scholarly journals Selective Targeting of Cancerous Mitochondria and Suppression of Tumor Growth Using Redox-Active Treatment Adjuvant

2020 ◽  
Vol 2020 ◽  
pp. 1-30
Author(s):  
Rumiana Bakalova ◽  
Severina Semkova ◽  
Donika Ivanova ◽  
Zhivko Zhelev ◽  
Thomas Miller ◽  
...  
Keyword(s):  
Immune System ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Mitochondrial Membrane ◽  
Combination Drug ◽  
Normal Cells ◽  
Mitochondrial Superoxide ◽  
Anticancer Effects ◽  
Redox Active

Redox-active substances and their combinations, such as of quinone/ascorbate and in particular menadione/ascorbate (M/A; also named Apatone®), attract attention with their unusual ability to kill cancer cells without affecting the viability of normal cells as well as with the synergistic anticancer effect of both molecules. So far, the primary mechanism of M/A-mediated anticancer effects has not been linked to the mitochondria. The aim of our study was to clarify whether this “combination drug” affects mitochondrial functionality specifically in cancer cells. Studies were conducted on cancer cells (Jurkat, Colon26, and MCF7) and normal cells (normal lymphocytes, FHC, and MCF10A), treated with different concentrations of menadione, ascorbate, and/or their combination (2/200, 3/300, 5/500, 10/1000, and 20/2000 μM/μM of M/A). M/A exhibited highly specific and synergistic suppression on cancer cell growth but without adversely affecting the viability of normal cells at pharmacologically attainable concentrations. In M/A-treated cancer cells, the cytostatic/cytotoxic effect is accompanied by (i) extremely high production of mitochondrial superoxide (up to 15-fold over the control level), (ii) a significant decrease of mitochondrial membrane potential, (iii) a decrease of the steady-state levels of ATP, succinate, NADH, and NAD+, and (iv) a decreased expression of programed cell death ligand 1 (PD-L1)—one of the major immune checkpoints. These effects were dose dependent. The inhibition of NQO1 by dicoumarol increased mitochondrial superoxide and sensitized cancer cells to M/A. In normal cells, M/A induced relatively low and dose-independent increase of mitochondrial superoxide and mild oxidative stress, which seems to be well tolerated. These data suggest that all anticancer effects of M/A result from a specific mechanism, tightly connected to the mitochondria of cancer cells. At low/tolerable doses of M/A (1/100-3/300 μM/μM) attainable in cancer by oral and parenteral administration, M/A sensitized cancer cells to conventional anticancer drugs, exhibiting synergistic or additive cytotoxicity accompanied by impressive induction of apoptosis. Combinations of M/A with 13 anticancer drugs were investigated (ABT-737, barasertib, bleomycin, BEZ-235, bortezomib, cisplatin, everolimus, lomustine, lonafarnib, MG-132, MLN-2238, palbociclib, and PI-103). Low/tolerable doses of M/A did not induce irreversible cytotoxicity in cancer cells but did cause irreversible metabolic changes, including: (i) a decrease of succinate and NADH, (ii) depolarization of the mitochondrial membrane, and (iii) overproduction of superoxide in the mitochondria of cancer cells only. In addition, M/A suppressed tumor growth in vivo after oral administration in mice with melanoma and the drug downregulated PD-L1 in melanoma cells. Experimental data suggest a great potential for beneficial anticancer effects of M/A through increasing the sensitivity of cancer cells to conventional anticancer therapy, as well as to the immune system, while sparing normal cells. We hypothesize that M/A-mediated anticancer effects are triggered by redox cycling of both substances, specifically within dysfunctional mitochondria. M/A may also have a beneficial effect on the immune system, making cancer cells “visible” and more vulnerable to the native immune response.

scholarly journals Metabolic Alterations in Cancer and Their Potential as Therapeutic Targets

2017 ◽  
pp. 825-832
Author(s):  
Jamie D. Weyandt ◽  
Craig B. Thompson ◽  
Amato J. Giaccia ◽  
W. Kimryn Rathmell
Keyword(s):  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Patient Outcomes ◽  
Metabolic Changes ◽  
Tumor Proliferation ◽  
Therapeutic Targeting ◽  
Normal Cells ◽  
Metabolic Alterations ◽  
Improve Patient

Otto Warburg’s discovery in the 1920s that tumor cells took up more glucose and produced more lactate than normal cells provided the first clues that cancer cells reprogrammed their metabolism. For many years, however, it was unclear as to whether these metabolic alterations were a consequence of tumor growth or an adaptation that provided a survival advantage to these cells. In more recent years, interest in the metabolic differences in cancer cells has surged, as tumor proliferation and survival have been shown to be dependent upon these metabolic changes. In this educational review, we discuss some of the mechanisms that tumor cells use for reprogramming their metabolism to provide the energy and nutrients that they need for quick or sustained proliferation and discuss the potential for therapeutic targeting of these pathways to improve patient outcomes.

scholarly journals The Effect of Plasma Activated Medium and PBS on Human Melanoma Cells Compared With Other Cancer and Normal Cells

2021 ◽  
Author(s):  
Dominika Sersenová ◽  
Zdenko Machala ◽  
Vanda Repiská ◽  
Helena Gbelcová
Keyword(s):  
Cancer Cells ◽  
Treatment Time ◽  
Ambient Air ◽  
Melanoma Cells ◽  
Clinical Applications ◽  
Dermal Fibroblasts ◽  
Apoptosis Induction ◽  
Normal Cells ◽  
Anticancer Effects ◽  
Cold Plasmas

Plasma medicine is a new field focusing on biomedical and clinical applications of cold physical plasmas, including their anticancer effects. Cold plasmas can be applied directly or indirectly as plasma activated liquids (PAL). The effect of plasma activated cell growth medium (PAM) and plasma activated phosphate buffered saline (PAPBS) were tested using a plasma pen generating streamer corona discharge in ambient air, on different cancer cell lines (melanoma A375, glioblastoma LN229 and pancreatic cancer MiaPaCa-2) and normal cells (human dermal fibroblasts HDFa). The viability reduction and apoptosis induction were detected in all cancer cells after incubation in PAL. In melanoma cells we focused on detailed insights to the apoptotic pathways. The anticancer effects depend on the plasma treatment time or PAL concentration. The first 30 minutes of incubation in PAL were enough to start processes leading to the cell death. In fibroblasts, no apoptosis induction was observed, only PAPBS, activated for longer time, slightly decreased their viability. Anticancer effects of PAM and PAPBS on cancer cells showed selectivity compared to normal fibroblasts, depended on correctly chosen activation time and PAL concentration. This selectivity, supported by optimum ratio of hydrogen peroxide and nitrites in PAL, is very promising for potential clinical applications.

scholarly journals Methionine stress induces a ferroptotic gene signature in methionine dependent cancer cells

2020 ◽  
Author(s):  
Katherine Wallis ◽  
Jordan T. Bird ◽  
Allen Gies ◽  
Sam G. Mackintosh ◽  
Alan J. Tackett ◽  
...  
Keyword(s):  
Stress Response ◽  
Oxidative Phosphorylation ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cell Line ◽  
Gene Promoters ◽  
Integrated Stress Response ◽  
Normal Cells ◽  
Methionine Restriction ◽  
Methionine Stress

ABSTRACTDietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood, except for the observation that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We found that replacing methionine with homocysteine generally induced hypomethylation in gene promoters. We isolated nuclear proteins and submitted it for tandem mass tag (TMT) proteomics. This analysis revealed that several proteins involved in the mitochondrial integrated stress response (ISR) were upregulated in response to the replacement of methionine to homocysteine in both cell lines, but to a much greater degree in the methionine dependent cell line. Consistent with the ISR signature, a proteomic analysis of a subcellular fraction enriched for mitochondrial content revealed a strong enrichment for proteins involved in oxidative phosphorylation. Analysis of cellular bioenergetics confirmed that homocysteine induces a decrease in ATP production from oxidative phosphorylation and glycolysis, but to a similar extent in methionine dependent and methionine independent cells. The mitochondrial integrated stress response shared a signature with ferroptosis. Methionine dependent cells displayed a strong ferroptotic signature, which was decreased by half in methionine independent cells. Consistent with ferroptosis, lipid peroxidation was significantly increased in methionine independent cells grown in homocysteine, and viability could be rescued partially but significantly with the inhibitor ferrostatin. Therefore, we propose that methionine stress induces ferroptotic cell death in methionine dependent cancer cells.

scholarly journals Selective Killing Natural Products and Drugs in Oral Cancer Treatments

2016 ◽  
pp. 1-2
Author(s):  
Hsueh-Wei Chang
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Side Effects ◽  
Oral Cancer ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Cancer Treatments ◽  
Normal Cells ◽  
Killing Effect ◽  
Anticancer Drug Discovery

Most cancer drugs are effective to kill cancer cells but also harm normal cells. Drugs and natural products with the selective killing effect may be helpful to solve this problem. The side effects of many anticancer drugs are partly derived from its damage to both cancer and normal cells without selection. This problem raises the need of anticancer drug discovery with the selective killing effect.

Redox-active nanoceria depolarize mitochondrial membrane of human colon cancer cells

2014 ◽  
Vol 16 (6) ◽  
Author(s):  
Saikat Kumar Jana ◽  
Priyanka Banerjee ◽  
Soumen Das ◽  
Sudipta Seal ◽  
Koel Chaudhury
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Mitochondrial Membrane ◽  
Human Colon ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
Redox Active ◽  
Human Colon Cancer Cells

scholarly journals Synthesis and Characterization of FITC Labelled Ruthenium Dendrimer as a Prospective Anticancer Drug

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 411 ◽  
Author(s):  
Sylwia Michlewska ◽  
Małgorzata Kubczak ◽  
Marta Maroto-Díaz ◽  
Natalia Sanz del Olmo ◽  
Paula Ortega ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Fluorescent Probe ◽  
Chemical Sensors ◽  
Cytotoxic Effect ◽  
Fluorescein Isothiocyanate ◽  
Synthesis And Characterization ◽  
Normal Cells ◽  
Anticancer Effects ◽  
Porphyrin Core

Metallodendrimers—dendrimers with included metals—are widely investigated as biocompatible equivalents to metal nanoparticles. Applications can be expected in the fields of catalysis, as chemical sensors in molecular recognition and as anticancer drugs. Metallodendrimers can also mimic certain biomolecules, for example, haemoprotein in the case of using a dendrimer with a porphyrin core. In previous papers, we showed the promising anticancer effects of carbosilane ruthenium dendrimers. The present paper is devoted to studying biocompatibility and the cytotoxic effect on normal and cancer cells of carbosilane ruthenium dendrimers labelled with fluorescent probe fluorescein isothiocyanate (FITC). The addition of fluorescent probe allowed tracking the metallodendrimer in both normal and cancer cells. It was found that carbosilane ruthenium dendrimer labelled with FITC in concentration up to 10 µmol/L was more cytotoxic for cancer cells than for normal cells. Thus, FITC labelled carbosilane ruthenium dendrimer is a good candidate for diagnostic imaging and studying anticancer effects of metallodendrimers in cancer therapy.

scholarly journals Nigericin decreases the viability of multidrug-resistant cancer cells and lung tumorspheres and potentiates the effects of cardiac glycosides

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769431 ◽  
Author(s):  
Juan Sebastian Yakisich ◽  
Neelam Azad ◽  
Vivek Kaushik ◽  
George A O’Doherty ◽  
Anand Krishnan V Iyer
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Multidrug Resistant ◽  
Culture Conditions ◽  
Chemotherapeutic Agents ◽  
Serum Starvation ◽  
Synthetic Analog ◽  
Antitumor Effects ◽  
Anticancer Effects

Multiple factors including tumor heterogeneity and intrinsic or acquired resistance have been associated with drug resistance in lung cancer. Increased stemness and the plasticity of cancer cells have been identified as important mechanisms of resistance; therefore, treatments targeting cancer cells independent of stemness phenotype would be much more effective in treating lung cancer. In this article, we have characterized the anticancer effects of the antibiotic Nigericin in cells displaying varying degrees of stemness and resistance to anticancer drugs, arising from (1) routine culture conditions, (2) prolonged periods of serum starvation. These cells are highly resistant to conventional anticancer drugs such as Paclitaxel, Hydroxyurea, Colchicine, Obatoclax, Wortmannin, and LY294002, and the multidrug-resistant phenotype of cells growing under prolonged periods of serum starvation is likely the result of extensive rewiring of signaling pathways, and (3) lung tumorspheres that are enriched for cancer stem-like cells. We found that Nigericin potently inhibited the viability of cells growing under routine culture conditions, prolonged periods of serum starvation, and lung tumorspheres. In addition, we found that Nigericin downregulated the expression of key proteins in the Wnt canonical signaling pathway such as LRP6, Wnt5a/b, and β-catenin, but promotes β-catenin translocation into the nucleus. The antitumor effects of Nigericin were potentiated by the Wnt activator HLY78 and by therapeutic levels of the US Food and Drug Administration–approved drug Digitoxin and its novel synthetic analog MonoD. We believe that Nigericin may be used in a co-therapy model in combination with other novel chemotherapeutic agents in order to achieve potent inhibition of cancers that display varying degrees of stemness, potentially leading to sustained anticancer effects.

scholarly journals Why cancer cells have a more hyperpolarised mitochondrial membrane potential and emergent prospects for therapy

2015 ◽  
Author(s):  
Michael D Forrest
Keyword(s):  
Membrane Potential ◽  
Cancer Cells ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Adenine Nucleotide ◽  
Proton Pumping ◽  
Cancer Drug ◽  
Mathematical Framework ◽  
Normal Cells ◽  
Anti Cancer

Cancer cells have a more hyperpolarised mitochondrial membrane potential (Ψ) than normal cells. Ψ = ~-220 mV in cancer cells as compared to ~-140 mV in normal cells. Until now it has not been known why. This paper explains this disparity, in a mathematical framework, and identifies molecular targets and operations unique to cancer cells. These are thence prospective cancer drug targets. BMS-199264 is proposed as an anti-cancer drug. It inhibits the reverse, proton-pumping mode of ATP synthase, which this paper identifies as crucial to cancer cells but not to healthy, normal adult cells. In the cancer cell model, the adenine nucleotide exchanger (ANT) is inversely orientated in the mitochondrial inner membrane as compared to normal cells. This predicts it to have a different drug interaction profile, which can be leveraged for cancer therapy. Uncouplers, which dissipate the proton motive force, are proposed as anti-cancer medicines e.g. 2,4-dinitrophenol.

scholarly journals E-cadherin promotes cell hyper-proliferation in breast cancer

2020 ◽  
Author(s):  
Gabriella C. Russo ◽  
Michelle N. Karl ◽  
David Clark ◽  
Julie Cui ◽  
Ryan Carney ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Adhesion Molecule ◽  
Intercellular Adhesion ◽  
Normal Cells ◽  
Mesenchymal Transition ◽  
E Cadherin

ABSTRACTThe loss of the intercellular adhesion molecule E-cadherin is a hallmark of the epithelial-mesenchymal transition (EMT), which promotes a transition of cancer cells to a migratory and invasive phenotype. E-cadherin is associated with a decrease in cell proliferation in normal cells. Here, using physiologically relevant 3D in vitro models, we find that E-cadherin induces hyper-proliferation in breast cancer cells through activation of the Raf/MEK/ERK signaling pathway. These results were validated and consistent across multiple in vivo models of primary tumor growth and metastatic outgrowth. E-cadherin expression dramatically increases tumor growth and, without affecting the ability of cells to extravasate and colonize the lung, significantly increases macrometastasis formation via cell proliferation at the distant site. Pharmacological inhibition of MEK1/2, blocking phosphorylation of ERK in E-cadherin-expressing cells, significantly depresses both tumor growth and macrometastasis. This work suggests a novel role of E-cadherin in tumor progression and identifies a potential new target to treat hyper-proliferative breast tumors.SUMMARYE-cadherin, an extensively studied transmembrane molecule ubiquitously expressed in normal epithelial tissues, promotes and maintains intercellular adhesion. In cancer, the loss of adhesion molecule E-cadherin is associated with onset of invasion via epithelial-to-mesenchymal transition (EMT) process.1 EMT consists of a highly orchestrated cascade of molecular events where epithelial cells switch from a non-motile phenotype to an invasive, migratory phenotype accompanied by a change in cell morphology.1,2 These processes are believed to then trigger metastasis in carcinomas (cancers of epithelial origin). Moreover, the expression of intercellular adhesion molecule E-cadherin (E-cad) is associated with a decrease in cell proliferation in normal cells. Classical experiments in fibroblasts and epithelial cells show that the expression of E-cad not only promotes cell-cell adhesion, but also reduces cell proliferation and onset of apoptosis.3,4 Altogether these results have long supported that E-cad acts as a tumor suppressor gene.1,2However, despite its role in cell-adhesion the requirement for loss of E-cad in metastasis has recently been re-assessed.5,6,7,8These investigations focus on E-cad’s role in EMT, even though the relationship between E-cad and proliferation is just as intriguing. While E-cad has been shown to have anit-proliferative effects in normal cells, E-cad also helps maintain a pluripotent and proliferative phenotype in stem cells, and notably is lost during differentiation, a non-proliferative step of stem cell progression.9,10 Yet, despite potentially important implications in our understanding of tumor progression, whether E-cad expression affects growth in cancer cells remains mostly unexplored.Here, utilizing a physiologically relevant 3D in vitro model and multiple in vivo models, we studied the impact of E-cad on cell proliferation at the primary tumor site and proliferation at a secondary site. Remarkably, E-cad upregulates multiple proliferation pathways, including hyper-activation of the ERK cascade within the greater MAPKinase pathway, resulting in a dramatic increase in cell proliferation in vitro and tumor growth in vivo. When the phosphorylation of ERK is blocked utilizing a MEK1/2 inhibitor, PD032590111, this effect is reversed in vitro and in vivo. Thus, E-cad plays an oncogenic role in tumorigenesis and merits evaluation as a potential new drug target.

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