Potential Anticancer Treatment Research Articles

Fundamentals of utilizing microbes in advanced cancer therapeutics: current understanding and potential applications.

One of the biggest health related issues in the twenty-first century is cancer. The current therapeutic platforms have not advanced enough to keep up with the number of rising cases. The traditional therapeutic approaches frequently fail to produce the desired outcomes. Therefore, developing new and more potent remedies is crucial. Recently, investigating microorganisms as potential anti-cancer treatments have garnered a lot of attention. Tumor-targeting microorganisms are more versatile at inhibiting cancer than the majority of standard therapies. Bacteria preferentially gather and thrive inside tumors, where they can trigger anti-cancerimmune responses. They can be further trained to generate and distribute anticancer drugs based on clinical requirements using straightforward genetic engineering approaches. To improve clinical outcomes, therapeutic strategies utilizing live tumor-targeting bacteria can be used either alone or in combination with existing anticancer treatments. On the other hand, oncolytic viruses that target cancer cells, gene therapy via viral vectors, and viral immunotherapy are other popular areas of biotechnological investigation. Therefore, virusesserve as a unique candidate for anti-tumor therapy.This chapter describes the role of microbes, primarily bacteria and viruses in anti-cancer therapeutics. The various approaches to utilizing microbes in cancer therapy are discussed and examples of microorganisms that are now in use or that are undergoing experimental research are briefly discussed. We further point out the hurdles and the prospects of microbes-based remedies for cancer treatment.

Exploring the Relationship between G-Quadruplex Nucleic Acids and Plants: From Plant G-Quadruplex Function to Phytochemical G4 Ligands with Pharmaceutic Potential.

G-quadruplex (G4) oligonucleotides are higher-order DNA and RNA secondary structures of enormous relevance due to their implication in several biological processes and pathological states in different organisms. Strategies aiming at modulating human G4 structures and their interrelated functions are first-line approaches in modern research aiming at finding new potential anticancer treatments or G4-based aptamers for various biomedical and biotechnological applications. Plants offer a cornucopia of phytocompounds that, in many cases, are effective in binding and modulating the thermal stability of G4s and, on the other hand, contain almost unexplored G4 motifs in their genome that could inspire new biotechnological strategies. Herein, we describe some G4 structures found in plants, summarizing the existing knowledge of their functions and biological role. Moreover, we review some of the most promising G4 ligands isolated from vegetal sources and report on the known relationships between such phytochemicals and G4-mediated biological processes that make them potential leads in the pharmaceutical sector.

Evaluation of MMR live attenuated vaccine oncolytic potential using Ehrlich ascites carcinoma in a murine model

MMR vaccine is a common vaccine that contains oncolytic viruses (Measles, Mumps, and Rubella) and could be used as a potential anti-cancer treatment. In this study, we assessed the anti-tumor activity of the MMR vaccine against Ehrlich ascites carcinoma (EAC) solid tumor induced in mice. The in vitro assay showed that vaccine IC50 in EAC was approximately 200 CCID50. The vaccine was intratumorally administrated twice weekly in EAC-bearing mice. The antitumor response of the vaccine was measured by tumor growth, survival rate, histopathologic examination, flow cytometry analysis, and body biochemical parameters. The MMR vaccine demonstrated a substantial reduction of tumor growth and prolongation of life span as well. The proliferation marker was significantly lower in the vaccine-treated group. Moreover, the apoptosis key parameter Casp-3 was also higher in the vaccine-treated group. The vaccine somewhat restored the deterioration of the biochemical parameters (LDH, GOT, GPT, MDA, NO, and PON-1) in the tumor-bearing mice. Finally, this study indicated the potential antitumor effect of MMR vaccine via anti‑proliferative, apoptotic activities, and modulating the antioxidant parameters. This study opens a new field of inquiry for future research on the vaccine’s anti-cancer properties.

Myeloid-derived suppressor cells: an emerging target for anticancer immunotherapy.

The clinical responses observed following treatment with immune checkpoint inhibitors (ICIs) support immunotherapy as a potential anticancer treatment. However, a large proportion of patients cannot benefit from it due to resistance or relapse, which is most likely attributable to the multiple immunosuppressive cells in the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs), a heterogeneous array of pathologically activated immature cells, are a chief component of immunosuppressive networks. These cells potently suppress T-cell activity and thus contribute to the immune escape of malignant tumors. New findings indicate that targeting MDSCs might be an alternative and promising target for immunotherapy, reshaping the immunosuppressive microenvironment and enhancing the efficacy of cancer immunotherapy. In this review, we focus primarily on the classification and inhibitory function of MDSCs and the crosstalk between MDSCs and other myeloid cells. We also briefly summarize the latest approaches to therapies targeting MDSCs.

A Combination of Two Probiotics, Lactobacillus sporogenes and Clostridium butyricum, Inhibits Colon Cancer Development: An In Vitro Study.

Cancer remains a leading cause of death worldwide and, even though several advances have been made in terms of specific treatment, the late-stage detection and the associated side effects of the conventional drugs sustain the search for better treatment alternatives. Probiotics are live microorganisms that have been proven to possess numerous health benefits for human hosts, including anticancer effects. In the present study, the in vitro effect of the association of two probiotic strains (PBT), Lactobacillus sporogenes and Clostridium butyricum, were tested against colon (HT-29 and HCT 116), lung (A549), and liver (HepG2) cancer cell lines, alone or in combination with 5-fluorouracil (5FU). Moreover, the underlying mechanism of PBT and PBT-5FU against the HT-29 cell line was evaluated using the Hoechst 33342 staining, revealing characteristic apoptotic modifications, such as chromatin condensation, nuclear fragmentation, and membrane blebbing. Furthermore, the increase in the expression of pro-apoptotic Bax, Bid, Bad, and Bak proteins and the inhibition of the anti-apoptotic Bcl-2 and Bcl-XL proteins were recorded. Collectively, these findings suggest that the two strains of probiotic bacteria, alone or in association with 5FU, induce apoptosis in colon cancer cells and may serve as a potential anticancer treatment.

Abstract 2651: The tankyrase inhibitor OM-153 demonstrates anti-tumor effect with a therapeutic index above 10

Abstract The catalytic enzymes tankyrase 1 and 2 (TNKS1/2) poly-ADP-ribosylate target proteins, including AXIN proteins, to earmark them for degradation by the ubiquitin-proteasomal system. Hence, inhibition of TNKS1/2 can stabilize AXIN proteins, and consequently β-catenin degradosomes, resulting in inhibition of WNT/β-catenin signaling. Although several potent small-molecules have been developed to inhibit TNKS1/2 and oncogenic WNT/β-catenin signaling, also showing convincing anti-tumor effects in numerous mouse cancer models, there are currently no TNKS1/2 inhibitors available in the clinic. The development has mainly been disadvantaged by concerns over previous reports unfolding intestinal toxicity, apparently caused by on-target and WNT/β-catenin signaling pathway-specific side effects, and a deficient therapeutic index. Here we show that the novel, highly potent and selective1,2,4-triazole-based TNKS1/2 inhibitor OM-153, displaying improved ADME-properties and mouse pharmacokinetics, reduced WNT/β-catenin signaling and tumor progression in COLO 320DM colon cancer xenografts upon peroral (PO) administration of 0.33-10 mg/kg twice daily (BID). In addition, combined OM-153 and anti-PD-1 treatment conferred a synergistic anti-tumor effect in a B16-F10 mouse melanoma model. In a 28-day repeated dose mouse toxicity study, body weight loss, intestinal damage and tubular damage in the kidney was documented after PO BID administration of 100 mg/kg. In contrast, in mice treated PO BID using 10 mg/kg, the intestinal architecture was intact and no atypical histopathological changes were observed in other organs, while clinical biochemistry and haematological analyses did not identify any changes indicating considerable toxicity. The results provide a scaffold for using OM-153 as a potential anti-cancer treatment and additional preclinical and clinical evaluations. Citation Format: Shoshy Alam Brinch, Enya Amundsen-Isaksen, Sandra Espada, Aleksandra Aizenshtadt, Lone Holmen, Clara Hammarström, Merete Høyem, Hanne Scholz, Gunnveig Grødeland, Sven T. Sowa, Albert Galera-Prat, Lari Lehtiö, Ilonka A.T.M. Meerts, Ruben G. G. Leenders, Anita Wegert, Stefan Krauss, Jo Waaler. The tankyrase inhibitor OM-153 demonstrates anti-tumor effect with a therapeutic index above 10 [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 2651.

Dopamine-Loaded Polymer-Drug Conjugates for Potential Synergistic Anti-Cancer Treatment

ABSTRACT The combination of dopamine with anticancer drugs can result in enhanced anticancer activity. Polymer-drug conjugates (PDCs) containing anticancer drugs, such as platinum-based drugs, and doxorubicin together with dopamine were prepared. PDCs were characterized followed by in vitro cytotoxicity studies using pheochromocytoma (PC12) cell lines. The particle size analysis revealed the particles sizes of the PDCs in the range of 15.68–179.8 nm with PDI in the range of 0.373–0.687. T3 and T6 displayed promising cytotoxic effects with IC50 values of 5.25 and 11.56 μg/mL when compared to the free drugs (29.65 μg/mL for K2PtCl4 and 14.96 μg/mL for procaine). The findings revealed that combining dopamine with anticancer drugs is a promising approach to develop effective therapeutics for the treatment of cancer.

Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology.

Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat). Despite this, no single study exists that characterizes them all under the same experimental conditions, preventing a clear interpretation of published results. Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein-protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds have very low activity and selectivity, suggesting some conclusions derived from their use should be taken with caution.

Discrete ARMA Model Applied for Tumor Growth Inhibition Modeling and LQR-based Chemotherapy Optimization

Mathematical models for tumor growth inhibition (TGI) are an important tool in the battle against cancer allowing preclinical evaluation of potential anti-cancer drugs and treatment schedules. In this article, an autoregressive moving average (ARMA) model for cancer tumor growth is estimated based on laboratory data of TGI in mice and presented. The model was proven capable of describing with accuracy the tumor growth under single-agent chemotherapy. At the same time, an optimal control problem was formulated to identify optimal drug dosages. The linear quadratic regulator (LQR) controller was used with success in optimizing both periodic and intermittent chemotherapy treatment schedules reducing the tumor mass while keeping dosages under acceptable toxicity

Abstract 2032: Vitamin B12 augments Ca2+ dependent cytotoxicity of diethyldithiocarbamate through excessive ER-vacuolization, oxidative stress and mitochondrial depolarization in MCF-7 cells in culture

Abstract Coordinated organization of intracellular organelles into functional networks is vital for cells. Mitochondrial and endoplasmic reticulum (ER) interaction in regulation of cell Ca2+ homeostasis is crucial for cell death and survival. Function of these intracellular organelles involved in two-way regulation of the status of major cell metabolites including protein, lipid exchange and intracellular Ca2+ homeostasis. Disulfiram and its derivatives recently attracted attention as a potential anticancer treatment (Kona et al., 2011). Combined use of hydroxycobalamin (vitamin B12b) and diethyldithiocarbamate (DDTC) demonstrated synergistic effect (combination index=0.25) and enhanced the cytotoxic effect of DDTC in number of transformed cell lines in culture (Solovieva et al., 2020). In the present work using MCF-7, human breast cancer cells in culture we demonstrate that combined action of DDTC and B12b resulted in induction of UPRER manifested by dilation of ER cisterns, increased level of polyubiquitinated proteins, and increased expression of CHOP. Confocal microscopy revealed disorganization of mitochondrial network and ER and treatment of these cells with B12b/DDTC and accompanied by mitochondrial depolarization (~50% after 6 h of exposure to drugs). Treatments also induced changes in morphology of mitochondrial network, and within 6 h of exposure, mitochondria demonstrated large amplitude swelling, characteristic feature of mitochondrial permeability transition pore opening. Drug exposure induced mitochondrial oxidative stress and increase in superoxide anion level (monitored with MitoSOX) and increased content of mitochondrial Ca2+ (xRhod-1) which almost doubled following treatment with B12b/DDTC. Short-time exposure of MCF-7 cells to mixture of drugs in Ca2+-free incubation media (2.5 mM EGTA) resulted in generation of significantly smaller size of vacuoles as compared with control. Similarly, pre-loading of cells with intracellular Ca2+ chelator (BAPTA, 5 µM, 30 min, 37oC) or inhibition of IP3 receptor(s) with 2-APB, delayed the drug-induced vacuolization. Taken together, our data indicate that the mechanism of B12b/DDTC-induced cytotoxicity in human MCF-7 cancer cell lines involves mitochondrial oxidative stress, activation of MPT pore and Ca2+ overload. Support of Funding Information: Russian Science Foundation № 19-75-20145 Citation Format: Marina E. Solovieva. Vitamin B12 augments Ca2+ dependent cytotoxicity of diethyldithiocarbamate through excessive ER-vacuolization, oxidative stress and mitochondrial depolarization in MCF-7 cells in culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2032.

Abstract 2412: Decursin inhibits tumor progression in head and neck squamous cell cancer by down regulating CXCR7 expression

Abstract Background: CX chemokine receptor 7 (CXCR7) is frequently overexpressed in a variety of tumors and plays a significant role in tumor growth and metastasis. Thus, inhibition of CXCR7 is an important potential anticancer treatment strategy. Decursin, a derivative from Angelica gigas Nakai has been reported to have anti-tumor activity in various cancers. However, little is known about its anti-tumor activity and underlying mechanisms of action in head and neck squamous cell cancer (HNSCC). Methods: CXCR7-overexpressing HNSCC cell lines were established in vitro. The effects of decursin on cell growth, motility, migration, and invasion were investigated using CCK-8, wound healing, and transwell assays. In addition, the mechanism by which decusin shows antitumor activity was investigated. Results: Overexpression of CXCR7 significantly increased cell proliferation, migration, invasion, and cell motility compared with control cells. Treatment with decursin decreased membrane expression of CXCR7 in a concentration dependent manner and significantly inhibited tumor progression by suppressing cell growth, migration, invasion, and motility. Decursin was found to induce G0/G1 cell cycle arrest and regulate cell cycle-related proteins such as Cyclin A and CDK2 in HNSCC cells. In addition, decursin inhibited CXCR7-induced STAT3/c-MYC activation. Conclusion: These results demonstrate that CXCR7 promotes cancer progression through the STAT3/c-Myc pathway in HNSCC and that decursin is a natural product that may target CXCR7 for HNSCC treatment. Citation Format: Mina Joo, Solbi Kim, Nayoung Kim, Myung-Won Lee, Heung Jin Jeon, Hyewon Ryu, Ik-Chan Song, Jin-Man Kim, Hyo Jin Lee. Decursin inhibits tumor progression in head and neck squamous cell cancer by down regulating CXCR7 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2412.

Ephedra alata fruit extracts: phytochemical screening, anti-proliferative activity and inhibition of DPPH, \u03b1-amylase, \u03b1-glucosidase, and lipase enzymes

BackgroundDiscovering and screening for potential anti-obesity, anti-diabetic, anticancer, and antioxidant treatments from natural products still in recent times the main goal for many pharmaceutical scientists. The present investigation aimed to evaluate the chemical constituents of Ephedra alata fruits various extracts and to assess their antioxidant, antiobesity, antidiabetic, and cytotoxic effects.ResultIn this work, high content of flavonoids and phenols were observed in the methanol fraction of E. alata fruits, which reached 98.95 mg of RUE/g and 33.22 mg of GAE/g, respectively. The methanol fraction has significant inhibitory activity against DPPH, α-amylase, α-glucosidase, and lipase with an IC50 value of 1.07, 9.43, 46.16, and 66.48 µg/mL. respectively. Also has anticancer activity against HeLa cancer cell line. While the acetone fraction has potent antioxidant activity with IC50 5 µg/mL.ConclusionThe DPPH and digestive enzymes assays results showed that the methanolic fraction of E. alata fruits has potent antioxidant, anti-diabetic, and anti-obesity activities, which can be an excellent candidate for biological and chemical analysis and can be further subjected for isolation of the therapeutically active compounds with anticancer potency.

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Sialylation is an integral part of cellular function, governing many biological processes including cellular recognition, adhesion, molecular trafficking, signal transduction and endocytosis. Sialylation is controlled by the levels and the activities of sialyltransferases on glycoproteins and lipids. Altered gene expression of these enzymes in cancer yields to cancer-specific alterations of glycoprotein sialylation. Mounting evidence indicate that hypersialylation is closely associated with cancer progression and metastatic spread, and can be of prognostic significance in human cancer. Aberrant sialylation is not only a result of cancer, but also a driver of malignant phenotype, directly impacting key processes such as tumor cell dissociation and invasion, cell-cell and cell-matrix interactions, angiogenesis, resistance to apoptosis, and evasion of immune destruction. In this review we provide insights on the impact of sialylation in tumor progression, and outline the possible application of sialyltransferases as cancer biomarkers. We also summarize the most promising findings on the development of sialyltransferase inhibitors as potential anti-cancer treatments.

Novel Single Inhibitor of HDAC6/8 and Dual Inhibitor of PI3K/HDAC6 as Potential Alternative Treatments for Prostate Cancer.

Background: Prostate cancer is the second most frequently diagnosed malignancy worldwide. Here, the cytotoxic and antimetastatic effects of a new HDAC6/8 inhibitor, LASSBio-1911, and a new dual-PI3K/HDAC6 inhibitor, LASSBio-2208, were evaluated against PC3 prostate cancer cell line. Methods: A MTT assay was used to assess the cell viability. Annexin V/propidium iodide (PI) was used to detect apoptotic cell death and to analyze the cell cycle distribution. Interleukin 6 (IL-6) levels were measured by ELISA. A cell scratch assay was performed to assess cell migration, and the expression of proteins was estimated by Western blotting. Results: LASSBio-1911 and LASSBio-2208 exert cytotoxic effects against PC3 cells. However, LASSBio-2208 was demonstrated to be more potent than LASSBio-1911. The apoptosis assays showed that both compounds trigger apoptotic processes and cause the arrest of cells in the G2/M phase of the cell cycle. The Western blot analysis revealed that LASSBio-2208 significantly decreased the expression of p-JNK and JAK2. However, both compounds reduced the expression of p-STAT3, IL-6 secretion, and cell migration. Conclusions: LASSBio-1911 and LASSBio-2208 demonstrated significant activity in reducing cell viability and migration. These compounds can be further used as prototypes for the development of new potential anticancer alternative treatments.

The electrical pulse application enhances intra-cellular localization and potentiates cytotoxicity of curcumin in breast cancer cells

Breast cancer is the most common cancer of women, and fifth leading cause of mortality worldwide. Existing breast cancer regimens are costly and produce severe side effects. This highlights a need for the development of efficient novel therapies, which are cost effective and limit side effects. An electrical pulse (EP)-based chemo therapy, known as electrochemotherapy (ECT) using the natural compound curcumin could be an effective alternative. ECT is a non-surgical modality, which produces excellent anti-tumor efficacy at small drug concentrations due to increased uptake of drugs. In clinics, ECT is shown to be effective in treating advanced, recurrent, and metastatic breast cancers, which are refractory to multiple modalities. ECT with curcumin triggers apoptotic cell death in breast cancer cells and could be an effective alternative, due to curcumin’s low cost and reduced side-effects. However, there is a lack of studies quantifying the uptake of curcumin in response to EP application. Towards this, we determined the uptake of different curcuminoids (curcumin, desmethoxycurcumin, and bisdemethoxycurcumin) upon EP application and their impact on cell cytotoxicity. Additionally, we studied the combined effect of calcium chloride (CaCl2) and a curcuminoids (Cur) mixture, based on initial studies suggesting calcium electroporation as a potential inexpensive anti-cancer treatment. Our results indicate EP with Cur increases cellular uptake, cell shrinkage, and cytotoxicity. The EP + Cur resulted in the highest uptake of the bisdemethoxycurcumin. Further, EP also potentiated the cytotoxicity of CaCl2 and of the Cur and CaCl2 combination against breast cancer cells and caused apoptosis. Our preliminary data pave the way to further studies on Cur and CaCl2 combination treating breast cancer.

Immuno-Oncolytic Viruses: Emerging Options in the Treatment of Colorectal Cancer.

Colorectal cancer is the third most common neoplasm in the world and the third leading cause of cancer-related deaths in the USA. A safer and more effective therapeutic intervention against this malignant carcinoma is called for given the limitations and toxicities associated with the currently available treatment modalities. Immuno-oncolytic or oncolytic virotherapy, the use of viruses to selectively or preferentially kill cancer cells, has emerged as a potential anticancer treatment modality. Oncolytic viruses act as double-edged swords against the tumors through the direct cytolysis of cancer cells and the induction of antitumor immunity. A number of such viruses have been tested against colorectal cancer, in both preclinical and clinical settings, and many have produced promising results. Oncolytic virotherapy has also shown synergistic antitumor efficacy in combination with conventional treatment regimens. In this review, we describe the status of this therapeutic approach against colorectal cancer at both preclinical and clinical levels. Successes with and the challenges of using oncolytic viruses, both as monotherapy and in combination therapy, are also highlighted.

Effect of extremely low frequency electromagnetic field parameters on the proliferation of human breast cancer

ABSTRACT Extremely low-frequency electromagnetic field (ELF-EMF) exposures influence many biological systems. These effects are mainly related to the intensity, duration, frequency, and pattern of the ELF-EMF. Our intent was to characterize the effect of specific pulsed electromagnetic fields on the in vitro proliferation of MCF-7 adenocarcinoma and MDA-MB-231 breast cancer cell lines and one non-cancerous M10 breast epithelial cell line. The following four important parameters of ELF-EMF were examined: frequencies (7.83 ± 0.3, 23.49 ± 0.3, and 39.15 ± 0.3 Hz), flux density (0.5 and 1 mT), exposure duration (12, 24, and 48 h), and the exposure methodology (continuous exposure versus switching exposure). The viability of MDA-MB-231 cells exposed to the optimized ELF-EMF pattern (7.83 ± 0.3 Hz, 1 mT, and 6 h switching exposure) was 40.1%. By contrast, the optimized ELF-EMF parameters that were most cytotoxic to breast cancer MDA-MB-231 cells were not damaging to normal M10 cells. In vitro studies also showed that exposure of MDA-MB-231 cells to the optimized ELF-EMF pattern promoted Ca2+ influx and resulted in apoptosis. These data confirm that exposure to this specific ELF-EMF pattern can influence cellular processes and inhibit cancer cell growth. The specific ELF-EMF pattern determined in this study may provide a potential anti-cancer treatment in the future.

DIPG-83. USING COPPER CHELATING AGENTS TO TARGET RECEPTOR TYROSINE KINASE SIGNALLING IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

DIPG is a universally fatal pediatric brain cancer. Receptor tyrosine kinase (RTK) pathway alterations are among the defining characteristics in many patients. Copper is a transition metal essential for cellular signaling, known to impact PI3K/AKT and MAPK/ERK pathways. Copper chelating agents are clinically approved for use in children with Wilson’s Disease, documented to reduce brain copper levels and are cited as potential cancer therapeutics. Due to copper’s wide cellular integration, we propose that targeting copper in DIPG through use of copper chelators is a viable therapeutic strategy and are strong candidates for combination therapy. Cytotoxicity assays performed in a panel of DIPG cell lines using copper chelator tetraethylenepentamine (TEPA) demonstrated a millimolar range of efficacy. To identify copper integrated pathways, western blots were performed on DIPG cell lines dosed with sub-lethal copper concentrations, which increased phosphorylated expression of AKT, ERK1/2, ERK5 and STAT3. Conversely, western blots performed after TEPA treatment demonstrated reduced phosphorylated expression of all these proteins compared to controls. Western blots investigating TEPA in combination with Everolimus and Trametinib demonstrated synergistic targeting of these proteins. Our results indicate that adding copper in the culture media initiated two RTK-mediated downstream signal transductions, including AKT and ERK and additionally STAT signaling. The use of copper chelator TEPA affected copper homeostasis and reduced DIPG cell proliferation. Our study proposes copper plays an important role in RTK-mediated signaling promoting DIPG proliferation. This implies that reducing copper with clinically available chelation agents can represent a potential anti-cancer treatment for DIPG.

Fatty Acid Profile and In Vitro Anticancer Activity of Two Marine Sponge- Associated Bacteria

Background: Colorectal cancer represents one of the prominent causes of mortality worldwide in men and women. The objective of this study was to search for new potential anticancer compounds, both in prevention and treatment of colorectal cancer. The anticancer potential of marine bacterial extracts against Human colorectal carcinoma cell line (HCT116) was evaluated as well as the partial identification of bioactive metabolites. Methods: All bacterial extracts were tested for their cytotoxicity against HCT116 cell line by means of MTT assay. The highly cytotoxic dichloromethane extracts of marine sponge-associated bacteria Vibrio sp. and Bacillus sp. were analyzed by GC-MS. Results: Two fractions, Vib3 and Bac3, exhibited a very interesting cytotoxicity against human colorectal carcinoma (HCT116) cell line, with a percentage of cytotoxicity of 96.04 % and 29.48 %, respectively. Discussion: The GC-MS analysis revealed the presence of two major fatty acids, palmitic and oleic acids, in Vib3 fraction and fatty acid esters and phenolic compounds in Bac3 fraction. Conclusion: Based on previous literature, it may be hypothesized that the anticancer activity of bacterial extracts could be, at least partially, to the fatty acids fraction.

Effect of berberine associated with photodynamic therapy in cell lines.

Cervical cancer is a serious worldwide health problem. In view of the potentially harmful effects of current conventional therapies, photodynamic therapy may be an option as it is a minimally invasive therapy and can promote selective cytotoxic activity for neoplastic cells in the target tissue., Berberine (BBR) as an isolated molecule is a natural compound that has antineoplastic properties and potential action as a photosensitizer agent. The purpose of this study was to evaluate the use of berberine as a photosensitizer in photodynamic therapy (PDT) protocols and observe the effects produced by this association in cervical carcinoma cells and in immortalized keratinocytes. Incubation with 2.5 μM berberine promoted less than 10 % of cellular death in both cell lines studied. In addition, by fluorescence microscopy, we demonstrated that berberine was internalized by the cells, and after a period of 48 h, it was still present in the intracellular environment preferentially localized in the cytoplasm. After photodynamic therapy using berberine as a photosensitizer and visible light activation at 447 (±10) nm, we observed a phototoxic effect, which resulted in 19.84 % cell viability for Caski cells and 47.22 % cell viability for HaCaT. Treatment with berberine associated with photodynamic therapy promoted an increase in the production of reactive species of oxygen (ROS) and caspase-3 activity, indicating a preferential cell death mechanism by caspase-dependent apoptosis. Therefore, we demonstrated that berberine is an efficient photosensitizer and that its association with photodynamic therapy may be a potential anticancer treatment strategy for cervical cancer.