Rate Of Cancer Cells Research Articles

Simultaneous estimation of the cellular water exchange rate, intracellular volume fraction, and longitudinal relaxation rate in cancer cells.

The purpose of the current study was to investigate the feasibility of simultaneously estimating the cellular water efflux rate ( ), intracellular longitudinal relaxation rate ( ), and intracellular volume fraction ( ) of a cell suspension using multiple samples with different gadolinium concentrations. Numerical simulation studies were conducted to assess the uncertainty in the estimation of , , and from saturation recovery data using single (SC) or multiple concentrations (MC) of gadolinium-based contrast agent (GBCA). In vitro experiments with 4 T1 murine breast cancer and SCCVII squamous cell cancer models were conducted at 11 T to compare parameter estimation using the SC protocol with that using the MC protocol. The cell lines were challenged with a Na+ /K+ -ATPase inhibitor, digoxin, to assess the treatment response in terms of , , and . Data analysis was conducted using the two-compartment exchange model for parameter estimation. The simulation study data demonstrate that the MC method, compared with the SC method, reduces the uncertainty of the estimated by decreasing the interquartile ranges from 27.3% ± 3.7% to 18.8% ± 5.1% and the median differences from ground truth from 15.0% ± 6.3% to 7.2% ± 4.2%, while estimating and simultaneously. In the cell studies, the MC method demonstrated reduced uncertainty in overall parameter estimation compared with the SC approach. MC method-measured parameter changes in cells treated with digoxin increased by 11.7% (p = 0.218) and by 5.9% (p = 0.234) for 4 T1 cells, respectively, and decreased by 28.8% (p = 0.226) and by 1.6% (p = 0.751) for SCCVII cells, respectively. did not change noticeably by the treatment. The results of this study substantiate the feasibility of using saturation recovery data of multiple samples with different GBCA concentrations for simultaneous measurement of the cellular water efflux rate, intracellular volume fraction, and intracellular longitudinal relaxation rate in cancer cells.

Scrophularıa oxysepala inhibit oral cancer cell line OECM-1 through induction of apoptosis

Oral cancer is a deadly malignancy that indicated high resistance to chemotherapeutic agents. Natural compounds derived from herbal medicine are many popular, and commonly used for treatment of several human disorders and malignancies in the world. In this study we aimed to investigate the anticancer activity of Scrophularıa oxysepala essential oil on oral cancer cell line OECM-1 and underlying mechanisms. The essential oil of S. oxysepala prepared by Clevenger instrument from dried leaves of plant. Cytotoxic effects of S. oxysepala essential oil was investigated by Tetrazolium staining on OECM-1 oral cancer cells. Moreover, the effects of S. oxysepala essential oil was investigated on apoptosis rate in cancer cells. The apoptosis-related genes (BAX, BCL2, SMAC, SURVIVIN) expression in treated cancer cells were evaluated by quantitative Real-Time PCR method. Our results indicated a significant cytotoxic effect of S. oxysepala essential oil against oral cancer cells in a time- and concentration-dependent manner. We observed several morphological changes in treated oral cancer cells by S. oxysepala essential oil that indicate cancer cell death and apoptosis. In addition, S. oxysepala essential oil induced apoptosis rate in treated cancer cells through regulation of BAX, BCL2, SMAC, and SURVIVIN genes expression. In general, our study demonstrated a significant cytotoxic effects of S. oxysepala essential oil against oral cancer cells, which may be due to induction of apoptosis through regulation of apoptosis-related genes expression.

Abstract 2613: A modified Luria-Delbrück assay allows quantification of colorectal cancer persister cells’ mutation rate

Abstract When cancer cells are exposed to lethal doses of targeted therapies, the emergence of a subpopulation of drug-tolerant persister cells (DTPs) is often observed. We previously reported that colorectal cancer (CRC) cells exposed to targeted therapies activate an adaptive mutability stress response, involving DNA damage induction and a switch to low-fidelity DNA replication. Therefore, targeted treatment might lead to increased mutation rate in DTPs, but mutation rates of cancer cells during treatment have not been quantitatively assessed. Here, we combined biological experiments and mathematical modelling to characterize emergence and dynamics of DTPs. From this, we extrapolated parameters governing dynamics of cancer cells populations and designed a modified Luria-Delbrück assay on mammalian cells (MC-LD) to quantify mutations rates of CRC cells under standard growth conditions and during exposure to targeted therapy. We selected mismatch repair proficient CRC cell lines sensitive to different clinically used therapeutic agents, and derived clones to be used for experiments. By monitoring cell dynamics in drug-response growth assays, we found that CRC cells exposed to targeted therapy display a biphasic killing curve reaching a stable plateau, a pattern indicative of emergence of DTPs. By fitting model estimation to population growth assays, we predicted that, even if a subgroup of DTPs predated treatment, the majority of them emerged only upon exposure to targeted therapies. We also observed that DTPs slowly replicate under treatment, as shown by Carboxy fluorescein succinimidyl ester (CFSE) analysis and staining with 5-ethynyl-2’-deoxyuridine (EdU). We used these population dynamics parameters to design the MC-LD assay. CRC clones were plated in several 96-multiwell plates each, and after an expansion phase in standard culture conditions, treatment was added. After 3-4 weeks, a minority of wells showed growth of resistant colonies: based on the measured growth rates, we could predict that the resistant cells arose before treatment by spontaneous mutation. The remaining wells contained a homogenous population of DTPs. After several weeks of treatment, when pre-treatment resistant clones would have already emerged, late-emerging resistant colonies appeared in a subset of wells in which DTPs had previously been detected. Using the number of residual DTPs and resistant colonies to infer mutation rates, we found a 7- to 50-fold increase (depending on the cell line) in DTPs’ mutation rate compared to sensitive cells.In conclusion, we developed a new assay which allows quantitative comparisons of spontaneous and drug-induced mutation rates in cancer cells and showed that adaptive mutability in DTPs leads to increased mutation rates. This approach could be used to measure whether and how a wide range of environmental conditions affect DTP phenotype and mutation rates in mammalian cells. Citation Format: Alberto Sogari, Mariangela Russo, Simone Pompei, Mattia Corigliano, Giovanni Crisafulli, Andrea Bertotti, Marco Gherardi, Federica Di Nicolantonio, Marco Cosentino Lagomarsino, Alberto Bardelli. A modified Luria-Delbrück assay allows quantification of colorectal cancer persister cells’ mutation rate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2613.

Abstract A038: Does mutation rate of cancer cells change as the stage of the disease advances?

Abstract Tumorigenesis begins with cells that have normal mutation rates. As the cells become immortal and accumulate different numbers of mutations along the way, current literature splits in two describing if and how mutation rates increase as the cancer progresses. Some argue that as the mutation rates are small (mutation rate in healthy cells is per nucleotide site per cell division) and malignant cells are loaded with thousands of different types of mutations, they must have acquired a mutator phenotype early in their development. Others argue that immortality of malignant cells, and their rate of proliferation is responsible for their genetic instability and number of mutations observed in their genome. We conduct a review of the literature with the key words “mutation rate” and “cancer” in their title. We review 123 papers and found that description of mutation rates varied in the published work. This leads to estimates of mutation rates in cancer from per nucleotide site per cell division. Some of this variation in mutational rates arises across different organs of the body, for instance liver cells have a higher mutation rate than heart and brain. Cancer treatments such as chemotherapy influence mutation rate, and mutation rate of drug and multidrug resistance cancer cell is higher than newly diagnosed cancer cells. Further, mutation rate is defined differently in different literature, some papers measure the mutation rate in a population or a gene, some calculate it per base pair, genome, or mitosis. Here we provide a comprehensive picture of published mutation rates across different cancer types in order to inform cancer models and treatment plans for individual patients. We propose a unified framework for discussing and reporting mutation rate of cancer cells and formulations on how to switch between definitions. Citation Format: Fargam Neinavaie, Andrew Kramer. Does mutation rate of cancer cells change as the stage of the disease advances? [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A038.

Abstract IA020: Dynamics of response and resistance to cancer therapy

Abstract Despite the effectiveness of many cancer therapies in reducing tumor burden for significant amounts of time in a subset of patients, primary and acquired resistance to treatment remain one of the biggest challenges in the effort to cure cancer. Successful management, or prevention, of resistance requires deciphering the mechanisms by which it arises, and in particular whether it stems from pre-existing cell populations or arises de novo during therapy. Using evolutionary principles and mathematical techniques together with patient data, we aim to develop a precise mathematical understanding of the dynamics of response and resistance to various cancer therapies, including targeted therapies and immunotherapy. Our work shows that therapies that maximize the killing rate of cancer cells may not be optimal, and that instead the parameters determining the fraction of resistant cells and their growth rate have a larger effect on the long-term control of cancer. Citation Format: Ivana Bozic. Dynamics of response and resistance to cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA020.

Toxicity Effects of Lipid Nanoparticles Containing Artemisia Absinthium L Essential Oil on BRC-03 Breast Cancer Cell Line

Background & Objective: According to research, breast cancer is the second most common cancer among women. Nanomaterials of various materials significantly increase the solubility, stability and effective drug delivery, and in recent years research on the effectiveness of essential oils and plant extracts in inhibiting the growth of cancer cells is expanding. Artemisia belongs to the Asteraceae family. In many studies, the effectiveness of the essential oil and extract of this plant in inhibiting the growth of cancer cells has been reported.
 Materials & Methods: In this experiment, nanoparticles containing Artemisia absinthium L essential oil (thistle) were first synthesized by homogenizer & sonication method and then their physicochemical properties were determined, such as particle size, particle size distribution, zeta potential, percentage of loading efficiency. Then, the anti-apoptotic effect of lipid nanoparticles containing Artemisia essential oil in breast cancer cells (BRC-03) was evaluated.
 Results: The results of cellular effect of lipid nanoparticles containing essential oil of Artemisia absinthium L (thistle) on breast cancer cells showed that increasing the concentration of lipid nanoparticles containing essential oil of this plant reduced the survival rate of cancer cells. Breast (BRC-03) was purified compared to essential oil (p <0.05).
 Conclusion: Nano-essential oil of this plant is effective in reducing the IC50 of the drug and in increasing the cytotoxicity of the essential oil of the plant. Lipid nanoparticles containing essential oil of Artemisia absinthium L (thistle) activated the apoptotic pathway in breast cancer cells.

DECR1 directly activates HSL to promote lipolysis in cervical cancer cells

Fatty acids have a high turnover rate in cancer cells to supply energy for tumor growth and proliferation. Lipolysis is particularly important for the regulation of fatty acid homeostasis and in the maintenance of cancer cells. In the current study, we explored how 2,4-Dienoyl-CoA reductase (DECR1), a short-chain dehydrogenase/reductase associated with mitochondrial and cytoplasmic compartments, promotes cancer cell growth. We report that DECR1 overexpression significantly reduced the triglyceride (TAG) content in HeLa cells; conversely, DECR1 silencing increased intracellular TAG content. Subsequently, our experiments demonstrate that DECR1 promotes lipolysis via effects on hormone sensitive lipase (HSL). The direct interaction of DECR1 with HSL increases HSL phosphorylation and activity, facilitating the translocation of HSL to lipid droplets. The ensuing enhancement of lipolysis thus increases the release of free fatty acids. Downstream effects include the promotion of cervical cancer cell migration and growth, associated with the enhanced levels of p62 protein. In summary, high levels of DECR1 serves to enhance lipolysis and the release of fatty acid energy stores to support cervical cancer cell growth.

We need to bring R0

If each cancer cell produces on average more than one cancer cell, we see a net growth of the tumors and metastases and vice versa. We review recent clinical results for microsatellite stable metastatic colorectal cancer (MSS-mCRC) suggesting immunotherapy combinations with personalized vaccines, checkpoint inhibitors, targeted therapies, multikinase inhibitors, chemotherapies, and radiation that simultaneously slow cancer cell growth rate and enhance T cell killing rate of cancer cells may in future synergize to control the disease.

Dietary Energy Modulation and Autophagy: Exploiting Metabolic Vulnerabilities to Starve Cancer.

Cancer cells experience unique and dynamic shifts in their metabolic function in order to survive, proliferate, and evade growth inhibition in the resource-scarce tumor microenvironment. Therefore, identification of pharmacological agents with potential to reprogram cancer cell metabolism may improve clinical outcomes in cancer therapy. Cancer cells also often exhibit an increased dependence on the process known as autophagy, both for baseline survival and as a response to stressors such as chemotherapy or a decline in nutrient availability. There is evidence to suggest that this increased dependence on autophagy in cancer cells may be exploitable clinically by combining autophagy modulators with existing chemotherapies. In light of the increased metabolic rate in cancer cells, interest is growing in approaches aimed at “starving” cancer through dietary and pharmacologic interventions that reduce availability of nutrients and pro-growth hormonal signals known to promote cancer progression. Several dietary approaches, including chronic calorie restriction and multiple forms of fasting, have been investigated for their potential anti-cancer benefits, yielding promising results in animal models. Induction of autophagy in response to dietary energy restriction may underlie some of the observed benefit. However, while interventions based on dietary energy restriction have demonstrated safety in clinical trials, uncertainty remains regarding translation to humans as well as feasibility of achieving compliance due to the potential discomfort and weight loss that accompanies dietary restriction. Further induction of autophagy through dietary or pharmacologic metabolic reprogramming interventions may enhance the efficacy of autophagy inhibition in the context of adjuvant or neo-adjuvant chemotherapy. Nonetheless, it remains unclear whether therapeutic agents aimed at autophagy induction, autophagy inhibition, or both are a viable therapeutic strategy for improving cancer outcomes. This review discusses the literature available for the therapeutic potential of these approaches.

CURCUMIN ACTIVITY AS A PHYTOTHERAPEUTIC AGENT IN THE PREVENTION AND TREATMENT OF SQUAMOUS CELL CANCER: A SCOPING REVIEW

Objective: To analyze the phytotherapeutic action of curcumin (CUR) in the prevention of and antineoplastic therapy for squamous cell cancer (SCC). Study Design: Two researchers (E.G.F.S. and Y.L.N.) performed electronic searches independently on Medline via PubMed, LILACS, and Web of Science using the search strategy (curcumin AND oral cancer). A total of 967 initial results were identified, and 21 articles were selected for the study. Results: CUR is a bioactive polyphenol component with chemopreventive, photodynamic, and therapeutic properties in the treatment of SCC. A study analyzed the performance of nanocurcumin as a chemoprotective agent, increasing the expression of pro-apoptotic proteins compared with the group treated with chemotherapeutic agents, demonstrating that the association of CUR with chemotherapeutic agents can improve apoptosis in malignant cells, thereby regulating the mortality rate of cancer cells. Analyzing the use of nanoformulations, a study revealed that the pharmaceutical association of CUR and silicon nanoparticles increased cell absorption by 5 times that compared to free CUR, thereby increasing its photodynamic activity and having a better effect on oral malignancies. Conclusion: Recent preclinical studies recommend the use of CUR related to adjuvants as the main unit in antitumor activity, however, additional research studies are needed to clarify its molecular mechanism.

Abstract 3553: Three-dimensional (3D) telomere signatures of sporadic pediatric papillary thyroid carcinoma (PTC)

Abstract The incidence of thyroid carcinoma has increased worldwide, including in pediatric patients. Papillary thyroid carcinoma (PTC) is the most common subtype. Previous studies have suggested that clinical presentation and outcome diverge between pediatric and adult PTC and that this difference is likely due to distinct genetic alterations. BRAF V600E point mutation is highly prevalent in adults, while genetic fusions (RET/PTC, AGK-BRAF, ETV6-NTRK3) are the most prevalent events in the pediatric population. As telomere loss or dysfunction results in aneuploidy and chromosomal rearrangements, which can promote carcinogenesis, we investigated the three-dimensional (3D) structure of the telomeres in the nuclei from 21 pediatric patients (≤18 y.o), representing 16 PTC cases (with paired normal and tumor tissues for five of them) and five normal thyroid tissues from patients undergoing thyroidectomy for reasons other than cancer. We performed quantitative fluorescence in situ hybridization (FISH), 3D imaging, and 3D telomere analysis using TeloView® software to examine telomere dysfunction. The parameters examined included total number of signals (numbers of telomeres), total number of telomere aggregates, a/c ratio (indicating the phase of the cell cycle), total intensity (telomere length) and nuclear volume. Thyroid cancer cells showed lower average intensity of signals (p<0.0001) and lower intensity signals (p<0.0001), as well as higher nuclear volume (p<0.0001), compared to normal thyroid cells. In addition, tumour cells showed a higher a/c ratio (p<0.0001), indicating that they are more actively dividing than normal cells, which correlates with the high proliferation rate of cancer cells. We did not observe any alterations related to the total number of telomere signals and total number of aggregates, which suggests no significant aneuploidies occurring with these samples. The 3D nuclear telomere signature was able to detect differences in telomere architecture in tumours, compared to normal. Further analysis is necessary to define whether nuclear telomere architecture and specific genetic alterations observed in pediatric thyroid cancer are associated. Citation Format: Luiza Sisdelli, Maria Isabel Cordioli, Fernanda Vaisman, Osmar Monte, Carlos Longui, Adriano N. Cury, Monique O. Freitas, Aline Rangel-Pozzo, Sabine Mai, Janete Cerutti. Three-dimensional (3D) telomere signatures of sporadic pediatric papillary thyroid carcinoma (PTC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3553.

PD-L1-targeted microbubbles loaded with docetaxel produce a synergistic effect for the treatment of lung cancer under ultrasound irradiation.

Immunotherapy is gradually becoming as important as traditional therapy in the treatment of cancer, but adverse drug reactions limit patient benefits from PD1/PD-L1 checkpoint inhibitor drugs in the treatment of non-small cell lung cancer (NSCLC). As a chemotherapeutic drug for NSCLC, docetaxel (DTX) can synergize with PD1/PD-L1 checkpoint inhibitors but increase haematoxicity and neurotoxicity. Herein, anti-PD-L1 monoclonal antibody (mAb)-conjugated and docetaxel-loaded multifunctional lipid-shelled microbubbles (PDMs), which were designed with biologically safe phospholipids to produce synergistic antitumour effects, reduced the incidence of side effects and promoted therapeutic effects under ultrasound (US) irradiation. The PDMs were prepared by the acoustic-vibration method and then conjugated with an anti-PD-L1 mAb. The material features of the microbubbles and their cytotoxic effects, cellular apoptosis and cell cycle inhibition were studied. A subcutaneous tumour model was established to test the drug concentration-dependent and antitumour effects of the PDMs combined with US irradiation, and an orthotopic lung tumour model simultaneously confirmed the antitumour effect of this synergistic treatment. The PDMs achieved higher cellular uptake than free DTX, especially when combined with US irradiation. The PDMs combined with US irradiation also induced an increased rate of cellular apoptosis and an elevated G2-M arrest rate in cancer cells, which was positively correlated with PD-L1 expression. An in vivo study showed that synergistic treatment had relatively strong effects on tumour growth inhibition, increased survival time and decreased adverse effect rates. Our study possibly provides a well-controlled design for immunotherapy and chemotherapy and has promising potential for clinical application in NSCLC treatment.

Mathematical model of immunotherapy response to antibodies as a treatment for cancer

Immunotherapy is a significant cancer treatment as it uses the body’s natural immune system to fight cancer. To help boost the immune system, monoclonal antibodies (MABs) are used as they bind to cancer cells helping the immune system recognize these cells. In this paper, we present a mathematical model of nonlinear partial differential equations describing the interaction between the immune cells, MABs, and cancer cells. After nondimensionalizing the model, we analyzed the long-term behavior and found later that it is consistent with the numerical results. Then, we calculated the numerical solutions of the model with different values of the parameters (relative growth rate of cancer cells and the number of immune cells that are removed after killing a cancer cell) to determine the values that help increase the effectiveness of the treatment. We have considered the continuous delivery of antibodies over a certain period of time. These simulations showed that immune cells will eradicate cancer if the number of immune cells that are removed after killing a cancer cell is less than one. However, if each immune cell kills only one cancer cell, then the treatment reduces the cancer to a steady state or almost a steady state. On the other hand, if the relative growth rate of cancer cells is very small and each cancer cell needs more than one immune cell to kill it, then again, we get a steady state for cancer. However, if the relative growth rate is not small, then the cancer will grow after an initial decrease. This study could be implemented into a clinical trial with different delivery protocols of the drug to improve cancer treatment.

Thermodynamic Modeling of the Competition Between Cancer and Normal Cells

AbstractOne of the recognized differences between normal and cancer cells is in their metabolic profile. Tumor cells tend to produce energy through glycolysis rather than the much more efficient oxidative phosphorylation pathway, which healthy cells generally prefer. This phenomenon is identified as the Warburg effect. Although several functional explanations have been proposed for the Warburg effect, the competitive advantage of it is still subject of debate. Here we present a thermodynamic model to simulate the competition of cancer and normal cells in terms of bioenergetics. Our model shows that the Warburg effect has an advantage because the entropy production rate is increased and metabolic efficiency is decreased for cancer cells. Although inefficiency is generally considered a competitive disadvantage for living organisms, the thermodynamic model shows that it is not always the case. Indeed, when the energy resources are abundant and the system has a limited ability to export entropy, the organism with a higher rate of entropy production will have a higher chance of survival despite its lower metabolic efficiency. This thermodynamic model predicts that as long as there are enough nutrients in circulating blood, there are two thermodynamic strategies to control cancer cell populations, i. e., (i) decreasing the entropy production rate of cancer cells and (ii) increasing normal cells’ entropy production rate.

LncRNA SRA1 is down-regulated in HPV-negative cervical squamous cell carcinoma and regulates cancer cell behaviors.

LncRNA SRA1 plays important roles in several types of human diseases. The present study aimed to explore the role of SRA1 in cervical squamous cell carcinoma (CSCC). In the present study, we showed that plasma SRA1 was down-regulated in human papillomavirus (HPV)-negative CSCC patients but not in HPV-positive CSCC patients compared with healthy females. Down-regulated SRA1 distinguished HPV-negative CSCC patients from HPV-positive CSCC patients and healthy females. In HPV-negative CSCC patients, miR-9 was up-regulated and inversely correlated with SRA1. In HPV-negative CSCC cells, SRA1 overexpression caused the down-regulated miR-9, while miR-9 overexpression failed to affect SRA1. Moreover, SRA1 overexpression caused decreased, while miR-9 overexpression caused increased proliferation, migration and invasion rates of cancer cells. In addition, miR-9 overexpression attenuated the effects of SRA1 overexpression. Therefore, SRA1 is down-regulated in HPV-negative CSCC and regulates cancer cell behaviors possibly by down-regulating miR-9.

Restraining the Proliferation of Acute Lymphoblastic Leukemia Cells by Genistein through Up-regulation of B-cell Translocation Gene-3 at Transcription Level

Background: Acute lymphoblastic leukemia (ALL) is a highly prevalent pediatric cancer accounting for approximately 78% of leukemia cases in patients younger than 15 years old. Different studies have demonstrated that B-cell translocation gene 3 (BTG3) plays a suppressive role in the progress of different cancers. Genistein is considered a natural and biocompatible compound and a new anti-cancer agent. In this study, we evaluate the effect of genistein on BTG3 expression and proliferation of ALL cancer cells. Materials and Methods: ALL cell lines (MOLT4, MOLT17, and JURKAT) were cultured in standard conditions. Cytotoxicity of genistein was detected using MTT assay. The cells were treated with different concentrations of genistein (10, 25, 40, and 55μM) for 24, 48, and 72 hours, and then cell viability and growth rate were measured. The quantitative real-time polymerase chain reaction was applied to investigate the effect of genistein on BTG3 expression. Results: The percentage of vital cells treated with genistein significantly decreased compared to the non-treated cells, showed an inverse relationship with an increasing genistein concentration. The present study suggests a dose of 40μM for genistein as a potent anticancer effect. Genistein could elevate BTG3 for 1.7 folds in MOLT4 and JURKAT and 2.7 folds in MOLT17 cell lines at transcription level conveged with 60 to 90% reduction in the proliferation rate of cancer cells. Conclusion: Up-regulation of BTG3 as a tumor suppressor gene can be induced by genistein. It seems that BTG3 reactivation can be introduced as another mechanism of anti-proliferative effect of genistein and could be considered as a retardant agent candidate against hematopoietic malignancy.[GMJ. 2019;inpress:e1229]

The strong propensity of Cadherin-23 for aggregation inhibits cell migration.

Cadherin‐23 (Cdh23), a long‐chain non‐classical cadherin, exhibits strong homophilic and heterophilic binding. The physiological relevance of strong heterophilic binding with protocadherin‐15 at neuroepithelial tip links is well‐studied. However, the role of Cdh23 homodimers in physiology is less understood, despite its widespread expression at the cell boundaries of various human and mouse tissues, including kidney, muscle, testes, and heart. Here, we performed immunofluorescence studies that revealed that Cdh23 is present as distinct puncta at the cell–cell boundaries of cancer cells. Analysis of patient data and quantitative estimation of Cdh23 in human tissues (normal and tumor) also indicated that Cdh23 is down‐regulated via promoter methylation in lung adenocarcinoma (AD) and esophageal squamous cell carcinoma (SCC) cells; we also observed a clear inverse correlation between Cdh23 expression and cancer metastasis. Using HEK293T cells and four types of cancer cells differentially expressing Cdh23, we observed that cell migration was faster in cells with reduced levels of Cdh23 expression. The cell migration rate in cancer cells is further accelerated by the presence of excretory isoforms of Cdh23, which loosen its cell‐adhesion ability by competitive binding. Overall, our data indicate the role of Cdh23 as a suppressor of cell migration.

Synthesis and biological evaluation of anthraquinone derivatives as allosteric phosphoglycerate mutase 1 inhibitors for cancer treatment

Phosphoglycerate mutase 1 (PGAM1) coordinates glycolysis, pentose phosphate pathway, and serine synthesis to promote tumor growth through the regulation of its substrate 3-phosphoglycerate (3 PG) and product 2-phosphoglycerate (2 PG). Herein, based on our previously reported PGAM1 inhibitor PGMI-004A, we have developed anthraquinone derivatives as novel allosteric PGAM1 inhibitors and the structure−activity relationship (SAR) was investigated. In addition, we determined the co-crystal structure of PGAM1 and the inhibitor 8g, demonstrating that the inhibitor was located at a novel allosteric site. Among the derivatives, compound 8t was selected for further study, with IC50 values of 0.25 and approximately 5 μM in enzymatic and cell-based assays, respectively. Mechanistically, compound 8t reduced the glycolysis and oxygen consumption rate in cancer cells, which led to decreased adenosine 5′-triphosphate (ATP) production and subsequent 5′ adenosine monophosphate-activated protein kinase (AMPK) activation. The inhibitor 8t also exhibited good efficacy in delaying tumor growth in H1299 xenograft model without obvious toxicity. Taken together, this proof-of-principle work further validates PGAM1 as a potential target for cancer therapy and provides useful information on anti-tumor drug discovery targeting PGAM1.

LncRNA MIR503HG functioned as a tumor suppressor and inhibited cell proliferation, metastasis and epithelial-mesenchymal transition in bladder cancer.

Bladder cancer is the most common malignancy with high recurrence. Currently, the long noncoding RNAs (lncRNAs) have been suggested to play vital roles in the pathogenesis of bladder cancer. The present study investigated the role of lncRNA MIR503 host gene (MIR503HG) in the pathogenesis of bladder cancer by using both in vitro and in vivo functional assays. The expression of MIR503HG was downregulated in bladder cancer tissues and cell lines. Low expression of MIR503HG was associated with advanced tumor stage, advanced histological grade, and lymph node metastasis. Ectopic expression of MIR503HG inhibited cell proliferation, cell growth, cell invasion, and migration, and also promoted cell apoptosis and inhibited cell cycle progression in SW780 cells. In parallel, T24 cells were used for loss-of-function studies. Knockdown of MIR503HG promoted the cancer cell proliferation and increased the migration and invasion abilities of T24 cells. In addition, knockdown of MIR503HG reduced the cell apoptotic rate in cancer cells and promoted cell cycle progression. Furthermore, MIR503HG overexpression decreased the epithelial-mesenchymal transition-related mRNA and protein levels of ZEB1, Snail, N-cadherin, and vimentin, with an increase in E-cadherin level. Consistently, knockdown of MIR503HG showed the opposite effects. In vivo xenograft, nude mice results showed that overexpression of MIR503HG suppressed the tumor growth and tumor metastasis. In conclusion, our results identified a novel lncRNA MIR503HG that exhibited significant antiproliferation, antimigration/invasion effects on bladder cancer cells both in vitro and in vivo, which may hold a therapeutic promise to treat bladder cancer.

Anticancer, Antibacterial, and Phytochemicals Derived From Extract of Aerva javanica (Burm.f.) Juss. ex Schult. Grown Naturally in Saudi Arabia

Aerva javanica (Burm.f.) Juss. ex Schult. (Amaranthaceae family) has many pharmaceutical properties. This study aimed to determine the anticancerous effect of A. javanica methanol extract (AJME) on breast cancer cell lines and prostate cancer cell lines. The antibacterial potency of A. javanica solvent extracts was tested against Micrococcus luteus, Staphylococcus aureus, Pseudomonas aeruginosa, and Shigella flexneri. A screening of five concentrations of A. javanica was done on prostate and breast cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The results showed that AJME had various levels of cytotoxicity toward both cancer cell lines. A significant decrease in the rate of cancer cells was associated with a higher concentration of the plant extract. The half maximal inhibitory concentration IC50 value was 4.50 μg/ml for the breast cancer cells and 14.51 μg/ml for the prostate cancer cells. The dried and fresh solvent extracts made with methanol and chloroform demonstrated maximum potency against all the tested pathogenic microbes. The petroleum ether and acetone extracts showed moderate activity, while the diethyl ether and hot water extracts had the lowest antibacterial activity. The gas chromatography-mass spectroscopy analysis showed that AJME had various chemical compounds that have many biological benefits. In conclusion, A. javanica is a promising candidate as a natural herb to treat cancers, more so in breast cancer than in prostate cancer, and it has potential as an antimicrobial agent against multidrug-resistant microbes.