Treatment Of Human Cancer Research Articles

Can Nitric Oxide-Based Therapy Be Improved for the Treatment of Cancers? A Perspective.

Since the early observations that nitric oxide (•NO) at high concentrations is cytotoxic to cancer cells and that it may play an important role in the treatment of human cancers, a significant number of compounds (NO-donors) have been prepared to deliver •NO to tumors. •NO also sensitizes various clinically active anticancer drugs and has been shown to induce the reversal of multi-drug resistance in tumor cells expressing ATP-binding cassette-transporter proteins. For the successful treatment of cancers, •NO needs to be delivered precisely to tumors, and its adverse toxicity must be limited. Like other chemotherapeutics, the precise delivery of drugs has been a problem and various attempts have been made, such as the encapsulation of drugs in lipid polymers, to overcome this. This prospective study examines the use of various strategies for delivering •NO (using NO-donors) for the treatment of cancers. Finding and utilizing such a delivery system is an important step in delivering cytotoxic concentrations of •NO to tumors without adverse reactions, leading to a successful clinical outcome for patient management.

A proteogenomics data-driven knowledge base of human cancer.

By combining mass-spectrometry-based proteomics and phosphoproteomics with genomics, epi-genomics, and transcriptomics, proteogenomics provides comprehensive molecular characterization of cancer. Using this approach, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) has characterized over 1,000 primary tumors spanning 10 cancer types, many with matched normal tissues. Here, we present LinkedOmicsKB, a proteogenomics data-driven knowledge base that makes consistently processed and systematically precomputed CPTAC pan-cancer proteogenomics data available to the public through ∼40,000 gene-, protein-, mutation-, and phenotype-centric web pages. Visualization techniques facilitate efficient exploration and reasoning of complex, interconnected data. Using three case studies, we illustrate the practical utility of LinkedOmicsKB in providing new insights into genes, phosphorylation sites, somatic mutations, and cancer phenotypes. With precomputed results of 19,701 coding genes, 125,969 phosphosites, and 256 genotypes and phenotypes, LinkedOmicsKB provides a comprehensive resource to accelerate proteogenomics data-driven discoveries to improve our understanding and treatment of human cancer. A record of this paper's transparent peer review process is included in the supplemental information.

Gendered Hormonal Binaries and the Development of the Category of "Hormone-Dependent Cancers," 1940-1980.

This article considers the establishment of the category of "hormone-dependent cancers," identified around the middle of the twentieth century as cancers sustained by particular hormones. A comparison of hormonal treatments for prostate cancer and those for breast cancer reveals that the genesis of "hormone-dependent cancer" as a biomedical category relied upon assumptions that cast androgens and estrogens as opposing ends of a gendered hormonal binary of health and disease. In the 1930s, cancer researchers claimed "female sex hormones" (estrogens) exacerbated breast cancer and "male sex hormones" (androgens) prevented it. In the early 1940s, Dr. Charles Huggins applied the opposite logic to the treatment of human prostate cancer, which he determined to be "hormone-dependent." As "hormone dependency" was also recognized in human breast cancer over the subsequent decades, estrogen claimed a prominent place in discussions of breast cancer's causation, diagnosis, and treatment. This close association between estrogen and breast cancer contributed to reinterpretations of both biomedical categories.

The Effect of Green Tea Catechins on Solarum lycopersicum Infected with Agrobacterium tumefaciens

Agrobacterium tumefaciens is a soil-borne pathogen that causes crown-gall disease and growth stunting. Current preventative treatments are not feasible for organic or GMO-free farms. A potential natural alternative to such control methods is the use of green tea (containing epigallocatechin-3-gallate (EGCG). In this study, the effect of green tea catechins on tumor progression in Solanum lycopersicum (tomato plants) infected with A. tumfaciens was investigated. It was hypothesized that plants treated with green tea catechins would have fewer signs of oxidative stress, and smaller tumors. Tomato plants, grown from seed were watered with green tea or tap water for 9 weeks before inoculation. The control groups included: 1) plants watered with 100ml of water and inoculated with A. tumefaciens; 2) plants watered with 100ml water only; 3) plants watered with 100ml of green tea with an EGCG content of 119 mg. The experimental group included plants watered with green tea and inoculated with A. tumefaciens. After 14 weeks, a leaf Spectrometer was used to measure signs of oxidative stress and tumor size was measured. The p-value from Anthocyanin Reflectance (0.038) and Chlorophyll Content (0.020) showed a significant relationship between treatments and the interaction of treatment and infection cohorts respectively. There was no observed significance between tumor size (p= 0.13). However, these significant relationships suggest that pre-treatment with Green Tea Catechins (EGCG) is an effective Non-GMO option for preventing profit loss from A.tumefaciens infection. EGCG can also be considered a compound of interest for further research in human cancer treatment.

Marine Natural Compound (Neviotin A) Displays Anticancer Efficacy by Triggering Transcriptomic Alterations and Cell Death in MCF-7 Cells.

We investigated the anticancer mechanism of a chloroform extract of marine sponge (Haliclona fascigera) (sample C) in human breast adenocarcinoma (MCF-7) cells. Viability analysis using MTT and neutral red uptake (NRU) assays showed that sample C exposure decreased the proliferation of cells. Flow cytometric data exhibited reactive oxygen species (ROS), nitric oxide (NO), dysfunction of mitochondrial potential, and apoptosis in sample C-treated MCF-7 cells. A qPCR array of sample C-treated MCF-7 cells showed crosstalk between different pathways of apoptosis, especially BIRC5, BCL2L2, and TNFRSF1A genes. Immunofluorescence analysis affirmed the localization of p53, bax, bcl2, MAPKPK2, PARP-1, and caspase-3 proteins in exposed cells. Bioassay-guided fractionation of sample C revealed Neviotin A as the most active compound triggering maximum cell death in MCF-7, indicating its pharmacological potency for the development of a drug for the treatment of human breast cancer.

Investigation of In Vitro antiproliferative activity properties of Spartium junceum L. (Spanish broom) against MDA-MB-231 and HepG2 cancer cell lines

Cancer is among the top global public health burdens leading to millions of deaths each year. The study aims to investigate the antiproliferative effect of Spartium junceum L. flowers on different cancer cell lines. The ethanolic extract of the flowers was prepared in the present study. Phytochemical analysis of the plant extract revealed the presence of several phenolic compounds such as cinnamic acid and its derivatives (chlorogenic, p-coumaric, ferulic acids), protocatechuic acid, epicatechin and luteolin. This extract was tested against human breast (MDA-MB-231) and liver (HepG2) cancer cell lines to find out its antiproliferative activity. It was determined that the extract was effective against both cell lines with IC50 values of 2.37 ± 0.47 and 0.98 ± 0.01 µL/mL for MDA-MB-231 and HepG2, respectively. Particularly, the extract was found to be more effective in the liver cancer cell line than the breast cancer cell line. All these obtained findings led us to believe that this medicinal plant could be a promising antiproliferative agent candidate for the treatment of human liver and breast cancers.

Preclinical and clinical trials of oncolytic vaccinia virus in cancer immunotherapy: a comprehensive review.

Oncolytic virotherapy has emerged as a promising treatment for human cancers owing to an ability to elicit curative effects via systemic administration. Tumor cells often create an unfavorable immunosuppressive microenvironment that degrade viral structures and impede viral replication; however, recent studies have established that viruses altered via genetic modifications can serve as effective oncolytic agents to combat hostile tumor environments. Specifically, oncolytic vaccinia virus (OVV) has gained popularity owing to its safety, potential for systemic delivery, and large gene insertion capacity. This review highlights current research on the use of engineered mutated viruses and gene-armed OVVs to reverse the tumor microenvironment and enhance antitumor activity in vitro and in vivo, and provides an overview of ongoing clinical trials and combination therapies. In addition, we discuss the potential benefits and drawbacks of OVV as a cancer therapy, and explore different perspectives in this field.

A Nanobody-Bioorthogonal Catalyst Conjugate Triggers Spatially Confined Prodrug Activation for Combinational Chemo-immunotherapy.

Checkpoint inhibitors have been used with chemotherapy to improve antitumor efficacy. However, overcoming the immunosuppressive effect of chemotherapeutics remains a challenge. We report a nanobody-catalyst conjugate Ru-PD-L1 by fusing a ruthenium catalyst to an anti-PD-L1 nanobody. After administration of Ru-PD-L1 and a doxorubicin (DOX) prodrug, Ru-PD-L1 disrupts the PD-L1/PD-1 interaction and catalyzes the uncaging of the DOX prodrug. The spatially confined release of DOX reduces its systemic toxicity and leads to immunogenic cell death (ICD). The induced ICD triggers antitumor immune responses, which are further amplified by PD-L1 blockade to elicit synergistic chemo-immunotherapy, substantially increasing the number of tumor-infiltrating T-cells by 49.7% compared with the controls, thereby exhibiting high antitumor activity and low cytotoxicity in murine models. The combinational treatment could inhibit the growth of mice tumors by 67.7% compared to the control group. This combinational approach circumvents the negative immunogenic effects of chemotherapeutics and provides a potential chemo-immunotherapy strategy for human cancer treatment.

Virtual screening of novel mTOR inhibitors for the potential treatment of human colorectal cancer

The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 μM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 μM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 μM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.

Strawberry (Fragaria × ananassa) and Kiwifruit (Actinidia deliciosa) Extracts as Potential Radioprotective Agents: Relation to Their Phytochemical Composition and Antioxidant Capacity

Ionising radiation is an important form of treatment for human cancer; however, the side effects associated with oxidative damage caused by radiation compromise its effectiveness. This work aimed to quantify the major bioactive components of freeze-dried kiwifruit (KD) and strawberry (SD) extracts and assess their potential efficacy as radioprotective agents in human blood lymphocytes. Their possible genotoxic and cytotoxic effects were also evaluated. The study was conducted by pre-treating human lymphocytes with KD and SD (50, 400, and 800 µg/mL) before radiation at 2 Gy. The results showed that SD presented a higher antioxidant capacity (12.6 mmol Trolox equivalents/100 g db) and higher values of total phenolic compounds (2435 mg of gallic acid equivalents/100 g db), while KD had the highest vitamin C content (322 mg ascorbic acid/100 g db). Regarding phenolic compounds, pelargonidin-3-glucoside was the most abundant in SD (1439 mg/1000 g db) and quercetin-3-O-galactoside in KD (635 mg/1000 g db). None of the tested concentrations of both fruit extracts showed a genotoxic effect. SD (800 µg/mL) reduced the sister chromatid exchange frequency and mitotic index. The efficacy of KD (400 and 800 µg/mL) in lowering the dicentric chromosome frequency demonstrated its radioprotective activity.

Dual Drug Loaded Potassium-contained Graphene Oxide as a Nanocarrier in Cocktailed Drug Delivery for the Treatment of Human Breast Cancer.

The combinatorial use of anticancer drugs, dual or multiple, with a specific nanocarrier is one of the most promising attempts in drug delivery. The current work reports potassium contained graphene oxide (K-GO) as a nanocarrier in the drug delivery system of two anticancer drugs, gefitinib (GEF) and camptothecin (CPT), simultaneously. To characterize K-GO, K-GO-related single and combined drug systems, different techniques have been performed and studied using the following spectroscopic tools, such as Thermo Gravimetric Analysis (TGA 4000), UV-visible spectroscopy, Raman spectroscopy, and Transmission electron microscopy (TEM). The in vitro cytotoxicity tests of K-GO, single drug system, and the combined drug system were also performed in the human breast cancer MDA-MB-231 cells. The release profile of the dual drug conjugates grafted onto the surface of K-GO was found to be up to 38% in PBS solution over 72 hours. The percentage of MDA-MB-231 cell viability was about 18% when treated with K-GO-GEF-CPT combined system; for K-GO, K-GO-GEF, and K-GO-CPT, the cell viability was 79%, 31%, and 32%, respectively. We studied the loading, release, and delivery of two anticancer drugs onto the fluorescent nanocarrier. Features, such as superb aqueous solubility, excellent biocompatibility, richness in potassium, and fluorescent nature, which can monitor the delivery of drugs, make them a promising nanocarrier for single or multiple drug delivery. Furthermore, our novel findings revealed that the loading capacity and cytotoxicity of the combined drug-loaded system are superior to the capacity of the individual drug system for human breast cancer cells.

Discovery of SMD-3040 as a Potent and Selective SMARCA2 PROTAC Degrader with Strong in vivo Antitumor Activity.

SMARCA2 is an attractive synthetic lethality target for human cancers with SMARCA4 deficiency. Herein, we report the design, synthesis, and biological evaluation of selective SMARCA2 protein degraders developed using the proteolysis targeting chimera (PROTAC) technology. Our efforts have led to the discovery of a series of potent and selective SMARCA2 degraders, exemplified by SMD-3040. SMD-3040 degrades SMARCA2 protein with a low nanomolar DC50 and Dmax > 90% and demonstrates an excellent degradation selectivity for SMARCA2 protein over SMARCA4 protein. It displays potent cell growth inhibitory activity in a panel of SMARCA4-deficient cancer cell lines and has much weaker activity in SMARCA4 wild-type cancer cell lines. SMD-3040 achieves strong tumor growth inhibition in two SMARCA4-deficient xenograft models at well-tolerated dose schedules. Further optimization of SMD-3040 may lead to the discovery of new therapies for the treatment of human cancers with SMARCA4 deficiency.

Targeting oncogenic KRAS in non-small cell lung cancer with EGFR aptamer-conjugated multifunctional RNA nanoparticles

KRAS mutations are one of the most common oncogenic driver mutations in human cancers, including non-small cell lung cancer (NSCLC), and have established roles in cancer pathogenesis and therapeutic resistance. The development of effective inhibitors of mutant KRAS represents a significant challenge. Three-way junction (3WJ)-based multi-functional RNA nanoparticles have the potential to serve as an effective invivo siRNA delivery platform with the ability to enhance tumor targeting specificity and visualize biodistribution through an imaging moiety. Herein, we assembled novel EGFRapt-3WJ-siKRASG12C mutation targeted nanoparticles to target EGFR-expressing human NSCLC harboring a KRASG12C mutation to silence KRASG12C expression in a tumor cell-specific fashion. We found that EGFRapt-3WJ-siKRASG12Cnanoparticles potently depleted cellular KRASG12C expression, resulting in attenuation of downstream MAPK pathway signaling, cell proliferation, migration/invasion ability, and sensitized NSCLC cells to chemoradiotherapy. Invivo, these nanoparticles induced tumor growth inhibition in KRASG12C NSCLC tumor xenografts. Together, this study suggests that the 3WJ pRNA-based platform has the potential to suppress mutant KRAS activity for the treatment of KRAS-driven human cancers, and warrants further development for clinical translation.

Emerging Insights into Liver X Receptor α in the Tumorigenesis and Therapeutics of Human Cancers.

Liver X receptor α (LXRα), a member of the nuclear receptor superfamily, is identified as a protein activated by ligands that interacts with the promoters of specific genes. It regulates cholesterol, bile acid, and lipid metabolism in normal physiological processes, and it participates in the development of some related diseases. However, many studies have demonstrated that LXRα is also involved in regulating numerous human malignancies. Aberrant LXRα expression is emerging as a fundamental and pivotal factor in cancer cell proliferation, invasion, apoptosis, and metastasis. Herein, we outline the expression levels of LXRα between tumor tissues and normal tissues via the Oncomine and Tumor Immune Estimation Resource (TIMER) 2.0 databases; summarize emerging insights into the roles of LXRα in the development, progression, and treatment of different human cancers and their diversified mechanisms; and highlight that LXRα can be a biomarker and therapeutic target in diverse cancers.

Genetic and chemical targeting of the ATPase complex TIP48 and 49 impairs acute myeloid leukemia.

The chromatin-associated AAA+ ATPases Tip48 and Tip49 are the core components of various complexes implicated in diverse nuclear events such as DNA repair and gene regulation. Although they are frequently overexpressed in many human cancers, their functional significance remains unclear. Here, we show that loss of Tip49 triggered p53-dependent apoptosis and inhibited leukemia development in vivo. To examine the impact of chemical inhibition of this complex on leukemia, we have developed the novel compound DS-4950, which interferes with the ATPase activity of the Tip48/49. Administration of DS-4950 was well-tolerated in healthy mice, and the drug effectively reduced tumor burden and improved survival. We also provide evidence that the dependency on Tip48/49 is widely conserved in non-hematologic malignancies with wild type p53. These results demonstrated that the Tip48/49 ATPases are functionally necessary and therapeutically targetable for the treatment of human cancers.

TARGETING TREG CELLS BY TNFR2 ANTIBODY INDUCES TUMOR REGRESSION IN VIVO

Abstract Background Tumor necrosis factor receptor 2 (TNFR2) is considered an appealing target due to its low-level expression on immune cells, but it could be upregulated on regulatory T cells (Tregs) in the tumor microenvironment which plays key roles in Treg proliferation and function. It has been demonstrated that Tregs with high TNFR2 expression were the most suppressive subsets among all Treg populations in the tumor. While early studies showed that TNFR2 co-stimulates naïve T cells, it has been revealed later that TNFR2 also limits CD8+ T-cell-mediated viral clearance and anti-tumor immunity by inducing rapid contraction of CD8+ T cells. Consistent with these findings, several publications reported that anti-TNFR2 antibody treatment exhibited robust antitumor efficacy. In short, TNFR2 signaling is critical in regulating immune response in different diseases. In the current study, the anti-human TNFR2 antibody SBT-1901 was developed and the anti-tumor activity was evaluated. Materials and methods SBT-1901 was generated through hybridoma and humanization technologies. The binding affinity and specificity were tested by ELISA, FACS, and OCTET. The function of SBT-1901 was tested in TNFR2-Fas overexpressing Ramos cells and in Treg proliferation assay. The in vivo anti-tumor activity and pharmacokinetics of SBT-1901 were evaluated in the human TNFR2 transgenic mouse model (Biocytogen) bearing MC38 tumor. Results SBT-1901 binds to the extracellular domain of human and cynomolgus TNFR2 with the affinity of single digit-nanomolar. It competes with TNFα for binding to TNFR2 receptor and inhibits TNFα-induced TNFR2-Fas overexpressing RAMOS cell death. SBT-1901 also blocks TNFα induced Treg proliferation in human PBMC. In addition, SBT-1901 significantly inhibits MC38 tumor growth in a dose-dependent manner as a monotherapy and enhances anti-tumor efficacy of mPD-1 antibody in a combination study in human TNFR2 transgenic mouse model. SBT-1901 is currently under preclinical development. Conclusions Our studies show that SBT-1901 exhibits a very potent anti-tumor efficacy in vivo as a single agent or the combination. Therefore, it is highly valuable to further develop SBT-1901 for human cancer treatment.

Establishment of Primary Adult Skin Fibroblast Cell Lines from African Savanna Elephants (Loxodonta africana).

Following population declines of the African savanna elephant (Loxodonta africana) across the African continent, the establishment of primary cell lines of endangered wildlife species is paramount for the preservation of their genetic resources. In addition, it allows molecular and functional studies on the cancer suppression mechanisms of elephants, which have previously been linked to a redundancy of tumor suppressor gene TP53. This methodology describes the establishment of primary elephant dermal fibroblast (EDF) cell lines from skin punch biopsy samples (diameter: ±4 mm) of African savanna elephants (n = 4, 14-35 years). The applied tissue collection technique is minimally invasive and paves the way for future remote biopsy darting. On average, the first explant outgrowth was observed after 15.75 ± 6.30 days. The average doubling time (Td) was 93.02 ± 16.94 h and 52.39 ± 0.46 h at passage 1 and 4, respectively. Metaphase spreads confirmed the diploid number of 56 chromosomes. The successful establishment of EDF cell lines allows for future elephant cell characterization studies and for research on the cancer resistance mechanisms of elephants, which can be harnessed for human cancer prevention and treatment and contributes to the conservation of their genetic material.

An Updated Review Summarizing the Anticancer Efficacy of Melittin from Bee Venom in Several Models of Human Cancers.

Apitherapy (using bee products) has gained broad recognition in cancer therapeutics globally. Honeybee venom has a broad range of biological potential, and its utilization is rapidly emerging in apitherapy. Bee products have significant potential to strengthen the immune system and improve human health. Thus, this review is targeted toward recapitulating the chemo-preventive potential of melittin (MEL), which constitutes a substantial portion of honeybee venom. Honeybee venom (apitoxin) is produced in the venom gland of the honeybee abdomen, and adult bees utilize it as a primary colony defense mechanism. Apitoxin comprises numerous biologically active compounds, including peptides, enzymes, amines, amino acids, phospholipids, minerals, carbohydrates, and volatile components. We are mainly focused on exploring the potential of melittin (a peptide component) of bee venom that has shown promising potential in the treatment of several human cancers, including breast, stomach, lung, prostate, ovary, kidney, colon, gastric, esophageal, cervical cancers, melanoma, osteosarcoma, and hepatocellular carcinoma. This review has summarized all potential studies related to the anticancerous efficacy of melittin (apitoxin), its formulations, conjugates, and nano-formulations against several human carcinomas, which would further pave the way for future researchers in developing potent drugs for cancer management.

Green supported silver nanoparticles over modified reduced graphene oxide: Investigation of its antioxidant and anti-ovarian cancer effects

Abstract A green biosynthesis of silver nanoparticles (AgNPs) decorated Mentha longifolia root extract-functionalized graphene oxide (GO) nanohybrid material has been described. Initially, the Mentha longifolia root was coated on GO’s surface. The phytochemicals of the plant acted as reducing agent for reduction of silver ions and GO to form the rGO-Mentha/Ag nanocomposite. The nanocomposite was characterized using FE-SEM, EDX, FT-IR, TEM, elemental mapping, and XRD analysis. The cells treated with rGO-Mentha/Ag nanocomposite were assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay for 48 h about the cytotoxicity and anti-human ovarian cancer properties on normal (HUVEC) and human ovarian cancer cell lines, i.e., SKOV3 and A2780. The IC50 of rGO-Mentha/Ag nanocomposite were 181.2 and 196.4 µg/mL against SKOV3 and A2780cell lines, respectively. The viability of malignant human ovarian cell line reduced dose-dependently in the presence of rGO-Mentha/Ag nanocomposite. After clinical study, rGO-Mentha/Ag nanocomposite can be introduced as a novel composite in the treatment of human ovarian cancer.

Electrochemical Synthesis of New Isoxazoles and Triazoles Tethered with Thiouracil Base as Inhibitors of Histone Deacetylases in Human Breast Cancer Cells

Histone deacetylases (HDACs) are an attractive drug target for the treatment of human breast cancer (BC), and therefore, HDAC inhibitors (HDACis) are being used in preclinical and clinical studies. The need to understand the scope of the mode of action of HDACis, as well as the report of the co-crystal structure of HDAC6/SS-208 at the catalytic site, provoked us to develop an isoxazole-based lead structure called 4-(2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio) pyrimidin-4-yl) morpholine (5h) and 1-(2-(((3-(p-tolyl) isoxazol-5-yl)methyl)thio) pyrimidin-4-yl) piperidin-4-one (6l) that targets HDACs in human BC cells. We found that the compound 5h or 6l could inhibit the proliferation of BC cells with an IC50 value of 8.754 and 11.71 µM, respectively. Our detailed in silico analysis showed that 5h or 6l compounds could target HDAC in MCF-7 cells. In conclusion, we identified a new structure bearing triazole, isoxazole, and thiouracil moiety, which could target HDAC in MCF-7 cells and serve as a base to make new drugs against cancer.