Improve Cancer Therapy Research Articles

A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers.

STAT3 and KRAS regulate cell proliferation, survival, apoptosis, cell migration, and angiogenesis. Aberrant expression of STAT3 and mutant active forms of KRAS have been well-established in the induction and maintenance of multiple cancers. STAT3 and KRAS mutant proteins have been considered anti-cancer targets; however, they are also considered to be clinically “undruggable” intracellular molecules, except for KRAS(G12C). Here we report a first-in-class molecule, a novel, single domain camelid VHH antibody (15 kDa), SBT-100, that binds to both STAT3 and KRAS and can penetrate the tumor cell membrane, and significantly inhibit cancer cell growth. Additionally, SBT-100 inhibits KRAS GTPase activity and downstream phosphorylation of ERK in vitro. In addition, SBT-100 inhibits the growth of multiple human cancers in vitro and in vivo. These results demonstrate the feasibility of targeting hard-to-reach aberrant intracellular transcription factors and signaling proteins simultaneously with one VHH to improve cancer therapies.

Regulation of Cell Death Mechanisms by Melatonin: Implications in Cancer Therapy.

Cancer therapy is based on the killing of cancer cells using various therapeutic agents, such as radiation, chemotherapy or targeted therapy drugs, and immunotherapy. Cancer cells may undergo apoptosis, mitotic catastrophe, necrosis, autophagy, mitophagy, senescence, etc., depending on the therapeutic modality and nature of cancer cells. Mutations in some critical genes, such as p53 and Phosphatase and Tensin Homolog (PTEN) tumor suppressor genes, are associated with immune escape of cancer cells and tumor progression. Furthermore, the overexpression of some genes. such as phosphatidylinositol-3-kinase (PI3K), Nuclear Factor of Kappa B (NF-κB), cyclooxygenase-2 (COX-2) and mammalian Target of Rapamycin (mTOR), is associated with the resistance of cancer cells to various types of cell death. Melatonin is known as a circadian regulator hormone that has several anti-cancer properties. It has the ability to activate tumor suppressor genes and attenuate the expression of survival genes in cancer cells. Modulation of cell death or survival genes that have been disrupted or overexpressed in cancer cells can improve cancer therapy. In this review, we explain the potential of melatonin in regulating various mechanisms of cancer cell death.

5-Fluorouracil uptake and release from pH-responsive nanogels: An experimental and computational study

Chemotherapy is the treatment of choice in cancer therapy even though anti-tumor agents cause frequent and harmful effects on organs and tissues. Nanogels can efficiently improve cancer therapy by increasing the antineoplastic concentration in tumor sites and acting on cancer cells for prolonged periods without significantly affecting normal tissues. In this research, a pH-responsive Polyvinylpyrrolidone (PVP)-based nanogel for the controlled release of 5-Fluorouracil (5-FU) was developed. Nanogels were synthesized using γ-radiation, and 5-FU was loaded into nanogels by physical entrapment. These formulations were characterized by spectroscopy techniques, electronic microscopy, and light scattering measurements. Drug loading and release from nanogels are strongly influenced by %PVP and irradiation dose. Simulations showed a higher drug-polymer affinity at low pH according to experimental loading values (encapsulation efficiency = 17% and drug loading = 83%). The sustained release profile responds to pH change from 1.2 to 7.4, increasing the release rate in acid conditions. Furthermore, nanogels have a negative surface charge, spherical morphology, and diameter of 41.0 ± 0.9 nm. These properties show its potential as a nanocarrier of 5-FU for cancer treatment.

Analysis of the Equilibrium Phase in Immune-Controlled Tumors Provides Hints for Designing Better Strategies for Cancer Treatment.

When it comes to improving cancer therapies, one challenge is to identify key biological parameters that prevent immune escape and maintain an equilibrium state characterized by a stable subclinical tumor mass, controlled by the immune cells. Based on a space and size structured partial differential equation model, we developed numerical methods that allow us to predict the shape of the equilibrium at low cost, without running simulations of the initial-boundary value problem. In turn, the computation of the equilibrium state allowed us to apply global sensitivity analysis methods that assess which and how parameters influence the residual tumor mass. This analysis reveals that the elimination rate of tumor cells by immune cells far exceeds the influence of the other parameters on the equilibrium size of the tumor. Moreover, combining parameters that sustain and strengthen the antitumor immune response also proves more efficient at maintaining the tumor in a long-lasting equilibrium state. Applied to the biological parameters that define each type of cancer, such numerical investigations can provide hints for the design and optimization of cancer treatments.

Cytotoxic Activity of Zinc Oxide Nanoparticles Mediated by Euphorbia Retusa

Background: Cancer is a dangerous threat that creates extremely high rates of death and morbidity in various regions of the world. Finding suitable therapeutics to improve cancer therapy while avoiding side effects is critical. The most appropriate innovative therapeutics, which combine natural ingredients and nanomaterials, can improve the biological activity of cancer chemotherapeutics. Methods: Phenolic profiling using high-resolution mass spectrometry and the synthesis of zinc oxide nanoparticles was achieved through the reaction of zinc acetate with Euphorbia retusa extract. The characterization of ZnONPs was performed by UV, IR, Zeta potential, XRD, SEM, and TEM. The cytotoxic activity of the ZnONPs was evaluated using a SRB assay against lung, liver, and breast cancer cell lines. Moreover, the mechanism of cytotoxic activity was evaluated in the form of caspase-8 promoters and anti-inflammatory mechanisms using the Western blot method. Results: The high-resolution LC/MS/MS of the E. retusa led to the identification of 22 compounds in the plant for the first time. The Er-ZnONPs had hexagonal shapes, were approximately 100 nm in size, and consisted of aggregated particles of about 10 nm. The E. retusa ZnONPs exhibited cytotoxic activity against HA-549 (IC50 = 22.3 µg/mL), HepG2 (IC50 = 25.6), Huh-7 (IC50 = 25.7), MCF-7 (IC50 = 37.7), and MDA-MB-231 (IC50 = 37). Conclusions: E. retusa are rich in phenolics that are capable of synthesizing ZnONPs, which possess cytotoxic activity, via caspase-8 promotion and anti-inflammatory mechanisms.

Identification and validation of a prognostic signature related to hypoxic tumor microenvironment in cervical cancer.

BackgroundHypoxia is a common microenvironment condition in most malignant tumors and has been shown to be associated with adverse outcomes of cervical cancer patients. In this study, we investigated the effects of hypoxia-related genes on tumor progress to characterize the tumor hypoxic microenvironment.MethodsWe retrieved a set of hypoxia-related genes from the Molecular Signatures Database and evaluated their prognostic value for cervical cancer. A hypoxia-based prognostic signature for cervical cancer was then developed and validated using tumor samples from two independent cohorts (TCGA-CESC and CGCI-HTMCP-CC cohorts). Finally, we validated the hypoxia prediction of ccHPS score in eight human cervical cancer cell lines treated with the hypoxic and normoxic conditions, and 286 tumor samples with hypoxic category (more or less) from Gene Expression Omnibus (GEO) database with accession GSE72723.ResultsA risk signature model containing nine hypoxia-related genes was developed and validated in cervical cancer. Further analysis showed that this risk model could be an independent prognosis factor of cervical cancer, which reflects the condition of the hypoxic tumor microenvironment and its remodeling of cell metabolism and tumor immunity. Furthermore, a nomogram integrating the novel risk model and lymphovascular invasion status was developed, accurately predicting the 1-, 3- and 5-year prognosis with AUC values of 0.928, 0.916 and 0.831, respectively. These findings provided a better understanding of the hypoxic tumor microenvironment in cervical cancer and insights into potential new therapeutic strategies in improving cancer therapy.

Immunogenic cell death‐inducing small molecule inhibitors: Potential for immunotherapy of cancer

AbstractSmall molecule inhibitors (SMIs) of key signalling pathways are known to induce multiple types of regulated cell death, including immunogenic cell death (ICD). The resulting antitumor immunity helps to overcome the resistance of cancer cells to cell death, resulting in improved cancer therapy. SMIs, especially those inducing multimodal cell death and ICD, can be critical components in rational combinations for cancer immunotherapy.

Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, Galectine-3 and NLRP3-MyD88-chemokine pathways.

e14516 Background: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed or are under investigation for cancer therapy for improving cancer therapy outcomes. However, several ICIs-induced side effects emerged in a fraction of these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. We studied the pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models. Methods: C57/Bl6 mice were treated with Ipilimumab, Pembrolizumab or Nivolumab (15 mg/kg) through intraperitoneal injections for 10 days. Before (T0) and after treatments (T10), analysis of fractional shortening, ejection fraction, radial and longitudinal strain were performed through 2D-echocardiography (Vevo 2100, Visual Sonics Fujfilm). Fibrosis, necrosis, hypertrophy and vascular/myocardial NF-kB expression were analyzed through Immunohistochemistry (IHC) of treated cardiac tissues. Systemic levels of SDF-1, myocardial expression of DAMPs (Fibronectin-EDA, S100/Calgranulin, Galectine-3), NLRP3, MyD88 and twelve cytokines/growth factors have been analyzed. In parallel, in a human in vitro model, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (200 nM) for 72h. After treatment, production of DAMPs and 12 cytokines/growth factors were analyzed in the supernatant through colorimetric and enzymatic assays. Results: Radial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. No myocardial hypertrophy was seen with the exception of the pembrolizumab group. Systemic SDF-1 was drastically increased after treatment with ICIs. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 inflammasome and MyD88. Conclusions: This study demonstrates that therapy with anti-CTLA-4 and anti-PD-1 antibodies increases systemic SDF-1 and myocardial NLRP3, MyD88 and DAMPs expression in preclinical models. A significant secretion of pro-inflammatory cytokines in myocardial tissue was also induced after ICIs therapy. Significant histological changes were seen and strong vascular NF-kB expression was observed in all groups.

Plasma activated liquid synergistically enhances response to radiation for improved cancer therapy

AbstractPlasma activated liquid (PAL) is an emerging cancer treatment. Two prostate cell lines and one melanoma cell line were used in clonogenic assays to assess the cytotoxicity of PAL and radiation individually and in combination, using the multiplicative survival method to quantify interactions between the treatments. PAL applied before a dose of radiation synergistically increases cytotoxicity in cancer cells, while in immortalized normal cells, the combined treatment was found to be antagonistic. These results demonstrate the potential to improve the therapeutic window of cancer treatment, giving a higher cancer response rate with less toxicity.

SERTAD1 Sensitizes Breast Cancer Cells to Doxorubicin and Promotes Lysosomal Protein Biosynthesis.

Acquired chemoresistance of tumor cells is an unwanted consequence of cancer treatment. Overcoming chemoresistance is particularly important for efficiently improving cancer therapies. Here, using multiple lines of evidence, we report the suppressive role of SERTAD1 in apoptosis/anoikis. Among various breast cancer cell lines, higher SERTAD1 expression was found in MCF7 and MDA-MB-231 in suspension than in adherent cell culture. We revealed an unexpected phenomenon that different types of cell deaths were induced in response to different doses of doxorubicin (Dox) in breast cancer cells, presumably via lysosomal membrane permeabilization. A low dose of Dox highly activated autophagy, while a high dose of the chemotherapy induced apoptosis. Inhibition of SERTAD1 promoted the sensitivity of breast cancer cells to Dox and paclitaxel, leading to a significant reduction in tumor volumes of xenograft mice. Simultaneously targeting cancer cells with Dox and autophagy inhibition successfully induced higher apoptosis/anoikis. The novel role of SERTAD1 in maintaining cellular homeostasis has also been suggested in which lysosomal contents, including LAMP1, LAMP2, CTSB, and CTSD, were reduced in SERTAD1-deficient cells.

Promoted checkpoint inhibitor-based tumor immunotherapy by small-molecule prodrug hydrogelator

Abstract Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has shown great promise in harnessing host immune system to combat cancer. That said, only a portion of patients has benefit directly from the anti–programmed cell death protein 1 (anti-PD1) therapy, whereas the others with an immunosuppressive tumor microenvironment (TME) achieve poor clinical outcomes. Hence, promoting an immune-stimulating TME that favors tumor-infiltrating lymphocytes is an important means to maximize the cancer immunotherapeutic potentials. Small-molecule prodrugs conferred intratumoral delivery of ICI agents have emerged as novel local delivery approaches to enhance antitumor immunity for cancer therapy. Our recent study revealed a combined chemoimmunotherapy could serve as a reservoir for extended release of DNA-damaging agent camptothecin and ICI agent anti-PD1 antibody, thus eliciting robust and durable systemic antitumor immunity in mice. The underlying mechanisms on how this carrier-free therapeutic system boosts immune sensing of immunogenic tumors and priming of CD8+ T cells against tumor antigens and the impact of microbiota will be discussed. Together, these results provide important insights into the use of small-molecule prodrugs as both chemotherapeutic and carrier, to awaken and enhance antitumor immune system for improved cancer therapy. Supported by NIH grant R01CA244350

Extracellular matrix in cancer progression and therapy.

The tumor ecosystem with heterogeneous cellular compositions and the tumor microenvironment has increasingly become the focus of cancer research in recent years. The extracellular matrix (ECM), the major component of the tumor microenvironment, and its interactions with the tumor cells and stromal cells have also enjoyed tremendously increased attention. Like the other components of the tumor microenvironment, the ECM in solid tumors differs significantly from that in normal organs and tissues. We review recent studies of the complex roles the tumor ECM plays in cancer progression, from tumor initiation, growth to angiogenesis and invasion. We highlight that the biomolecular, biophysical, and mechanochemical interactions between the ECM and cells not only regulate the steps of cancer progression, but also affect the efficacy of systemic cancer treatment. We further discuss the strategies to target and modify the tumor ECM to improve cancer therapy.

Metallopolysaccharide-Based Smart Nanotheranostic for Imaging-Guided Precise Phototherapy and Sequential Enzyme-Activated Ferroptosis.

Phototheranostic offers a regional-focused tumor treatment upon photoirradiation. However, it is difficult to completely eradicate solid tumors using a conventional phototheranostic owing to the residual tumor cells outside the laser irradiation range. Herein, we fabricated a metallopolysaccharide-based smart nanotheranostic (Fe-dHA) via a nanoassembly-driven method, in which Fe3+ ions were coordinated to dopamine-modified biopolysaccharide hyaluronic acid (dHA). Taking advantage of the structural backbone and intrinsic dual-information-related functions of HA as well as the bi-functional Fe(III)-coordination centers, Fe-dHA can efficiently target tumor cells for phototheranostic. Additionally, it can be activated by endogenous overexpressed hyaluronidase to achieve sequential ferroptosis in tumor cells. The precise imaging and effective tumor inhibition using this metallopolysaccharide-based nanotheranostic were significantly demonstrated in vivo and in vitro. Thus, this rationally designed Fe-dHA provided a simple metallopolysaccharide strategy to develop an "all-in-one" smart nanotheranostic to synergize different therapeutic modalities for improving cancer therapy.

Microbes-myeloid-tumor: a colonic triad against T cells

Immune checkpoint blockade has dramatically improved cancer therapy but remains ineffective for most colorectal tumors. In this issue of Immunity, Peuker etal. describe a microbiota-myeloid-tumor cell crosstalk that inhibits CD8+ Tcells and promotes colorectal cancer progression.

5-O-(N-Boc-l-Alanine)-Renieramycin T Induces Cancer Stem Cell Apoptosis via Targeting Akt Signaling.

Cancer stem cells (CSCs) drive aggressiveness and metastasis by utilizing stem cell-related signals. In this study, 5-O-(N-Boc-l-alanine)-renieramycin T (OBA-RT) was demonstrated to suppress CSC signals and induce apoptosis. OBA-RT exerted cytotoxic effects with a half-maximal inhibitory concentration of approximately 7 µM and mediated apoptosis as detected by annexin V/propidium iodide using flow cytometry and nuclear staining assays. Mechanistically, OBA-RT exerted dual roles, activating p53-dependent apoptosis and concomitantly suppressing CSC signals. A p53-dependent pathway was indicated by the induction of p53 and the depletion of anti-apoptotic Myeloid leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2) proteins. Cleaved poly (ADP-ribose) polymerase (Cleaved-PARP) was detected in OBA-RT-treated cells. Interestingly, OBA-RT exerted strong CSC-suppressing activity, reducing the ability to form tumor spheroids. In addition, OBA-RT could induce apoptosis in CSC-rich populations and tumor spheroid collapse. CSC markers, including prominin-1 (CD133), Octamer-binding transcription factor 4 (Oct4), and Nanog Homeobox (Nanog), were notably decreased after OBA-RT treatment. Upstream CSCs regulating active Akt and c-Myc were significantly decreased; indicating that Akt may be a potential target of action. Computational molecular modeling revealed a high-affinity interaction between OBA-RT and an Akt molecule. This study has revealed a novel CSC inhibitory effect of OBA-RT via Akt inhibition, which may improve cancer therapy.

Role and regulation of autophagy in cancer

Autophagy is an intracellular self-degradative mechanism which responds to cellular conditions like stress or starvation and plays a key role in regulating cell metabolism, energy homeostasis, starvation adaptation, development and cell death. Numerous studies have stipulated the participation of autophagy in cancer, but the role of autophagy either as tumor suppressor or tumor promoter is not clearly understood. However, mechanisms by which autophagy promotes cancer involves a diverse range of modifications of autophagy associated proteins such as ATGs, Beclin-1, mTOR, p53, KRAS etc. and autophagy pathways like mTOR, PI3K, MAPK, EGFR, HIF and NFκB. Furthermore, several researches have highlighted a context-dependent, cell type and stage-dependent regulation of autophagy in cancer. Alongside this, the interaction between tumor cells and their microenvironment including hypoxia has a great potential in modulating autophagy response in favour to substantiate cancer cell metabolism, self-proliferation and metastasis. In this review article, we highlight the mechanism of autophagy and their contribution to cancer cell proliferation and development. In addition, we discuss about tumor microenvironment interaction and their consequence on selective autophagy pathways and the involvement of autophagy in various tumor types and their therapeutic interventions concentrated on exploiting autophagy as a potential target to improve cancer therapy.

Interactions between miRNAs and Double-Strand Breaks DNA Repair Genes, Pursuing a Fine-Tuning of Repair.

The repair of DNA damage is a crucial process for the correct maintenance of genetic information, thus, allowing the proper functioning of cells. Among the different types of lesions occurring in DNA, double-strand breaks (DSBs) are considered the most harmful type of lesion, which can result in significant loss of genetic information, leading to diseases, such as cancer. DSB repair occurs through two main mechanisms, called non-homologous end joining (NHEJ) and homologous recombination repair (HRR). There is evidence showing that miRNAs play an important role in the regulation of genes acting in NHEJ and HRR mechanisms, either through direct complementary binding to mRNA targets, thus, repressing translation, or by targeting other genes involved in the transcription and activity of DSB repair genes. Therefore, alteration of miRNA expression has an impact on the ability of cells to repair DSBs, which, in turn, affects cancer therapy sensitivity. This latter gives account of the importance of miRNAs as regulators of NHEJ and HRR and places them as a promising target to improve cancer therapy. Here, we review recent reports demonstrating an association between miRNAs and genes involved in NHEJ and HRR. We employed the Web of Science search query TS (“gene official symbol/gene aliases*” AND “miRNA/microRNA/miR-”) and focused on articles published in the last decade, between 2010 and 2021. We also performed a data analysis to represent miRNA–mRNA validated interactions from TarBase v.8, in order to offer an updated overview about the role of miRNAs as regulators of DSB repair.

Bioinspired Electron Polarization of Nanozymes with a Human Self-Generated Electric Field for Cancer Catalytic Therapy.

Reactive oxygen species (ROS) production efficiencies of the nanocatalysts are highly desired for cancer therapy, but currently the ROS generation efficiency is still far from defecting the tumors. Therefore, improving their ROS generation ability is highly desirable for cancer therapy. Herein, inspired by the electrostatic preorganization effect during the catalysis of natural protein enzymes, a human self-driven catalysis-promoting system, TENG-CatSystem is developed, to improve catalytic cancer therapy. The TENG-CatSystem is mainly composed of three elements: a human self-driven triboelectric nanogenerator (TENG) as the electric field stimulator to provide electric pulses with high biosafety, a nanozyme comprising a 1D ferriporphyrin covalent organic framework coated on a carbon nanotube (COF-CNT) to generate ROS, and a COF-CNT-embedded conductive hydrogel that can be injected into the tumor tissues to increase local accumulation of COF-CNT and decrease the electrical impedances of tissues. Under the human self-generated electric field provided by the wearable TENG, the peroxidase-like activity of the COF-CNT is fourfold higher than that without an electric field. Highly malignant 4T1 breast carcinoma in mice is significantly suppressed using the TENG-CatSystem. The human self-driven TENG-CatSystem not only demonstrates high catalytic ROS generation efficiency for improved cancer therapy, but also offers a new therapeutic mode for self-driven at-home therapy.

Recent Advancements in Mitochondria-Targeted Nanoparticle Drug Delivery for Cancer Therapy.

Mitochondria are critical subcellular organelles that produce most of the adenosine triphosphate (ATP) as the energy source for most eukaryotic cells. Moreover, recent findings show that mitochondria are not only the “powerhouse” inside cells, but also excellent targets for inducing cell death via apoptosis that is mitochondria-centered. For several decades, cancer nanotherapeutics have been designed to specifically target mitochondria with several targeting moieties, and cause mitochondrial dysfunction via photodynamic, photothermal, or/and chemo therapies. These strategies have been shown to augment the killing of cancer cells in a tumor while reducing damage to its surrounding healthy tissues. Furthermore, mitochondria-targeting nanotechnologies have been demonstrated to be highly efficacious compared to non-mitochondria-targeting platforms both in vitro and in vivo for cancer therapies. Moreover, mitochondria-targeting nanotechnologies have been intelligently designed and tailored to the hypoxic and slightly acidic tumor microenvironment for improved cancer therapies. Collectively, mitochondria-targeting may be a promising strategy for the engineering of nanoparticles for drug delivery to combat cancer.

Cross-Reacting Material 197, a Specific Inhibitor of HB-EGF, and Its Anticancer Effects

Genetic heterogeneity and metastasis remain the most challenging aspects of cancer treatment.Recent studies have introduced a mutant of diphtheria toxin,cross-reacting material197 (CRM197), as a new promising biological anticancer drug to improve cancer therapy in patients previously resistant to chemotherapy. Weak toxicity of CRM197accounts forthe stimulation ofcell apoptosis and the antitumor effect. Increasing evidence has indicated that the expression of heparin-binding epidermal growth factor-like (HB-EGF) growth factorincreases in most cancer cells, and CRM197 is its specific inhibitor.This study has focused on the structure, properties, and anticancer activity of CRM197.