Drugs For Treatment Of Cancer Research Articles

Abstract 4433: Secondary electrospray ionization mass spectrometry for volatile analysis of lung cancer

Abstract Lung cancer remains a leading cause of cancer-related mortality globally, necessitating innovative approaches for early detection and improved understanding of its metabolic landscape and consequences. Secondary Electrospray Ionization Mass Spectrometry (SESI-MS), an innovative analytical technique, has emerged as a powerful tool for the analysis of volatile organic compounds (VOCs) associated with various diseases, from metabolic disorders to bacterial infections. In this proof-of-concept study, we first utilized SESI-MS analyses of four representative lung cancer cells of both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) to demonstrate its capability to profile VOCs released by lung cancer cells. The technique allows for real-time, non-invasive analysis of the headspace above cultured cells, enabling the detection of unique VOC signatures associated with different lung cancer subtypes. Meanwhile, SESI-MS also facilitated the discrimination specific cells based on distinct VOC patterns. Furthermore, we also performed cisplatin treatment experiments and observed the metabolic signature shift post drug treatment. These results collectively offered potential applications in early diagnosis and personalized treatment strategies. Next, we continued with in vivo investigations to further extend the utility of SESI-MS in lung cancer research. Animal models, mimicking human lung cancer pathophysiology, have been subjected to SESI-MS analysis to identify volatile biomarkers indicative of tumor development and progression. Several representative cancer drug treatments were performed to the lung cancer mice model, and the drug-induced responses were also monitored via SESI-MS breath analyses. The in vivo SESI-MS approach detected many interesting breath VOC features that could provide valuable insights into the dynamic changes in VOC profiles during various stages of lung cancer, and therefore has the potential to offer a deeper understanding of the disease's metabolic alterations and potential avenues for targeted therapeutic interventions. In conclusion, SESI-MS-based volatile analysis presents a robust and versatile approach for investigating lung cancer, and our ongoing work has the potential to bridge the gap between in vitro and in vivo models for better translational research outcomes. The detection of unique VOC signatures associated with lung cancer cells and tumors holds significant promise for early detection, subtype classification, and monitoring of treatment responses. As technology continues to advance, SESI-MS stands poised to play a pivotal role in transforming the landscape of lung cancer diagnostics and research. Citation Format: Jiangjiang (Chris) Zhu, Fouad Choueiry. Secondary electrospray ionization mass spectrometry for volatile analysis of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4433.

Exploring the NRF2-TP53 Signaling Network Through Machine Learning and Pan-Cancer Analysis: Identifying Potential targets for Cancer Prognosis Related to Oxidative Stress.

Oxidative stress (OXS) is closely related to tumor prognosis and immune response, while TP53 integrated with NRF2 is closely associated with the regulation of cancer-related OXS. Hence, constructing a TP53-NRF2 integrated OXS signature of pan-cancer is essential in predicting survival prognosis and facilitating cancer drug treatment. The pan-cancer analysis acquired the Cancer Genome Atlas (TCGA) transcriptome sequencing data from UCSC Xena, which consisted of 33 cancer types (n = 10440). The Random Forest, Lasso regression, and Cox regression analyses are used to construct an OXS score based on 25 OXS genes. Following this, based on the OXS signature, patients are categorized into low- and high-risk groups. The disparities between the two cohorts regarding survival prognosis, immune infiltration, and drug sensitivity are delved deeply. The expression level of genes is confirmed using immunohistochemistry. The prognosis of pan-cancer patients is adequately predicted by the OXS signature with the assistance of the machine-learning algorithm. A highly accurate nomogram is developed by combining the OXS signature and clinical features. The presence of immune cells indicated that the OXS signature can be associated with the critical pathways of immunotherapy for all types of cancer, and BCL2 showed promising results. Distinct inter-group differences are observed in the OXS signature for frequently utilized antineoplastic medications in clinical settings, including first-line drugs suggested in the guidelines. In summary, by conducting a thorough analysis of OXS genes, a new model based on OXSscore is successfully developed. This model can predict the clinical prognosis and drug sensitivity of pan-cancer with high accuracy. Potential stars in the field of cancer-related anti-OXS may include drugs that target BCL2.

Withanone as an Emerging Anticancer Agent and Understanding Its Molecular Mechanisms: Experimental and Computational Evidence.

Despite decades of research and effort, treating cancer is still a challenging task. Current conventional treatments are still unsatisfactory to fully eliminate and prevent re-emergence or relapses, and targeted or personalised therapy, which are more effective in managing cancer, may be unattainable or inaccessible for some. In the past, research in natural products have yielded some of the most commonly used cancer treatment drugs known today. Hence it is possible more are awaiting to be discovered. Withanone, a common withanolide found in the Ayurvedic herb Withania somnifera, has been claimed to possess multiple benefits capable of treating cancer. This review focuses on the potential of withanone as a safe cancer treatment drug based on the pharmacokinetic profile and molecular mechanisms of actions of withanone. Through these in silico and in vitro studies discussed in this review, withanone showspotent anticancer activities and interactions with molecular targets involved in cancer progression. Furthermore, some evidences also show the selective killing property of withanone, which highlights the safety and specificity of withanone in targeting cancer cell. By compiling these evidences, this review hopes to spark interest for future research to be conducted in more extensive studies involving withanone to generate more data, especially involving in vivo experiments and toxicity evaluation of withanone.

3D Bioprinting and Microfluidic-Based Devices for Cancer Detection and Drug Treatment: Focus on Prostate Cancer.

The burden of increasing cancer incidence among the population, and, in particular, of prostate cancer in men living in highly developed countries, brings with it, on one hand, the need for new devices that allow a faster and earlier diagnosis, ideally in a non-invasive way and with low consumption of expensive reagents, and on the other the need for the assessment of new in vitro models that allow a more reliable assessment of cancer features, including its microenvironment and sensibility to different drugs. At the crossroads of these features, microfluidic devices are found. These, taking advantage of the chemical-physical properties of cells and human samples, have demonstrated great sensitivity and sensibility at an on-chip scale. Many fields of biomedical sciences have tried to exploit all their potentialities: from the detection of antigens in the early phases of the disease (when they are very low concentrated, but the treatment is more effective) to isolation and characterization of circulating tumor cells. However, the development of in vitro 3D models to better assess and comprehend the fundamental dynamics of tumor microenvironment and metastasis using 3D bioprinting techniques. The aim of the present review is to describe the potential of these two different cutting-edge technologies for the detection and treatment of prostate cancer, in the perspective of a possible future combination of them that allows scientists to fill the gaps present in the field to improve patient care and treatment.

Development of an antifungal drug loaded spinel ferrite nanocarrier with enhanced antifungal activity and superior anticancer effect against human lung carcinoma cells

Mg1–xCuxFe2O4 (x = 0, 0.1) nanoparticle was successfully synthesized by the sol-gel method. Synthesized Mg0.9Cu0.1Fe2O4 nanoparticle was coated with the soluble starch and then conjugated with the antifungal drug ketoconazole. The detailed microstructural and structural characterizations of the nanoparticles and drug-loaded nanosystem were carried out by analyzing FTIR, EDS patterns and XRD data employing Rietveld refinement. The average particle sizes of different samples were determined from SEM and TEM image analysis. The antifungal activities of Mg0.9Cu0.1Fe2O4 nanoparticles (NP) and drug-conjugated nanoparticles (NP-DC) were revealed by agar cup assay and minimum inhibitory concentration (MIC) study against Candida Sp. A significant zone of fungal inhibition was obtained in the NP sample, and the antifungal efficacy indicated that it can be a promising antifungal agent without any external drug. The zone of inhibition due to the NP-DC sample was larger than that of the pure drug ketoconazole. It revealed the significant enhancement of the efficacy of ketoconazole after its conjugation with the NP sample, which was confirmed by the MIC study. In the MIC study, it has been revealed that the NP-DC sample has a similar activity as 100wt % ketoconazole. But in the NP-DC sample, only 40 wt % ketoconazole was present. It confirms the significantly enhanced activity of pure drug after its conjugation with the NP sample. The NP-DC sample has also significant inhibitory activity against the growth of lung carcinoma cells (A549 cells) while it has no any significant toxic effect on the normal human WI38 cells (lung fibroblast cells) as indicated by MTT assay. The anti-cancer activity of the NP-DC sample is significantly higher than that of the pure drug ketoconazole. The ability of NP-DC to produce cellular ROS and induction of apoptosis has been confirmed to be the cause of the enhanced cytotoxic effect of the NP-DC sample against lung carcinoma cells. This significant enhancement of antifungal and anticancer efficacy indicates the formation of a new nanomedicine with a significant antifungal activity that can also inhibit the growth of human carcinoma cells with higher efficacy. Due to enhanced efficacy, a small amount of ketoconazole conjugated with NPs would be required for the treatment, which in turn, reduces the side effects of the drug and becomes more affordable to the patients. This new nanomedicine can also be used as a potential drug for cancer treatment.

Updates on Overcoming Bicalutamide Resistance: A Glimpse into Resistance to a Novel Antiandrogen.

The standard androgen deprivation therapy for advanced prostate cancer includes the use of bicalutamide, which is a well-known antagonist of androgen receptors. Despite numerous benefits of the drugs in prostate cancer treatment, there is always a risk of developing a resistant phenotype, which paves the way for a more aggressive and low-survival type of prostate cancer. Over the years, many studies have investigated the candidate mechanisms of such resistance and have managed to find possible therapeutic solutions. In this Review, we shed light on the heterogeneous dynamics of progression to resistance against bicalutamide treatment, referring to the most recent studies and the approaches that have been so far discussed. This Review tries to offer a deep and comprehensive understanding about how the resistant cells become sensitive to the drug and what corresponding pathways lead to an appropriate solution for the antiandrogen resistance challenge.

Palladium Metal Nanocomposites Based on PEI-Functionalized Nitrogen-Doped Graphene Quantum Dots: Synthesis, Characterization, Density Functional Theory Modeling, and Cell Cycle Arrest Effects on Human Ovarian Cancer Cells.

In this study, the synthesis, characterization, density functional theory calculations (DFT), and effect of polyethylenimine (PEI)-functionalized nitrogen-doped graphene quantum dots (PEI N-GQDs) and their palladium metal nanoparticles nanocomposites (PdNPs/PEI N-GQDs) on cancer cells were extensively investigated. The focus also includes investigating their cytotoxic and apoptotic effects on ovarian cancer cells, which pose a serious risk to women's health and have high death rates from delayed diagnosis, inadequate response to treatment, and decreased survival. Graphene quantum dots and their palladium nanocomposites were differentially effective against ovarian cancer cell lines. In particular, the smaller particle size and morphology of PdNPs/PEI N-GQDs nanocomposites compared with PEI N-GQDs probably enhance their activity through highly improved uptake by cells. These findings emphasize the importance of particle size in composite drugs for efficient cancer treatment. DFT results revealed that the Pd-containing nanocomposite, with a smaller highest occupied molecular orbital-lowest unoccupied molecular orbital gap, exhibited higher reactivity and anticancer effects in human ovarian cancer cell line, OVCAR-3. Significantly, the application of nanocomposites to ovarian cancer cells initiated apoptosis, offering valuable insights into the intricate interplay between nanomaterials and cancer biology.

Pancreatic Cancer Treatment Targeting the HGF/c-MET Pathway: The MEK Inhibitor Trametinib.

Pancreatic cancer is characterized by fibrosis/desmoplasia in the tumor microenvironment, which is primarily mediated by pancreatic stellate cells and cancer-associated fibroblasts. HGF/c-MET signaling, which is instrumental in embryonic development and wound healing, is also implicated for its mitogenic and motogenic properties. In pancreatic cancer, this pathway, along with its downstream signaling pathways, is associated with disease progression, prognosis, metastasis, chemoresistance, and other tumor-related factors. Other features of the microenvironment in pancreatic cancer with the HGF/c-MET pathway include hypoxia, angiogenesis, metastasis, and the urokinase plasminogen activator positive feed-forward loop. All these attributes critically influence the initiation, progression, and metastasis of pancreatic cancer. Therefore, targeting the HGF/c-MET signaling pathway appears promising for the development of innovative drugs for pancreatic cancer treatment. One of the primary downstream effects of c-MET activation is the MAPK/ERK (Ras, Ras/Raf/MEK/ERK) signaling cascade, and MEK (Mitogen-activated protein kinase kinase) inhibitors have demonstrated therapeutic value in RAS-mutant melanoma and lung cancer. Trametinib is a selective MEK1 and MEK2 inhibitor, and it has evolved as a pivotal therapeutic agent targeting the MAPK/ERK pathway in various malignancies, including BRAF-mutated melanoma, non-small cell lung cancer and thyroid cancer. The drug's effectiveness increases when combined with agents like BRAF inhibitors. However, resistance remains a challenge, necessitating ongoing research to counteract the resistance mechanisms. This review offers an in-depth exploration of the HGF/c-MET signaling pathway, trametinib's mechanism, clinical applications, combination strategies, and future directions in the context of pancreatic cancer.

Proton-sensing ion channels, GPCRs and calcium signaling regulated by them: implications for cancer.

Extracellular acidification of tumors is common. Through proton-sensing ion channels or proton-sensing G protein-coupled receptors (GPCRs), tumor cells sense extracellular acidification to stimulate a variety of intracellular signaling pathways including the calcium signaling, which consequently exerts global impacts on tumor cells. Proton-sensing ion channels, and proton-sensing GPCRs have natural advantages as drug targets of anticancer therapy. However, they and the calcium signaling regulated by them attracted limited attention as potential targets of anticancer drugs. In the present review, we discuss the progress in studies on proton-sensing ion channels, and proton-sensing GPCRs, especially emphasizing the effects of calcium signaling activated by them on the characteristics of tumors, including proliferation, migration, invasion, metastasis, drug resistance, angiogenesis. In addition, we review the drugs targeting proton-sensing channels or GPCRs that are currently in clinical trials, as well as the relevant potential drugs for cancer treatments, and discuss their future prospects. The present review aims to elucidate the important role of proton-sensing ion channels, GPCRs and calcium signaling regulated by them in cancer initiation and development. This review will promote the development of drugs targeting proton-sensing channels or GPCRs for cancer treatments, effectively taking their unique advantage as anti-cancer drug targets.

Novel naphthoquinone-1H-1,2,3-triazole hybrids: Design, synthesis and evaluation as inductors of ROS-mediated apoptosis in the MCF-7 cells

The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.

Abstract 2396 Novel Ligase 1 and 4 Inhibitor Compounds as Potential Drugs for Cancer Treatment

Abstract 2396 Novel Ligase 1 and 4 Inhibitor Compounds as Potential Drugs for Cancer Treatment

Breakthrough study promises major advancements for bone cancer drug treatments

Nanotheranostic system is proven to target and kill osteosarcoma cells

Anthracyclines induce cardiotoxicity through a shared gene expression response signature.

TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.

Chitosan-TPP microcapsules for controlled drug release

Production of chitosan/sodium tripolyphosphate (CS/TPP) microcapsules via spray drying involves atomizing an emulsion containing CS, TPP, acetic acid (AcOH), and folic acid (FA) into fine droplets exposed to high-temperature, low-pressure gas flow. Solvent evaporation within the drying chamber leads to solid particle formation. Spray drying is valuable for creating solid CS/TPP microcapsules. Precise equipment parameter adjustments, like inlet temperature and gas flow rate, enable the study of microcapsule morphology, size, and properties. This adaptability allows for customization to specific pH dissolution ranges. The production method's impact on CS/TPP microcapsules was studied by modifying spray drier parameters, including inlet temperature and aspirator pressure, to enhance understanding of their behavior in solution under varied production conditions.
 In chitosan delivery systems, various approaches can encapsulate drug agents like folic acid, an analog to the cancer treatment drug methotrexate. Agents can be added to the chitosan solution pre-crosslinking, incorporated into gelation-inducing agents pre-mixing with chitosan, or included in the crosslinking mixture. Experiments were conducted to assess CS/TPP microcapsules' behavior when encapsulating agents like folic acid. Release profiles were analyzed to understand their drug delivery capabilities and potential as controlled release carriers.

Co-Delivery of siRNA and Docetaxel to Cancer Cells by NLC for Therapy.

The present study aims to develop a delivery system that can carry small interference RNA (siRNA) with small-molecule chemotherapeutic drugs, which can be used in cancer treatment. The drug delivery system combines the advantages of a therapeutic agent with two different mechanisms to ensure that it is used efficiently for cancer therapy. In this study, a nanostructured lipid carrier system was prepared, Docetaxel was loaded to these systems, and the Eph siRNA was adsorbed to the outer surface. In addition, DOTAP was added to the lipophilic phase to load a positive charge on the lipidic structure for interaction with the cells. Moreover, characterization, cytotoxicity, and transfection procedures were performed on the whole system. This candidate system was also compared to Taxotere, which is the first approved Docetaxel-containing drug on the market. Given the results, it was determined that the particle size of NLC-DTX was 165.3 ± 3.5 nm, the ζ potential value was 38.2 ± 1.7 mV, and the PDI was 0.187 ± 0.024. Entrapment efficacy of nanoparticles was found to be 92.89 ± 0.21%. It was determined that the lipidic system prepared in vitro release analyses were able to provide sustained release and exhibit cytotoxicity, even at doses lower than the dose used for Taxotere. The formulations prepared had a higher level of effect on cells when compared with pure DTX and Taxotere, but they also exhibited time-dependent cytotoxicity. It was also observed that the use of Eph siRNA together with the chemotherapeutic agent via formulation also contributed to this cell death. The results of the present study indicate that there is a promising carrier system in order to deliver hydrophilic nucleic acids, such as siRNA, together with lipophilic drugs in cancer treatment.

Monoclonal Antibody Development for Cancer Treatment Using the Phage Display Library Platform

Thirty-four years ago, the groundbreaking work of John McCafferty and Sir Gregory Winter in developing phage display technology revolutionized the discovery of human antibodies, paving the way for diverse applications. Since then, numerous phage-derived antibodies have been successfully developed and advanced into clinical studies, resulting in the approval of more than a dozen therapeutic antibodies. These antibodies have demonstrated efficacy across a spectrum of medical conditions, ranging from autoimmune diseases to various cancers. In this article, we provide an in-depth review of the development of phage display libraries as powerful platforms for therapeutic antibody discovery, elucidating the intricate procedures involved in antibody development. Additionally, we conduct a review of the current ntibody drugs for cancer treatment that have been developed using the phage display platform. Furthermore, we discuss the challenges inherent in this technology, offering insights into potential solutions to enhance crucial steps and facilitate more efficient drug discovery in the field of phage display technology.

Repurposing Drugs for Overcoming Therapy Resistance in Colon Cancer – A Review

Colorectal cancer is a common type of cancer worldwide. Colorectal cancer is a prevalent form of cancer that is observed globally. The survival prospects for individuals with advanced stages of this disease are notably diminished. The chance of getting colorectal cancer is 4% to 5%. Getting older, having chronic illnesses, and certain lifestyle choices raise the risk of getting colorectal cancer. Surgery, as well as neoadjuvant radiation treatment (for those affected by rectal cancer) and adjunctive chemotherapy (for stage III/IV colon cancer patients and high-risk stage II colon cancer patients), stand as the most employed therapeutic interventions. Treating CRC has improved, but the medicines are expensive and have side effects. Therefore, alternative methods that are more affordable and still effective need to be explored. The use of existing drugs to treat diseases is becoming more popular due to high attrition rates, economic burden, slow drug discovery, and development. Many methods have been proposed to find repurposed therapeutic candidates, which can save time and money. Repurposing drugs is more successful and efficient than creating new drugs for rare diseases. Using existing drugs for cancer treatment is a major priority. Non-cancer drugs should not be overlooked since they have the potential to address both identified and unidentified weaknesses in cancer. Unlike targeted therapy, old generic drugs used in multiple ways can benefit patients. This review delves into the present body of evidence regarding the utilization of established medications as a plausible therapeutic avenue for patients suffering from CRC. The focus is to illustrate the possible competitors and their complex ways of functioning, including medications that have the ability to combat malaria, parasitic infections, inflammation, high blood pressure, high cholesterol levels, and diabetes.

Association of changes in expression of HDAC and SIRT genes after drug treatment with cancer cell line sensitivity to kinase inhibitors

ABSTRACT Histone deacetylases (HDACs) and sirtuins (SIRTs) are important epigenetic regulators of cancer pathways. There is a limited understanding of how transcriptional regulation of their genes is affected by chemotherapeutic agents, and how such transcriptional changes affect tumour sensitivity to drug treatment. We investigated the concerted transcriptional response of HDAC and SIRT genes to 15 approved antitumor agents in the NCI-60 cancer cell line panel. Antitumor agents with diverse mechanisms of action induced upregulation or downregulation of multiple HDAC and SIRT genes. HDAC5 was upregulated by dasatinib and erlotinib in the majority of the cell lines. Tumour cell line sensitivity to kinase inhibitors was associated with upregulation of HDAC5, HDAC1, and several SIRT genes. We confirmed changes in HDAC and SIRT expression in independent datasets. We also experimentally validated the upregulation of HDAC5 mRNA and protein expression by dasatinib in the highly sensitive IGROV1 cell line. HDAC5 was not upregulated in the UACC-257 cell line resistant to dasatinib. The effects of cancer drug treatment on expression of HDAC and SIRT genes may influence chemosensitivity and may need to be considered during chemotherapy.

Phenolic compounds induce ferroptosis-like death by promoting hydroxyl radical generation in the Fenton reaction

Phenolic compounds are industrially versatile chemicals, also the most ubiquitous pollutants. Recently, biosynthesis and biodegradation of phenols has attracted increasing attention, while phenols’ toxicity is a major issue. Here, we evolved phloroglucinol-tolerant Escherichia coli strains via adaptive evolution, and three mutations (ΔsodB, ΔclpX and fetAB overexpression) prove of great assistance in the tolerance improvement. We discover that phloroglucinol complexes with iron and promotes the generation of hydroxyl radicals in Fenton reaction, which leads to reducing power depletion, lipid peroxidation, and ferroptosis-like cell death of E. coli. Besides phloroglucinol, various phenols can trigger ferroptosis-like death in diverse organisms, from bacteria to mammalian cells. Furthermore, repressing this ferroptosis-like death improves phloroglucinol production and phenol degradation by corresponding strains respectively, showing great application potential in microbial degradation or production of desired phenolic compounds, and phloroglucinol-induced ferroptosis suppresses tumor growth in mice, indicating phloroglucinol as a promising drug for cancer treatment.

The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells

ABSTRACT The antipsychotic drug pimozide has been demonstrated to inhibit cancer. However, the precise anti-cancer mechanism of pimozide remains unclear. The purpose of this study was to investigate the effects of pimozide on human MCF-7 and MDA-MB-231 breast cancer cell lines, and the potential involvement in the RAF/ERK signaling. The effects of pimozide on cells were examined by 4,5-dimethylthiazol-2-yl-3,5-diphenylformazan, wound healing, colony formation, transwell assays, and caspase activity assay. Flow cytometry and acridine orange and ethidium bromide staining were performed to assess changes in cells. Transmission electron microscopy and monodansylcadaverine staining were used to observe autophagosomes. The cyclic adenosine monophosphate was evaluated using the FRET system. Immunohistochemistry, immunofluorescence, RNA interference, and western blot investigated the expression of proteins. Mechanistically, we focus on the RAF1/ERK signaling. We detected pimozide was docked to RAF1 by Schrodinger software. Pimozide down-regulated the phosphorylation of RAF1, ERK 1/2, Bcl-2, and Bcl-xl, up-regulated Bax, and cleaved caspase-9 to induce apoptosis. Pimozide might promote autophagy by up-regulating cAMP. The enhancement of autophagy increased the conversion of LC3-I to LC3-II and down-regulated p62 expression. But mTOR signaling was not involved in promoting autophagy. The knockdown of RAF1 expression induced autophagy and apoptosis in breast cancer cells, consistent with the results of pimozide or sorafenib alone. Blocked autophagy by chloroquine resulted in the impairment of pimozide-induced apoptosis. These data showed that pimozide inhibits breast cancer by regulating the RAF/ERK signaling pathway and might activate cAMP-induced autophagy to promote apoptosis and it may be a potential drug for breast cancer treatment.