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Oxidative Medicine and Cellular... 2022Artemisinin (ART) is a bioactive molecule derived from the Chinese medicinal plant Artemisia annua (Asteraceae). ART and artemisinin derivatives (ARTs) have been... (Review)
Review
Artemisinin (ART) is a bioactive molecule derived from the Chinese medicinal plant Artemisia annua (Asteraceae). ART and artemisinin derivatives (ARTs) have been effectively used for antimalaria treatment. The structure of ART is composed of a sesquiterpene lactone, including a peroxide internal bridge that is essential for its activity. In addition to their well-known antimalarial effects, ARTs have been shown recently to resist a wide range of tumors. The antineoplastic mechanisms of ART mainly include cell cycle inhibition, inhibition of tumor angiogenesis, DNA damage, and ferroptosis. In particular, ferroptosis is a novel nonapoptotic type of programmed cell death. However, the antitumor mechanisms of ARTs by regulating ferroptosis remain unclear. Through this review, we focus on the potential antitumor function of ARTs by acting on ferroptosis, including the regulation of iron metabolism, generation of reactive oxygen species (ROS), and activation of endoplasmic reticulum stress (ERS). This article systematically reviews the recent progress in ferroptosis research and provides a basis for ARTs as an anticancer drug in clinical practice.
Topics: Anti-Infective Agents; Artemisinins; Ferroptosis; Humans; Medicine, Chinese Traditional; Neoplasms; Plants
PubMed: 35028002
DOI: 10.1155/2022/1458143 -
Biotechnology Advances 2021Molecular farming in plants is an emerging platform for the production of pharmaceutical proteins, and host species such as tobacco are now becoming competitive with... (Review)
Review
Molecular farming in plants is an emerging platform for the production of pharmaceutical proteins, and host species such as tobacco are now becoming competitive with commercially established production hosts based on bacteria and mammalian cell lines. The range of recombinant therapeutic proteins produced in plants includes replacement enzymes, vaccines and monoclonal antibodies (mAbs). But plants can also be used to manufacture toxins, such as the mistletoe lectin viscumin, providing an opportunity to express active antibody-toxin fusion proteins, so-called recombinant immunotoxins (RITs). Mammalian production systems are currently used to produce antibody-drug conjugates (ADCs), which require the separate expression and purification of each component followed by a complex and hazardous coupling procedure. In contrast, RITs made in plants are expressed in a single step and could therefore reduce production and purification costs. The costs can be reduced further if subcellular compartments that accumulate large quantities of the stable protein are identified and optimal plant growth conditions are selected. In this review, we first provide an overview of the current state of RIT production in plants before discussing the three key components of RITs in detail. The specificity-defining domain (often an antibody) binds cancer cells, including solid tumors and hematological malignancies. The toxin provides the means to kill target cells. Toxins from different species with different modes of action can be used for this purpose. Finally, the linker spaces the two other components to ensure they adopt a stable, functional conformation, and may also promote toxin release inside the cell. Given the diversity of these components, we extract broad principles that can be used as recommendations for the development of effective RITs. Future research should focus on such proteins to exploit the advantages of plants as efficient production platforms for targeted anti-cancer therapeutics.
Topics: Animals; Antibodies, Monoclonal; Immunotoxins; Recombinant Proteins; Nicotiana
PubMed: 33373687
DOI: 10.1016/j.biotechadv.2020.107683 -
Nano Letters Jul 2022We have previously shown the plant virus Cowpea mosaic virus (CPMV) to be an efficacious in situ cancer vaccine, providing elimination of tumors and tumor-specific...
We have previously shown the plant virus Cowpea mosaic virus (CPMV) to be an efficacious in situ cancer vaccine, providing elimination of tumors and tumor-specific immune memory. Additionally, we have shown that CPMV recruits Natural Killer (NK) cells within the tumor microenvironment. Here we aimed to determine whether a combination of CPMV and anti-4-1BB monoclonal antibody agonist to stimulate tumor-resident and CPMV-recruited NK cells is an effective dual therapy approach to improve NK cell function and in situ cancer vaccination efficacy. Using murine models of metastatic colon carcinomatosis and intradermal melanoma, intratumorally administered CPMV + anti-4-1BB dual therapy provided a robust antitumor response, improved elimination of primary tumors, and reduced mortality compared to CPMV and anti-4-1BB monotherapies. Additionally, on tumor rechallenge there was significant delay/prevention of tumor development and improved survival, highlighting that the CPMV + anti-4-1BB dual therapy enables potent and durable antitumor efficacy.
Topics: Animals; Comovirus; Humans; Killer Cells, Natural; Melanoma; Mice; Tumor Microenvironment; Vaccination
PubMed: 35713326
DOI: 10.1021/acs.nanolett.2c01328 -
Biomacromolecules Oct 2022Ovarian cancer is the foremost cause of gynecological cancer and a major cause of cancer death in women. Treatment for advanced stage is surgical debulking followed by...
Ovarian cancer is the foremost cause of gynecological cancer and a major cause of cancer death in women. Treatment for advanced stage is surgical debulking followed by chemotherapy; however, most patients relapse with more aggressive and therapy-resistant tumors. There is a need to develop drug delivery approaches to deliver platinum therapies to tumors to increase efficacy while maintaining safety. Toward this goal, we utilized the protein nanotubes from the plant virus, tobacco mosaic virus (TMV), as a drug carrier. Specifically, the nanochannel of TMV was loaded with the active dication form of cisplatin (cisPt), making use of the negatively charged Glu acid side chains that line the interior channel of TMV. We achieved a loading efficiency with ∼2700 cisPt per TMV; formulation stability was established with drug complexes stably loaded into the carrier for 2 months under refrigerated storage. TMV-cisPt maintained its efficacy against ovarian tumor cells with an IC of ∼40 μM. TMV-cisPt exhibited superior efficacy free cisPt in ovarian tumor mouse models using intraperitoneal ID8-Defb29/Vegf-a-Luc (mouse) tumors and subcutaneous A2780 (human) xenografts. TMV-cisPt treatment led to reduced tumor burden and increased survival. Using ID8-Defb29/Vegf-a-Luc-bearing C57BL/6 mice, we also noted reduced tumor growth when animals were treated with TMV alone, which may indicate antitumor immunity induced by the immunomodulatory nature of the plant virus nanoparticle. Biodistribution studies supported the efficacy data, showing increased cisPt accumulation within tumors when delivered the TMV carrier free cisPt administration. Finally, good safety profiles were noted. The study highlights the potential of TMV as a drug carrier against cancer and points to the opportunity to explore plant viruses as chemo-immuno combination cancer therapeutics.
Topics: Animals; Cell Line, Tumor; Cisplatin; Drug Carriers; Female; Humans; Mice; Mice, Inbred C57BL; Ovarian Neoplasms; Platinum; Tissue Distribution; Nicotiana; Tobacco Mosaic Virus; Vascular Endothelial Growth Factor A
PubMed: 36053908
DOI: 10.1021/acs.biomac.2c00831 -
Cancer Research Sep 2023In prostate cancer, there is an urgent need for objective prognostic biomarkers that identify the metastatic potential of a tumor at an early stage. While recent...
UNLABELLED
In prostate cancer, there is an urgent need for objective prognostic biomarkers that identify the metastatic potential of a tumor at an early stage. While recent analyses indicated TP53 mutations as candidate biomarkers, molecular profiling in a clinical setting is complicated by tumor heterogeneity. Deep learning models that predict the spatial presence of TP53 mutations in whole slide images (WSI) offer the potential to mitigate this issue. To assess the potential of WSIs as proxies for spatially resolved profiling and as biomarkers for aggressive disease, we developed TiDo, a deep learning model that achieves state-of-the-art performance in predicting TP53 mutations from WSIs of primary prostate tumors. In an independent multifocal cohort, the model showed successful generalization at both the patient and lesion level. Analysis of model predictions revealed that false positive (FP) predictions could at least partially be explained by TP53 deletions, suggesting that some FP carry an alteration that leads to the same histological phenotype as TP53 mutations. Comparative expression and histologic cell type analyses identified a TP53-like cellular phenotype triggered by expression of pathways affecting stromal composition. Together, these findings indicate that WSI-based models might not be able to perfectly predict the spatial presence of individual TP53 mutations but they have the potential to elucidate the prognosis of a tumor by depicting a downstream phenotype associated with aggressive disease biomarkers.
SIGNIFICANCE
Deep learning models predicting TP53 mutations from whole slide images of prostate cancer capture histologic phenotypes associated with stromal composition, lymph node metastasis, and biochemical recurrence, indicating their potential as in silico prognostic biomarkers. See related commentary by Bordeleau, p. 2809.
Topics: Male; Humans; Mutation; Prostatic Neoplasms; Prognosis; Prostate; Phenotype; Tumor Suppressor Protein p53
PubMed: 37352385
DOI: 10.1158/0008-5472.CAN-22-3113 -
Journal of Nanobiotechnology Dec 2021Lactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive...
Lactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive tumor microenvironment (TME). Herein, we report on a "lactate treatment plant" (i.e., nanofactory) that can dynamically trap pro-tumor lactate and in situ transformation into anti-tumor cytotoxic reactive oxygen species (ROS) for a synergistic chemodynamic and metabolic therapy. To this end, lactate oxidase (LOX) was nano-packaged by cationic polyethyleneimine (PEI), assisted by a necessary amount of copper ions (PLNP). As a reservoir of LOX, the tailored system can actively trap lactate through the cationic PEI component to promote lactate degradation by two-fold efficiency. More importantly, the byproducts of lactate degradation, hydrogen peroxide (HO), can be transformed into anti-tumor ROS catalyzing by copper ions, mediating an immunogenic cell death (ICD). With the remission of immunosuppressive TME, ICD process effectively initiated the positive immune response in 4T1 tumor model (88% tumor inhibition). This work provides a novel strategy that rationally integrates metabolic therapy and chemodynamic therapy (CDT) for combating tumors.
Topics: Animals; Biocompatible Materials; Catalysis; Cell Line, Tumor; Cell Survival; Copper; Glutathione; Humans; Hydrogen Peroxide; Hydroxyl Radical; Immunogenic Cell Death; Lactic Acid; Mice; Mixed Function Oxygenases; Nanoparticles; Neoplasms; Polyethyleneimine; Tumor Microenvironment
PubMed: 34922541
DOI: 10.1186/s12951-021-01169-9 -
Frontiers in Oncology 2024Gliomas are prevalent malignant tumors in adults, which can be categorized as either localized or diffuse gliomas. Glioblastoma is the most aggressive and deadliest form... (Review)
Review
Gliomas are prevalent malignant tumors in adults, which can be categorized as either localized or diffuse gliomas. Glioblastoma is the most aggressive and deadliest form of glioma. Currently, there is no complete cure, and the median survival time is less than one year. The main mechanism of regulated cell death involves organisms coordinating the elimination of damaged cells at risk of tumor transformation or cells hijacked by microorganisms for pathogen replication. This process includes apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis, necrosis, parthanayosis, entosis, lysosome-dependent death, NETosis, oxiptosis, alkaliptosis, and disulfidaptosis. The main goal of clinical oncology is to develop therapies that promote the effective elimination of cancer cells by regulating cell death are the main goal of clinical oncology. Recently, scientists have utilized pertinent regulatory factors and natural small-molecule compounds to induce regulated cell death for the treatment of gliomas. By analyzing the PubMed and Web of Science databases, this paper reviews the research progress on the regulation of cell death and the role of natural small-molecule compounds in glioma. The aim is to provide help for the treatment of glioblastoma.
PubMed: 38304870
DOI: 10.3389/fonc.2024.1273841 -
Computational and Mathematical Methods... 2022Applied science nowadays works on the isolation and application of biological macromolecules (BMM). These BMM are isolates from plants using different techniques and... (Review)
Review
Applied science nowadays works on the isolation and application of biological macromolecules (BMM). These BMM are isolates from plants using different techniques and used as anticancer, antimicrobial, and anti-inflammatory drugs. Parthenolide (PLT) is one of the most important biological macromolecules and a naturally occurring sesquiterpene lactone that is isolated from a plant species (). The anti-cancer and anti-inflammatory effects of PTL isolated from . were previously reported and summarized in detail. These biological activities make it a vital candidate for further researches and drugs development. As per the previously obtained findings, the sesquiterpene is very much known for some biological activities; therefore, the anti-cancer and anti-inflammatory activities of the sesquiterpene were critically reviewed. During the research process, PTL was found to be unstable in both acidic and basic conditions with low solubility, so structurally related compounds micheliolide (MCL) and Dimethylaminomicheliolide (DMAMCL) (a prodrug of MCL) were developed. In this article, we briefly review the therapeutic effects of PTL and its derivative DMAPT on inflammatory diseases and tumors, focusing on the current application of PTL in targeted therapy and combination therapy, together with anti-inflammatory and anti-tumor functions of MCL and DMAMCL. The uniqueness of this biological macromolecule is not to harm the normal cell but target the cancerous cells. Therefore, the current literature review might be helpful and useful for prospects based on the effects of MCL and DMAMCL on cancer.
Topics: Anti-Inflammatory Agents; Humans; Lactones; Neoplasms; Sesquiterpenes; Sesquiterpenes, Guaiane
PubMed: 35898475
DOI: 10.1155/2022/3744837 -
The New Phytologist Jul 2021Ustilago maydis is a biotrophic fungus causing smut disease in corn. The infectious forms are dikaryotic hyphae. Here we analyze mutants lacking the nlt1 transcription...
Ustilago maydis is a biotrophic fungus causing smut disease in corn. The infectious forms are dikaryotic hyphae. Here we analyze mutants lacking the nlt1 transcription factor and investigate why these mutants are unable to induce leaf tumors. The study involved reverse genetics, complementation, epistasis analysis, microscopy, gene expression analysis by quantitative reverse transcriptase PCR and virulence assays. We show that nlt1 mutants colonize maize leaves efficiently but fail to undergo karyogamy and are attenuated in late proliferation. Nlt1 activates transcription of ros1, a transcription factor controlling karyogamy, and represses see1, an effector previously shown to contribute to leaf tumor induction. In mononuclate solopathogenic strains, nlt1 mutants cause attenuated leaf tumor formation. In actively dividing maize organs, nlt1 mutants undergo karyogamy and induce tumor formation. Sporisorium reilianum, a smut fungus unable to induce leaf tumors, possesses an ortholog of nlt1 that controls the fusion of dikaryotic nuclei late in infection during cob colonization. Our results have established a regulatory connection between nlt1, ros1 and see1 and suggest the existence of two stages contributing to leaf tumor formation, one before nuclear fusion and involving nlt1 and one after karyogamy that is nlt1 independent.
Topics: Basidiomycota; Fungal Proteins; Plant Diseases; Plant Leaves; Plant Tumors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Ustilago; Zea mays
PubMed: 33786841
DOI: 10.1111/nph.17377 -
International Journal of Molecular... Aug 2022N-myc downstream-regulated gene 2 (NDRG2) is a tumor-suppressor gene that suppresses tumorigenesis and metastasis of tumors and increases sensitivity to anti-cancer... (Review)
Review
N-myc downstream-regulated gene 2 (NDRG2) is a tumor-suppressor gene that suppresses tumorigenesis and metastasis of tumors and increases sensitivity to anti-cancer drugs. In this review, we summarize information on the clinicopathological characteristics of tumor patients according to NDRG2 expression in various tumor tissues and provide information on the metastasis inhibition-related cell signaling modulation by NDRG2. Loss of NDRG2 expression is a prognostic factor that correlates with TNM grade and tumor metastasis and has an inverse relationship with patient survival in various tumor patients. NDRG2 inhibits cell signaling, such as AKT-, NF-κB-, STAT3-, and TGF-β-mediated signaling, to induce tumor metastasis, and induces activation of GSK-3β which has anti-tumor effects. Although NDRG2 operates as an adaptor protein to mediate the interaction between kinases and phosphatases, which is essential in regulating cell signaling related to tumor metastasis, the molecular mechanism of NDRG2 as an adapter protein does not seem to be fully elucidated. This review aims to assist the research design regarding NDRG2 function as an adaptor protein and suggests NDRG2 as a molecular target to inhibit tumor metastasis and improve the prognosis in tumor patients.
Topics: Adaptor Proteins, Signal Transducing; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Signal Transduction; Tumor Suppressor Proteins
PubMed: 36012631
DOI: 10.3390/ijms23169365