cell membrane to form an active tumor-targeting nanodrug (DOX@MPMOF), which has demonstrated the ability to effectively inhibit tumor growth and metastasis while exhibiting good biosafety.

MLumiOpto is a Mitochondrial-Targeted Gene Therapy for Treating Cancer.

Mitochondria are important in various aspects of cancer development and progression. Targeting mitochondria in cancer cells holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we developed mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. The therapeutic approach included synthesis of a blue light-gated cationic channelrhodopsin (CoChR) in the IMM and co-expression of a blue bioluminescence-emitting nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes were selectively delivered to cancer cells in vivo by an adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV (mAb-Exo-AAV). Induction with NLuc luciferin elicited robust endogenous bioluminescence, which activated CoChR, triggering cancer cell mitochondrial depolarization and subsequent cell death. Importantly, mLumiOpto demonstrated remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma and triple-negative breast cancer xenograft mouse models. Furthermore, the approach induced an anti-tumor immune response, increasing infiltration of dendritic cells and CD8+ T cells in the tumor microenvironment. These findings establish mLumiOpto as a promising therapeutic strategy by targeting cancer cell mitochondria in vivo.

Exopolysaccharides from the Green Microalga Strain Coelastrella sp. BGV-Isolation, Characterization, and Assessment of Anticancer Potential.

Algal metabolites have been extensively studied as potential anticancer therapeutics. Among them, polysaccharides have attracted much attention because of their beneficial biological effects and safety. In the present research, the chemical characteristics, antitumor, and proapoptotic activities of extracellular polysaccharides (EPS) isolated from a new Bulgarian strain of the green microalga Coelastrella sp. BGV were investigated. A fast and convenient method of precipitation with cold ethanol was used to isolate EPS from the culture medium. The chemical characteristics of the isolated EPS were examined by colorimetric and spectrophotometric analyses, HPSEC-RID and HPLC-UV chromatography, and FT-IR spectroscopy. The results showed that the isolated EPS sample consists of three carbohydrate fractions with different molecular weights (11.5 × 104 Da, 30.7 × 104 Da, and 72.4 × 104 Da, respectively) and contains 7.14 (w/w%) protein. HPLC-UV analysis revealed the presence of galactose and fucose. The total uronic acid content in the sample was 4.5 (w/w%). The IR-FT spectrum of EPS revealed the presence of various functional groups typical of a polysaccharide (or proteoglycan) composed primarily of neutral sugars. The anticancer potential of the obtained EPS was assessed using cell lines with cancerous and non-cancerous origins as in vitro experimental models. The results of the performed MTT assay showed that EPS reduced the viability of the cervical and mammary carcinoma cell lines HeLa and MCF-7, while the control non-cancer cell lines BALB/3T3 and HaCaT were less affected. The HeLa cell line showed the highest sensitivity to the effects of EPS and was therefore used for further studies of its anticancer potential. The ability of EPS to inhibit cancer cell migration was demonstrated by wound-healing (scratch) assay. The cell cycle FACS analysis indicated that the EPS treatment induced significant increases in the sub G1 cell population and decreases of the percentages of cells in the G1, S, and G2-M phases, compared to the control. The fluorescent microscopy studies performed using three different staining methods in combination with Annexin V-FITC flow cytometric analysis clearly demonstrate the ability of EPS to induce cancer cell death via the apoptosis pathway. Moreover, an altered pattern and intensity of the immunocytochemical staining for the apoptosis- and proliferation-related proteins p53, bcl2, and Ki67 was detected in EPS-treated HeLa cancer cells as compared to the untreated controls. The obtained results characterize the new local strain of green microalgae Coelastrella sp. BGV as a producer of EPS with selective antitumor activity and provide an opportunity for further studies of its pharmacological and biotechnological potential.

Investigation of Folate-Functionalized Magnetic-Gold Nanoparticles Based Targeted Drug Delivery for Liver: In Vitro, In Vivo and Docking Studies.

Magnetic nanoparticles used for targeted drug administration present a promising approach in cancer treatment owing to its notable advantages, such as targeted and enhanced encapsulation ability and improved bio protection compared with conventional drug delivery methods. Au shell-iron core nanoparticles (Fe3O4@Au) were manufactured by a chemical process, coated with dextran to encapsulate curcumin, and functionalized for precision drug delivery using folic acid to combat liver cancer. Dynamic light scattering, scanning electron microscopy, transmission electron microscopy, vibrational spectroscopy, and magnetometry were applied to assess the synthesis of the Fe3O4@Au-DEX-CU-FA compound. The mean size, zeta potential, and polydispersity of Fe3O4@Au-DEX-CU-FA were 63.3 ± 2.33 nm, -68.3 ± 1.78 mV, and 0.041 ± 0.008, respectively. Molecular docking models were created to examine the relationship between Fe3O4@Au-CU and BCL-XL, BAK, and to identify potential binding sites. The loading efficiency and release profile tests examined the medication delivery system's ability. MTT assay was subsequently utilized to determine the optimal dosage and therapeutic efficacy of Fe3O4@Au-DEX-CU-FA on cancer SNU-449 and healthy THLE-2 cell lines. Flow cytometry demonstrated that Fe3O4@Au-DEX-CU-FA effectively induced cancer cell death. Fe3O4@Au-DEX-FA showed a regulated release profile of free curcumin at 37 °C and pH values of 7.4 and 5.4. Real-time PCR revealed increased BAK expression and decreased BCL-XL expression. Nude tumor-bearing mice were used for in vivo experiments. Fe3O4@Au-DEX-CU-FA treatment dramatically reduced the swelling size compared with free CU and control treatments. It also resulted in a longer lifespan, expanded splenocyte proliferation, increased IFN-γ levels, and decreased IL-4 levels. The regular cells showed no cytotoxic effect compared with the cancer type, confirming that Fe3O4@Au-DEX-CU-FA maintained its potent anticancer actions. The data suggests that Fe3O4@Au-DEX-CU-FA possesses a promising potential as a therapeutic agent for combating tumors.

Hydroxychloroquine loaded hollow apoferritin nanocages for cancer drug repurposing and autophagy inhibition

Hydroxychloroquine sulfate (HCQ) is currently being repurposed for cancer treatment. The antitumor mechanism of HCQ is inhibition of cellular autophagy, but its therapeutic potential is severely limited by poor solubility, lack of tumor targeting and lower cellular uptake. Therefore, utilization of human H-chain apoferritin (HFn) composed only of heavy subunits is an attractive approach for tumor targeting drug delivery. This study focused on pH-triggered encapsulation of HCQ within the inner cavity of HFn to form HFn@HCQ nanoparticles for tumor-targeted drug delivery. Characterization using a range of techniques has been used to confirm the successful establishment of HFn@HCQ. HFn@HCQ exhibited pH-responsive release behavior, with almost no drug release at pH 7.4, but 80% release at pH 5.0. Owing to its intrinsic binding to transferrin receptor 1 (TfR1), HFn@HCQ was significantly internalized through TfR1-mediated endocytosis, with a 4.4-fold difference of internalization amount across cell lines. Additionally, HFn@HCQ enhanced the antitumor effect against four different cancer cell lines when compared against HCQ alone, especially in TfR1 high-expressing cells, where the inhibitory effect was 3-fold higher than free HCQ. The autophagy inhibition of HFn@HCQ has been demonstrated, which is a major pathway to induce cancer cell death. According to current findings, HFn based drug delivery is a promising strategy to target and kill TfR1 overexpressing tumor cells.

Biomimetic Functional Nanocomplexes for Photothermal Cancer Chemoimmunotheranostics

This study presents a novel multimodal cancer theranostic platform developed using tumor cell‐coated biomimetic carbon nanohorn (CNH) complexes that encapsulate the anticancer drug paclitaxel (PTX). This platform combines photothermal therapy, chemotherapy, and immunotherapy to fight against malignant colorectal cancer. These engineered nanocomplexes are designed to deliver sufficient PTX molecules into a targeted solid tumor in a light‐controllable manner while inducing significant photothermal and antitumor immune responses. The outstanding photothermal conversion property of the CNHs under near‐infrared light enables effective cancer cell ablation and awakening of cytotoxic immune responses. Tumor cell membrane‐coated CNHs show improved water dispersibility, immune evasion, and targeting capabilities alongside enhanced immune activation against tumors. The efficacy of the biomimetic functional CNH nanocomplexes is demonstrated through excellent tumor‐targeting, controlled drug‐releasing behavior, and induction of cancer cell death, contributing to a robust antitumor response. This study provides a promising approach to cancer treatment by integrating multiple therapeutic modalities into a single platform, potentially enhancing treatment efficacy to combat intractable cancer.

Engineering Cells for Cancer Therapy.

ConspectusCells, particularly living cells, serve as natural carriers of bioactive substances. Their inherent low immunogenicity and multifunctionality have garnered significant attention in the realm of disease treatment applications, specifically within the domains of cancer immunotherapy and regenerative tissue repair. Nevertheless, several prominent challenges impede their swift translation into clinical applications, including obstacles related to large-scale production feasibility and high utilization costs. To address these issues comprehensively, researchers have proposed the notion of bionic cells that are synthetically generated through chemical or biosynthetic means to emulate cellular functions and behaviors. However, artificial cell strategies encounter difficulties in fully replicating the intricate functionalities exhibited by living cells while also grappling with the complexities associated with design implementation for clinical translation purposes. The convergence of disciplines has facilitated the reform of living cells through a range of approaches, including chemical-, biological-, genetic-, and materials-based methods. These techniques can be employed to impart specific functions to cells or enhance the efficacy of therapy. For example, cells are engineered through gene transduction, surface modifications, endocytosis of drugs as delivery systems, and membrane fusion. The concept of engineered cells presents a promising avenue for enhancing control over living cells, thereby enhancing therapeutic efficacy while concurrently mitigating toxic side effects and ultimately facilitating the realization of precision medicine.In this Account, we present a comprehensive overview of our recent research advancements in the field of engineered cells. Our work involves the application of biological or chemical engineering techniques to manipulate endogenous cells for therapeutics or drug delivery purposes. For instance, to avoid the laborious process of isolating, modifying, and expanding engineered cells in vitro, we proposed the concept of in situ engineered cells. By applying a hydrogel loaded with nanoparticles carrying edited chimeric antigen receptor (CAR) plasmids within the postoperative cavity of glioma, we successfully targeted tumor-associated macrophages for gene editing, leading to effective tumor recurrence inhibition. Furthermore, leveraging platelet's ability to release microparticles upon activation at injury sites, we modified antiprogrammed death 1 (PD-1) antibodies on their surface to suppress postoperative tumor recurrence and provide immunotherapy for inoperable tumors. Similarly, by exploiting bacteria's active tropism toward sites of inflammation and hypoxia, we delivered protein drugs by engineered bacteria to induce cancer cell death through pyroptosis initiation and immunotherapy strategies. In the final section, we summarize our aforementioned research progress while providing an outlook on cancer therapy and the hurdles for clinical translation with potential solutions or future directions based on the concept of engineered cells.

Redox-active vitamin C suppresses human osteosarcoma growth by triggering intracellular ROS-iron–calcium signaling crosstalk and mitochondrial dysfunction

Pharmacological vitamin C (VC) has gained attention for its pro-oxidant characteristics and selective ability to induce cancer cell death. However, defining its role in cancer has been challenging due to its complex redox properties. In this study, using a human osteosarcoma (OS) model, we show that the redox-active property of VC is critical for inducing non-apoptotic cancer cell death via intracellular reactive oxygen species (ROS)-iron-calcium crosstalk and mitochondrial dysfunction. In both 2D and 3D OS cell culture models, only the oxidizable form of VC demonstrated potent dose-dependent cytotoxicity, while non-oxidizable and oxidized VC derivatives had minimal effects. Live-cell imaging showed that only oxidizable VC caused a surge in cytotoxic ROS, dependent on iron rather than copper. Inhibitors of ferroptosis, a form of iron-dependent cell death, along with classical apoptosis inhibitors, were unable to completely counteract the cytotoxic effects induced by VC. Further pharmacological and genetic inhibition analyses showed that VC triggers calcium release through inositol 1,4,5-trisphosphate receptors (IP3Rs), leading to mitochondrial ROS production and eventual cell death. RNA sequencing revealed down-regulation of genes involved in the mitochondrial electron transport chain and oxidative phosphorylation upon pharmacological VC treatment. Consistently, high-dose VC reduced mitochondrial membrane potential, oxidative phosphorylation, and ATP levels, with ATP reconstitution rescuing VC-induced cytotoxicity. In vivo OS xenograft studies demonstrated reduced tumor growth with high-dose VC administration, concomitant with the altered expression of mitochondrial ATP synthase (MT-ATP). These findings emphasize VC's potential clinical utility in osteosarcoma treatment by inducing mitochondrial metabolic dysfunction through a vicious intracellular ROS-iron-calcium cycle.

Novel Thiazole-Hydrazide Derivatives and Their Anticancer Properties

Objective: Cancer is described as uncontrolled cell division, and it is a major problem in Türkiye, as well as around the world. Current treatment options are insufficient in some cases, particularly the treatment rate for lung cancer cases, which is very low. Meanwhile, current pharmaceuticals have several side effects, such as drug-drug interactions, and cognitive disorders. Additionally, developing drug resistance is a major problem for current and future management of the disease. Accordingly, the search for new molecules or alternative treatment options is actively achieved. Methods: In this study, eight novel thiazole-hydrazide analogs were designed and synthesized, and their structural elucidation was performed via HRMS, 1H-NMR, and 13C-NMR. Their biological activity profile was investigated on A549 lung carcinoma and MCF7 breast adenocarcinoma cells. To determine the selective cytotoxicity on cancer cells, they were also tested against NIH/3T3 healthy cell line. Besides that, an in silico study was performed to understand the binding modes of the compounds. Results: The results showed that in the serial 4f and 4g, the most bulky analogues, showed no inhibition against any cell type, even at the highest concentration tested. On the other hand, 4a, 4b, 4d, 4e, and 4h showed less cytotoxicity on healthy cells than A549 cells, so they exhibited significant cytotoxicity and a selective profile against A549 cancer cells. While they also inhibited MCF7 cells. The major point is that para-chlorophenyl analogs at the fourth position on thiazole (4a and 4d) displayed a better anticancer profile than ortho-chlorophenyl analogs. These two compounds were also investigated for their apoptotic effects using in silico studies. Both experimental and in silicon studies revealed that the combination of thiazole and hydrazinoacetyl has a significant impact against cancer cells, and in silico study also suggested that tri-substitute thiazole ring has anticancer potential that induced cancer cell death via apoptosis. Conclusion: Results of this study was presented that compound 4a was the most potent compound against lung cancer cells (A549) and 4d was the most potent compound against breast cancer cells (MCF-7). Furthermore, analyzing the molecular docking study for promising compounds (4a and 4d) suggested that interactions with the loop region residues have a pivotal role in inducing caspase-3 enzyme activity. It was concluded that hybridization of thiazole and hydrazinoacetyl moieties is responsible for the anticancer activity.

T cell receptor-directed antibody-drug conjugates for the treatment of T cell-derived cancers

T cell-derived cancers are hallmarked by heterogeneity, aggressiveness, and poor clinical outcomes. Available targeted therapies are severely limited due to a lack of target antigens that allow discrimination of malignant from healthy T cells. Here we report a novel approach for the treatment of T cell diseases based on targeting the clonally rearranged T cell receptor displayed by the cancerous T cell population. As a proof of concept, we identified an antibody with unique specificity towards a distinct TCR and developed antibody-drug conjugates, precisely recognizing and eliminating target T cells while preserving overall T cell repertoire integrity and cellular immunity. Our anti-TCR antibody-drug conjugates demonstrated effective receptor-mediated cell internalization, associated with induction of cancer cell death with strong signs of apoptosis. Furthermore, cell proliferation-inhibiting bystander effects observed on target-negative cells may contribute to the molecules’ anti-tumor properties precluding potential tumor escape mechanisms. To our knowledge, this represents the first anti-TCR antibody-drug conjugate designed as custom-tailored immunotherapy for T cell-driven pathologies.

A biochemical assessment of apoptosis-inducing impact of Salinomycin in combination with ciprofloxacin on human leukemia KG1-a stem-like cells in the presence and absence of insulin.

Acute Myeloid Leukemia (AML) is a fast-developing invading cancer that impacts the blood and bone marrow, marked by the rapid proliferation of abnormal white blood cells. Chemotherapeutic agents, a primary treatment for AML, encounter clinical limitations such as poor solubility and low bioavailability. Previous studies have highlighted antibiotics as effective in inducing cancer cell death and potentially preventing metastasis. Besides, insulin is known to activate the PI3K/Akt pathway, often disrupted in cancers, leading to enhanced cell survival and resistance to apoptosis. In light of the above-mentioned points, we examined the anti-cancer impact of antibiotics Ciprofloxacin (CP) and Salinomycin (SAL) and their combination on KG1-a cells in the presence and absence of insulin. This was accomplished by exposing KG1-a cells to different doses of CP and SAL alone, in combination, and with or without insulin for 24-72h. Cell viability was evaluated using the MTT assay. Besides, apoptotic effects were examined using Hoechst staining and Annexin-V/PI flow cytometry. The expression levels of Bax, p53, BIRC5, Akt, PTEN, and FOXO1 were analyzed through Real-Time PCR. CP and SAL demonstrated cytotoxic and notable pro-apoptotic impact on KG1-a cells by upregulating Bax and p53 and downregulating BIRC5, leading to G0/G1 cell cycle arrest and prevention of the PI3K-Akt signaling pathway. Our findings demonstrated that combination of CP and SAL promote apoptosis in the KG1-a cell line by down-regulating BIRC5 and Akt, as well as up-regulating Bax, p53, PTEN, and FOXO1. Additionally, the findings strongly indicated that insulin effectively mitigates apoptosis by enhancing Akt expression and reducing FOXO1 and PTEN gene expression in the cells treated with CP and SAL. Our findings showed that the combined treatment of CP and SAL exhibit a strong anti-cancer effect on leukemia KG1-a cells. Moreover, it was discovered that the PI3K-Akt signaling can be a promising target in leukemia treatment particularly in hyperinsulinemia condition.

Biological Activity of Natural and Synthetic Peptides as Anticancer Agents.

Cancer is one of the leading causes of morbidity and death worldwide, making it a serious global health concern. Chemotherapy, radiotherapy, and surgical treatment are the most used conventional therapeutic approaches, although they show several side effects that limit their effectiveness. For these reasons, the discovery of new effective alternative therapies still represents an enormous challenge for the treatment of tumour diseases. Recently, anticancer peptides (ACPs) have gained attention for cancer diagnosis and treatment. ACPs are small bioactive molecules which selectively induce cancer cell death through a variety of mechanisms such as apoptosis, membrane disruption, DNA damage, immunomodulation, as well as inhibition of angiogenesis, cell survival, and proliferation pathways. ACPs can also be employed for the targeted delivery of drugs into cancer cells. With over 1000 clinical trials using ACPs, their potential for application in cancer therapy seems promising. Peptides can also be utilized in conjunction with imaging agents and molecular imaging methods, such as MRI, PET, CT, and NIR, improving the detection and the classification of cancer, and monitoring the treatment response. In this review we will provide an overview of the biological activity of some natural and synthetic peptides for the treatment of the most common and malignant tumours affecting people around the world.

Enhancing PDT efficacy in NMIBC: Efflux inhibitor mediated improvement of PpIX levels and efficacy of the combination of PpIX-PDT and SO-cleavable prodrugs.

Protoporphyrin IX (PpIX)-based photodynamic therapy (PDT) has shown limited efficacy in nonmuscle-invasive bladder cancer (NMIBC). To improve PDT efficacy, we developed singlet oxygen-cleavable prodrugs. These prodrugs, when combined with PpIX-PDT, induce cancer cell death through both PDT and drug release mechanisms. Inhibition of PpIX efflux was reported to be an effective strategy to improve PpIX-PDT in certain cancer cells. Our main goal was to investigate whether adding an efflux inhibitor to the combination of PpIX and prodrugs can improve the PpIX levels in bladder cancer cells and the release of active drugs, thus improving the overall efficacy of the treatment. We treated bladder cancer cell lines with lapatinib and evaluated intracellular PpIX fluorescence, finding significantly increased accumulation. Combining lapatinib with prodrugs led to significantly reduced cell viability compared to prodrugs or PpIX-PDT alone. The effect of lapatinib depended on the expression level of the efflux pump in bladder cancer cells. Interestingly, lapatinib increased paclitaxel (PTX) prodrug uptake by threefold compared to prodrug alone. Adding an efflux inhibitor (e.g., lapatinib) into bladder instillation solutions could be a straightforward and effective strategy for NMIBC treatment, particularly in tumors expressing efflux pumps, with the potential for clinical translation.

Multi-Cohort Transcriptomic Profiling of Medical Gas Plasma-Treated Cancers Reveals the Role of Immunogenic Cell Death.

The therapeutic potential of cold physical gas plasma operated at atmospheric pressure in oncology has been thoroughly demonstrated in numerous preclinical studies. The cytotoxic effect on malignant cells has been attributed mainly to biologically active plasma-generated compounds, namely, reactive oxygen and nitrogen species. The intracellular accumulation of reactive oxygen and nitrogen species interferes strongly with the antioxidant defense system of malignant cells, activating multiple signaling cascades and inevitably leading to oxidative stress-induced cell death. This study aims to determine whether plasma-induced cancer cell death operates through a universal molecular mechanism that is independent of the cancer cell type. Using whole transcriptome data, we sought to investigate the activation mechanism of plasma-treated samples in patient-derived prostate cell cultures, melanoma, breast, lymphoma, and lung cancer cells. The results from the standardized single-cohort gene expression analysis and parallel multi-cohort meta-analysis strongly indicate that plasma treatment globally induces cancer cell death through immune-mediated mechanisms, such as interleukin signaling, Toll-like receptor cascades, and MyD88 activation leading to pro-inflammatory cytokine release and tumor antigen presentation.

Examining 1-year mortality risk among patients with malignant melanoma undergoing immune checkpoint inhibitor therapy with a history of cannabis use.

11046 Background: Cannabis use has become an increased topic of discussion in the United States due to rise in legalization, thereby increasing its accessibility for recreational and medicinal use in diseases like cancer. Immune Checkpoint Inhibitor (ICI) therapy has also recently been increasing in patient with metastatic cancers such as melanoma by targeting PD1 or PD-L1 receptors to manipulate the body’s immune response to induce cancer cell death. Cannabis is mediated in part by the CB1 and CB2 receptors in the endocannabinoid system that is present in the natural immune system. Due to the body’s immune response to cannabis, it is hypothesized this could interfere with the activity of ICI therapy. However, research examining this is sparse. Therefore, the goal was to assess mortality in malignant melanoma patients with a history of cannabis use who undergo ICI therapy. Methods: A retrospective cohort study was performed with TriNetX, a federated database of ~100 million patients across 84 healthcare organizations. Patients &gt;17 years from 2012-2023 were identified based on ICI-therapy initiation within 1 month of malignant melanoma diagnosis. Cohorts were then created by history of those with and without cannabis use disorder. 1:1 propensity score matching was conducted to control for confounding comorbidities and demographics. Unadjusted and adjusted hazard ratios (aHR) with 95% CI were calculated for 1-year mortality after therapy initiation. HR’s were estimated using the Cox proportional hazard model. Survival curves were compared using the log-rank test. Results: A total 14589 melanoma patients who underwent ICI therapy were identified, of which 2.3% had documented cannabis use disorder. Prior to matching, melanoma patients with cannabis history had a statistically significant higher 1-year mortality compared to those with no cannabis history (HR [95%CI] = 1.29 [1.04,1.6], log rank test: p=0.0197). After matching, two balanced cohorts of 344 patients remained and adjusting for confounders revealed that melanoma patients with cannabis history had no significant difference in 1-year mortality risk compared to patients without cannabis history (1.18 [0.87,1.6], log rank test: p=0.293). Conclusions: Cannabis use among melanoma patients was shown to not have any meaningful difference in 1-year mortality risk compared to patients without cannabis use history while undergoing ICI-therapy. Additional studies, such as examining cannabis frequency and dosage, is warranted to further examine its effect.

Effects of common nutraceutical supplements marketed for cancer prevention on tumor cell growth.

e22504 Background: In 2022, there were 1.9 million new cancer cases in the US. Data indicates that many patients receiving a cancer diagnosis begin taking supplements, believing that these products improve health. Unfortunately, most supplements lack sufficient clinical trial data to substantiate their use. Our team explores the anticancer effects of natural compounds in common nutraceuticals. We have confirmed that six compounds induce cancer cell death in vitro. However, at sublethal doses, they exhibit a biphasic effect and promote cancer cell growth. Additionally, we conduct a systematic review of these compounds to aggregate data from clinical trials on their effects in a cancer context. Methods: From the medical literature, common phytochemicals reported to have anticancer properties &amp; sold in nutraceutical products were tested using established cancer cell lines, which include the breast, liver, colon, and ovary as the tissues of origin—cellular proliferation was measured by MTT assays. Half-maximal inhibitory concentration (IC50) was calculated, and in vitro assays described in the literature were modified to test low doses of the compounds over 96 hours. Chemicals identified to promote cell proliferation were used to conduct a systematic literature review in the PubMed database from all time through December 2023, using MeSH terms with the keywords "cancer" and "clinical trial" to tabulate compound effects in clinical trials. Results: 6 phytochemicals, reported to have anticancer properties, exhibited biphasic effects. High doses effectively suppressed cancer cells, while sublethal low doses (fractions of the IC50) induced the proliferation of cancer cells. These compounds &amp; enriched extracts include Curcumin, Resveratrol, Rosemary extract, Rosmarinic acid, Hederagenin, &amp; Kava extract. Curcumin &amp; Resveratrol, which dominate the nutraceutical market, were specifically chosen for a systematic literature review. Despite their widespread use, relatively few formal clinical trials have been conducted in the cancer setting, and most showed negative or minimal anticancer effects in treated patients. No pro-growth tumor effects were reported in these trials. However, the follow-up periods were short, and the study sample sizes were small. Conclusions: We discovered 6 compounds &amp; enriched extracts, widely marketed for anti-cancer properties, actually promote cancer cell growth at low doses. Curcumin &amp; Resveratrol, which are prevalent in the U.S. supplement market, have insufficient clinical trial data to validate their efficacy and safety. Furthermore, our findings raise concerns about the typical milligram-level consumption of these compounds. Clinical trials indicate that such dosages result in sublethal blood concentrations, which our study has shown can be problematic. Given these findings, we advise against using these supplements until more comprehensive data is available.