Novel Mitochondria-targeted Drugs for Cancer Therapy

2020 ◽  
Vol 20 ◽  
Author(s):  
Jindriska Leischner Fialova ◽  
Martina Raudenska ◽  
Milan Jakubek ◽  
Zdenek Kejik ◽  
Pavel Martasek ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Special Focus ◽  
Targeted Drugs ◽  
Cancer Cell Death ◽  
Rational Development ◽  
Cancer Pharmacology ◽  
Mitochondrial Signaling ◽  
Promising Area

: The search for mitochondria-targeted drugs has dramatically risen over the last decade. Mitochondria are essential organelles serving not only as a powerhouse of the cell but also as a key player in cell proliferation and cell death. Their central role in the energetic metabolism, calcium homeostasis and apoptosis makes them an intriguing field of interest for cancer pharmacology. In cancer cells, many mitochondrial signaling and metabolic pathways are altered. These changes contribute to cancer development and progression. Due to changes in the mitochondrial metabolism and changes in a membrane potential, cancer cells are more susceptible to mitochondria-targeted therapy and the loss of functional mitochondria leads to arrest of cancer progression and/or a cancer cell death. Identification of mitochondrial changes specific for tumor growth and progression, a rational development of new mitochondria-targeted drugs and research on delivery agents led to the advance of this promising area. This review will highlight the current findings in mitochondrial biology which are important for cancer initiation, progression and resistance and discuss approaches of cancer pharmacology with a special focus to the anti-cancer drugs referred to as ‘mitocans’.

Magneto Mitochondrial Dysfunction Mediated Cancer Cell Death Using Intracellular Magnetic Nano-Transducers

2021 ◽  
Author(s):  
Wooram Park ◽  
Seok-Jo Kim ◽  
Paul Cheresh ◽  
Jeanho Yun ◽  
Byeongdu Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Cancer Cell ◽  
High Sensitivity ◽  
Intrinsic Pathway ◽  
Cancer Cell Death

Mitochondria are crucial regulators of the intrinsic pathway of cancer cell death. The high sensitivity of cancer cells to mitochondrial dysfunction offers opportunities for emerging targets in cancer therapy. Herein,...

scholarly journals Hydrogen Phosphate Selectively Induces MDA-MB-231 Breast Cancer Cell Death in vitro

2021 ◽  
Author(s):  
Aya Shanti ◽  
Kenana Al Adem ◽  
Cesare Stefanini ◽  
Sungmun Lee
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Dihydrogen Phosphate ◽  
Human Breast ◽  
Hydrogen Phosphate ◽  
Cancer Cell Death ◽  
Phosphate Ions

Abstract Phosphate ions are the most abundant anions inside the cells, and they are increasingly gaining attention as key modulators of cellular function and gene expression. However, little is known about the effect of inorganic phosphate ions on cancer cells, particularly breast cancer cells. Here, we investigated the toxicity of different phosphate compounds to triple-negative human breast cancer cells (MDA-MB-231) and compared it to that of human monocytes (THP-1). We found that, unlike dihydrogen phosphate (H2PO4−), hydrogen phosphate (HPO42−) at 20 mM or lower concentrations induced breast cancer (MDA-MB-231) cell death more than immune (THP-1) cell death. We correlate this effect to the fact that phosphate in the form of HPO42− raises pH levels to alkaline levels which are not optimum for transport of phosphate into cancer cells. The results in this study highlight the importance of further exploring hydrogen phosphate (HPO42−) as a potential therapeutic for the treatment of breast cancer.

scholarly journals Remotely Activated Nanoparticles for Anticancer Therapy

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Luisa Racca ◽  
Valentina Cauda
Keyword(s):  
Cell Death ◽  
Therapeutic Effect ◽  
Causes Of Death ◽  
Anticancer Therapy ◽  
Therapeutic Agents ◽  
Special Focus ◽  
Cancer Cell Death ◽  
Mechanical Waves ◽  
Active Interaction

AbstractCancer has nowadays become one of the leading causes of death worldwide. Conventional anticancer approaches are associated with different limitations. Therefore, innovative methodologies are being investigated, and several researchers propose the use of remotely activated nanoparticles to trigger cancer cell death. The idea is to conjugate two different components, i.e., an external physical input and nanoparticles. Both are given in a harmless dose that once combined together act synergistically to therapeutically treat the cell or tissue of interest, thus also limiting the negative outcomes for the surrounding tissues. Tuning both the properties of the nanomaterial and the involved triggering stimulus, it is possible furthermore to achieve not only a therapeutic effect, but also a powerful platform for imaging at the same time, obtaining a nano-theranostic application. In the present review, we highlight the role of nanoparticles as therapeutic or theranostic tools, thus excluding the cases where a molecular drug is activated. We thus present many examples where the highly cytotoxic power only derives from the active interaction between different physical inputs and nanoparticles. We perform a special focus on mechanical waves responding nanoparticles, in which remotely activated nanoparticles directly become therapeutic agents without the need of the administration of chemotherapeutics or sonosensitizing drugs.

scholarly journals Immunomodulatory activity of IR700-labelled affibody targeting HER2

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Justyna Mączyńska ◽  
Chiara Da Pieve ◽  
Thomas A. Burley ◽  
Florian Raes ◽  
Anant Shah ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Light Irradiation ◽  
Immunomodulatory Activity ◽  
Her2 Positive ◽  
Immunological Responses ◽  
Cancer Cell Death ◽  
Immature Dendritic Cells

Abstract There is an urgent need to develop therapeutic approaches that can increase the response rate to immuno-oncology agents. Photoimmunotherapy has recently been shown to generate anti-tumour immunological responses by releasing tumour-associated antigens from ablated tumour cell residues, thereby enhancing antigenicity and adjuvanticity. Here, we investigate the feasibility of a novel HER2-targeted affibody-based conjugate (ZHER2:2395-IR700) selectively to induce cancer cell death in vitro and in vivo. The studies in vitro confirmed the specificity of ZHER2:2395-IR700 binding to HER2-positive cells and its ability to produce reactive oxygen species upon light irradiation. A conjugate concentration- and light irradiation-dependent decrease in cell viability was also demonstrated. Furthermore, light-activated ZHER2:2395-IR700 triggered all hallmarks of immunogenic cell death, as defined by the translocation of calreticulin to the cell surface, and the secretion of ATP, HSP70/90 and HMGB1 from dying cancer cells into the medium. Irradiating a co-culture of immature dendritic cells (DCs) and cancer cells exposed to light-activated ZHER2:2395-IR700 enhanced DC maturation, as indicated by augmented expression of CD86 and HLA-DR. In SKOV-3 xenografts, the ZHER2:2395-IR700-based phototherapy delayed tumour growth and increased median overall survival. Collectively, our results strongly suggest that ZHER2:2395-IR700 is a promising new therapeutic conjugate that has great potential to be applicable for photoimmunotherapy-based regimens.

scholarly journals Mutant p53 and Cellular Stress Pathways: A Criminal Alliance That Promotes Cancer Progression

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 614 ◽  
Author(s):  
Gabriella D’Orazi ◽  
Mara Cirone
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Survival ◽  
Cellular Stress ◽  
Hypoxia Inducible Factor ◽  
Related Factor ◽  
Protective Mechanisms ◽  
Key Factor ◽  
The Unfolded Protein Response

The capability of cancer cells to manage stress induced by hypoxia, nutrient shortage, acidosis, redox imbalance, loss of calcium homeostasis and exposure to drugs is a key factor to ensure cancer survival and chemoresistance. Among the protective mechanisms utilized by cancer cells to cope with stress a pivotal role is played by the activation of heat shock proteins (HSP) response, anti-oxidant response induced by nuclear factor erythroid 2-related factor 2 (NRF2), the hypoxia-inducible factor-1 (HIF-1), the unfolded protein response (UPR) and autophagy, cellular processes strictly interconnected. However, depending on the type, intensity or duration of cellular stress, the balance between pro-survival and pro-death pathways may change, and cell survival may be shifted into cell death. Mutations of p53 (mutp53), occurring in more than 50% of human cancers, may confer oncogenic gain-of-function (GOF) to the protein, mainly due to its stabilization and interaction with the above reported cellular pathways that help cancer cells to adapt to stress. This review will focus on the interplay of mutp53 with HSPs, NRF2, UPR, and autophagy and discuss how the manipulation of these interconnected processes may tip the balance towards cell death or survival, particularly in response to therapies.

scholarly journals Development of a Cationic Amphiphilic Helical Peptidomimetic (B18L) As A Novel Anti-Cancer Drug Lead

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2448 ◽  
Author(s):  
Yuan Lyu ◽  
Steven Kopcho ◽  
Folnetti A. Alvarez ◽  
Bryson C. Okeoma ◽  
Chioma M. Okeoma
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Drug ◽  
Cancer Cell Death ◽  
Drug Lead ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Caspase Substrate ◽  
Dynamics Simulations

BST-2 is a novel driver of cancer progression whose expression confers oncogenic properties to breast cancer cells. As such, targeting BST-2 in tumors may be an effective therapeutic approach against breast cancer. Here, we sought to develop potent cytotoxic anti-cancer agent using the second-generation BST-2-based anti-adhesion peptide, B18, as backbone. To this end, we designed a series of five B18-derived peptidomimetics. Among these, B18L, a cationic amphiphilic α-helical peptidomimetic, was selected as the drug lead because it displayed superior anti-cancer activity against both drug-resistant and drug-sensitive cancer cells, with minimal toxicity on normal cells. Probing mechanism of action using molecular dynamics simulations, biochemical and membrane biophysics studies, we observed that B18L binds BST-2 and possesses membranolytic characteristics. Furthermore, molecular biology studies show that B18L dysregulates cancer signaling pathways resulting in decreased Src and Erk1/2 phosphorylation, increased expression of pro-apoptotic Bcl2 proteins, caspase 3 cleavage products, as well as processing of the caspase substrate, poly (ADP-ribose) polymerase-1 (PARP-1), to the characteristic apoptotic fragment. These data indicate that through the coordinated regulation of membrane, mitochondrial and signaling events, B18L executes cancer cell death and thus has the potential to be developed into a potent and selective anti-cancer compound.

scholarly journals ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1598 ◽  
Author(s):  
Mei-Chun Chen ◽  
Li-Lin Hsu ◽  
Sheng-Fan Wang ◽  
Chih-Yi Hsu ◽  
Hsin-Chen Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Glucose Deprivation ◽  
Glutathione Biosynthesis ◽  
Dependent Cell ◽  
Amp Activated Protein Kinase

xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes cell death. Further understanding the mechanism of glucose deprivation-induced cell death is important for developing anticancer treatments targeting the glucose metabolism. In this study, we found that breast cancer cells with a high expression of xCT demonstrated increased levels of reactive oxygen species (ROS) and were more sensitive to glucose deprivation than the cells with a low expression of xCT. However, AMP-activated protein kinase (AMPK) did not significantly affect glucose-deprivation-induced cell death. The antioxidant N-acetyl-cysteine prevented glucose-deprivation-induced cell death, and the glutathione biosynthesis inhibitor L-buthionine-S, R-sulfoximine enhanced glucose-deprivation-induced cell death. The inhibition of xCT by sulfasalazine or a knockdown of xCT reduced the glucose-deprivation-increased ROS levels and glucose-deprivation-induced cell death. Glucose deprivation reduced the intracellular glutamate, and supplementation with α-ketoglutarate prevented the glucose-deprivation-increased ROS levels and rescued cell death. The knockdown of sirtuin-3 (SIRT3) further enhanced the ROS levels, and promoted xCT-related cell death after glucose deprivation. In conclusion, our results suggested that ROS play a critical role in xCT-dependent cell death in breast cancer cells under glucose deprivation.

Energy metabolism targeted drugs synergize with photodynamic therapy to potentiate breast cancer cell death

2014 ◽  
Vol 13 (12) ◽  
pp. 1793-1803 ◽  
Author(s):  
Xiaolan Feng ◽  
Yi Zhang ◽  
Pan Wang ◽  
Quanhong Liu ◽  
Xiaobing Wang
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Photodynamic Therapy ◽  
Energy Metabolism ◽  
Combination Therapy ◽  
Breast Cancer Cells ◽  
Ros Generation ◽  
Targeted Drugs ◽  
Cancer Cell Death ◽  
Dependent Cell

Glycolytic inhibitors can synergistically enhance the photosensitivity of breast cancer cells by triggering cellular mitochondria- and caspase-dependent cell apoptosis, which was induced by additional ROS generation in combination therapy.

scholarly journals Selective imaging and cancer cell death via pH switchable near-infrared fluorescence and photothermal effects

2016 ◽  
Vol 7 (9) ◽  
pp. 5995-6005 ◽  
Author(s):  
Jingye Zhang ◽  
Zining Liu ◽  
Peng Lian ◽  
Jun Qian ◽  
Xinwei Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Near Infrared ◽  
Near Infrared Fluorescence ◽  
Ph Changes ◽  
Cancer Cell Death ◽  
Photothermal Effects

A theranostic probe is designed that specifically illuminates and photoablates cancer cells by sensing pH changes in the lysosomes and mitochondria.

Is metronomic vinorelbine (mVRL) able to inhibit both HUVEC and triple-negative breast cancer (TNBC) cells? The proof-of-concept VICTOR-0 study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14014-e14014
Author(s):  
Maria Grazia Cerrito ◽  
Davide Pelizzoni ◽  
Marco De Giorgi ◽  
Nunzio Digiacomo ◽  
Marialuisa Lavitrano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Umbilical Vein ◽  
Metastatic Breast ◽  
Proof Of Concept ◽  
Proliferating Cells ◽  
Drug Concentrations

e14014 Background: TNBC represents an important clinical challenge because of poor prognosis. One of the emerging strategy to achieve disease control while reducing toxicity is metronomic chemotherapy (mCHT) which targets the endothelial cells (ECs) and inhibits the tumor growth. mVRL is a promising option in patients (pts) with metastatic breast cancer (MBC), resulting in a median PFS of 7.7 months and median OS of 15.9. To better explain the effect of mVRL we studied the effects of metronomic doses of VRL in in vitro models and compared them with standard doses of the same drug. Methods: Cell viability and cytotoxicity assays were performed on TNBC cancer cells (MDA-MB-231) and Human Umbilical Vein Endothelial Cells (HUVEC). Cell lines were exposed to different concentration (0,01nM-1mM) of VRL for 4 and 96 h. To simulate the metronomic dosing schedule, we replaced the drug-enriched medium every 24h, while to simulate the conventional administration protocol (sCHT) cells were exposed to VRL for 4h, then the medium was changed and replaced with fresh medium without drug every 24 h. The IC50was calculated by non-linear regression fit of the mean values of data obtained in triplicate experiments. Results: A significant anti-proliferative activity was observed on both HUVEC and MDA cells treated with VRL in mCHT as compared to sCHT protocol (see Table). These lower drug concentrations did not have remarkable effects on cell death. Conversely, the higher dose utilized in sCHT produced important cell death in MDA as well as in HUVEC, even if in vivo, the higher dose of drug inducing the largest apoptosis of cancer cells also affectd healthy proliferating cells causing toxicity. Our findings suggest that mCHT inhibited the proliferation of both endothelial and tumour cells and can block cancer progression with minor side effects. Conclusions: This study provides the proof-of-concept that metronomic doses of VRL, but not the standard ones, are able to inhibit, at the same concentration, both the ECs and the TNBC cells. The clinical trial TEMPO-BREAST, which compares metronomic vs standard VRL, is ongoing in MBC pts. [Table: see text]

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