scholarly journals Mitochondria Targeting as an Effective Strategy for Cancer Therapy

2020 ◽  
Vol 21 (9) ◽  
pp. 3363 ◽  
Author(s):  
Poorva Ghosh ◽  
Chantal Vidal ◽  
Sanchareeka Dey ◽  
Li Zhang
Keyword(s):  
Cancer Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Mitochondrial Respiration ◽  
Mitochondrial Dynamics ◽  
Metastatic Tumor ◽  
Atp Production ◽  
Development Of Resistance ◽  
Mitochondrial Alterations ◽  
Mitochondria Targeting

Mitochondria are well known for their role in ATP production and biosynthesis of macromolecules. Importantly, increasing experimental evidence points to the roles of mitochondrial bioenergetics, dynamics, and signaling in tumorigenesis. Recent studies have shown that many types of cancer cells, including metastatic tumor cells, therapy-resistant tumor cells, and cancer stem cells, are reliant on mitochondrial respiration, and upregulate oxidative phosphorylation (OXPHOS) activity to fuel tumorigenesis. Mitochondrial metabolism is crucial for tumor proliferation, tumor survival, and metastasis. Mitochondrial OXPHOS dependency of cancer has been shown to underlie the development of resistance to chemotherapy and radiotherapy. Furthermore, recent studies have demonstrated that elevated heme synthesis and uptake leads to intensified mitochondrial respiration and ATP generation, thereby promoting tumorigenic functions in non-small cell lung cancer (NSCLC) cells. Also, lowering heme uptake/synthesis inhibits mitochondrial OXPHOS and effectively reduces oxygen consumption, thereby inhibiting cancer cell proliferation, migration, and tumor growth in NSCLC. Besides metabolic changes, mitochondrial dynamics such as fission and fusion are also altered in cancer cells. These alterations render mitochondria a vulnerable target for cancer therapy. This review summarizes recent advances in the understanding of mitochondrial alterations in cancer cells that contribute to tumorigenesis and the development of drug resistance. It highlights novel approaches involving mitochondria targeting in cancer therapy.

scholarly journals Inhibition of TLR4 Signaling Affects Mitochondrial Fitness Overcoming Bortezomib Resistance in Myeloma Plasma Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3073-3073
Author(s):  
Cesarina Giallongo ◽  
Daniele Tibullo ◽  
Giuseppina Camiolo ◽  
Fabrizio Puglisi ◽  
Daniela Cambria ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Mitochondrial Respiration ◽  
Research Funding ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Depolarization ◽  
Tlr4 Signaling ◽  
Mitochondrial Mass ◽  
Atp Production ◽  
Inflammatory Microenvironment

BACKGROUND Multiple myeloma (MM) is a B-cell malignancy critically dependent for survival and proliferation on signals coming from its inflammatory microenvironment in which toll-like receptors (TLR) may be potential linking elements between inflammation and cancer. It has been recently demonstrated that TLR4 pathway provides a protective effect against bortezomib (BTZ)-induced endoplasmic reticulum (ER) stress and pre-treatment of MM cells with LPS significantly reduces BTZ-induced apoptosis. AIM Since the acquisition of BTZ resistance is accompanied by an increased reliance on mitochondrial respiration, we investigated the role of TLR4 as stress-responsive mechanism that protect mitochondria during BTZ-induced ER stress as potential mechanism of drug resistance. RESULTS The activation of TLR4 signaling by LPS increased mitochondrial mass in human MM cell lines (HMCL: U266, MM1.S, OPM2, NCI-H929) and induced up-regulation of mitochondrial biogenesis markers (PGC1a, PRC and TFAM). After treatment with BTZ for 24h, all HMCL over-expressed TLR4 and its signaling was functional as suggested by up-regulation of MyD88 and MAPK activation. Compared to BTZ-sensitive cells (U266-S), U266-R showed higher levels of TLR4, p-p38 and p-ERK proteins and higher mitochondrial mass. Using a selective TLR4 inhibitor (TAK-242), we next treated U266-R cells with either 15nM BTZ, 20 μM TAK-242 or their combination. Combinatorial treatment significantly induced cell apoptosis (about 52%; p<0.001) that appeared to result from the deleterious effects of oxidative stress. Indeed, BTZ-induced intracellular ROS returned to normal levels after 3h and cells were able to up-regulate two anti-oxidant enzymes (GPX1 and GSTP1). On the contrary, TAK-242/BTZ activated a strong pro-oxidant status incresing ROS and RNS (reactive nitrogen species) levels, decreasing GSH ones and down-regulating GPX1 and GSTP1. Analyzing the effect of each treatment on mitochondrial polarization status, we observed about 6,7% of depolarized mitochondria after BTZ treatment, while TAK-242/BTZ combination induced a mitochondrial depolarization of about 69,3% (p<0.001). Moreover, cells treated with BTZ alone showed a compensatory up-regulation of the OXPHOS- (NDUFA-6 and MT-ND4) and mitochondrial fusion-related genes (mitofusin and OPA1) and TFAM. On the contrary, all these genes were down-regulated by TAK-242/BTZ combination. Also a dramatic drop in mitochondrial respiration was observed with a marked decrease in ATP production, consequent accumulation of AMP and a decreased NAD+/NADH and NADP+/NADPH ratio. Since high levels of oxidative stress and mitochondrial impairment activate mitophagy sensitizing cells to apoptosis, we evaluated co-localization of mitochondria (stained with MitoTracker) with the autophagosome marker LC3 using confocal microscopy. BTZ and TAK-242/BTZ increased Mitotracker/LC3 co-localization respectively of about 4,5 and 50 fold compared with control (BTZ vs combination: p<0.001). To evaluate whether TLR4 inhibition resensitizes resistant primary cells, CD138+ cells derived from 5 refractory/relapsed MM patients were treated with 5nM BTZ, 10mM TAK-242 or their combination. Compared to BTZ alone, combination treatment induced higher mitochondrial depolarization after 24h and significantly decreased viability of CD138+ cells after 48h. TLR4 inhibitor alone or in combination did never show cytotoxicity toward CD138- cells. CONCLUSION Taken together, these findings indicate thatTLR4 signaling is involved in the acquisition of bortezomib resistance protecting mitochondria during BTZ exposure and sustaining mitochondrial dynamics in BTZ-resitant cells. Inhibition of TLR4 may overcome bortezomib resistance in patients with relapsed/refractory MM. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Palumbo:Celgene: Honoraria; Amgen: Honoraria; Hospira: Honoraria; Teva: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Di Raimondo:Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

scholarly journals Breast Cancer Metastasis in the Skin with Hyperkeratotic Pigmentation Caused by Melanocyte Colonization

2018 ◽  
Vol 11 (3) ◽  
pp. 660-664
Author(s):  
Shino Ishihara-Yusa ◽  
Taku Fujimura ◽  
Chunbing Lyu ◽  
Masayuki Sugawara ◽  
Kazuhiro Sakamoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immunohistochemical Staining ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Rare Condition ◽  
Metastatic Tumor ◽  
Breast Cancer Metastasis ◽  
Keratinocyte Proliferation

Pigmented breast cancer in the skin caused by nonneoplastic melanocytes of epidermal origin is a rare condition of metastasis from breast cancer, but the pathogenesis of this phenomenon is almost unknown. In this report, we describe a case of breast cancer metastasis in the skin with prominent hyperkeratotic pigmentation caused by nonneoplastic melanocyte colonization. Immunohistochemical staining revealed that the metastatic tumor cells produced IL-23, which is reported not only to induce IL-17 but also to inhibit cell apoptosis in breast cancer cells, which affects tumor progression. In addition to IL-23, substantial numbers of IL-17-producing cells were detected at the peritumoral area, suggesting that IL-17 might induce not only melanogenesis but also keratinocyte proliferation and tumorigenesis. Our report suggests possible mechanisms of hyperkeratotic pigmentation of breast cancer metastasis in the skin.

scholarly journals Energy and Redox Homeostasis in Tumor Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Marcus Fernandes de Oliveira ◽  
Nívea Dias Amoêdo ◽  
Franklin David Rumjanek
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Oxidative Metabolism ◽  
Aerobic Glycolysis ◽  
Redox Homeostasis ◽  
Oxygen Species ◽  
Mitochondrial Fragmentation ◽  
Atp Production ◽  
Antiapoptotic Proteins ◽  
Widespread Belief

Cancer cells display abnormal morphology, chromosomes, and metabolism. This review will focus on the metabolism of tumor cells integrating the available data by way of a functional approach. The first part contains a comprehensive introduction to bioenergetics, mitochondria, and the mechanisms of production and degradation of reactive oxygen species. This will be followed by a discussion on the oxidative metabolism of tumor cells including the morphology, biogenesis, and networking of mitochondria. Tumor cells overexpress proteins that favor fission, such as GTPase dynamin-related protein 1 (Drp1). The interplay between proapoptotic members of the Bcl-2 family that promotes Drp 1-dependent mitochondrial fragmentation and fusogenic antiapoptotic proteins such as Opa-1 will be presented. It will be argued that contrary to the widespread belief that in cancer cells, aerobic glycolysis completely replaces oxidative metabolism, a misrepresentation of Warburg’s original results, mitochondria of tumor cells are fully viable and functional. Cancer cells also carry out oxidative metabolism and generally conform to the orthodox model of ATP production maintaining as well an intact electron transport system. Finally, data will be presented indicating that the key to tumor cell survival in an ROS rich environment depends on the overexpression of antioxidant enzymes and high levels of the nonenzymatic antioxidant scavengers.

Development of a novel berberine-mediated mitochondria-targeting nano-platform for drug-resistant cancer therapy

2016 ◽  
Vol 4 (42) ◽  
pp. 6856-6864 ◽  
Author(s):  
Jue Tuo ◽  
Yanqi Xie ◽  
Jia Song ◽  
Yizhen Chen ◽  
Qin Guo ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Therapy ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Multi Drug Resistance ◽  
Drug Resistant ◽  
Inhibit Tumor Growth ◽  
Mitochondria Targeting

A novel berberine-mediated mitochondria-targeting nano-platform was constructed to inhibit tumor growth and bypass the multi-drug resistance problem by targeting doxorubicin to mitochondria of tumor cells.

scholarly journals Effect of Flow-Induced Shear Stress in Nanomaterial Uptake by Cells: Focus on Targeted Anti-Cancer Therapy

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1916 ◽  
Author(s):  
Samar Shurbaji ◽  
Gulsen G. Anlar ◽  
Essraa A. Hussein ◽  
Ahmed Elzatahry ◽  
Huseyin C. Yalcin
Keyword(s):  
Shear Stress ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Cell Mechanics ◽  
Normal Tissue ◽  
Biomedical Applications ◽  
Shear Stresses ◽  
Anti Cancer

Recently, nanomedicines have gained a great deal of attention in diverse biomedical applications, including anti-cancer therapy. Being different from normal tissue, the biophysical microenvironment of tumor cells and cancer cell mechanics should be considered for the development of nanostructures as anti-cancer agents. Throughout the last decades, many efforts devoted to investigating the distinct cancer environment and understanding the interactions between tumor cells and have been applied bio-nanomaterials. This review highlights the microenvironment of cancer cells and how it is different from that of healthy tissue. We gave special emphasis to the physiological shear stresses existing in the cancerous surroundings, since these stresses have a profound effect on cancer cell/nanoparticle interaction. Finally, this study reviews relevant examples of investigations aimed at clarifying the cellular nanoparticle uptake behavior under both static and dynamic conditions.

Co-Delivery of Paclitaxel and siRNA with pH-Responsive Polymeric Micelles for Synergistic Cancer Therapy

2021 ◽  
Vol 17 (2) ◽  
pp. 322-329
Author(s):  
Liuqi Shi ◽  
Huayang Feng ◽  
Zhanrong Li ◽  
Jun Shi ◽  
Lin Jin ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Polymeric Micelles ◽  
Subsurface Layer ◽  
Polymeric Micelle ◽  
Or Gene ◽  
Polymeric Vectors

Due to the complex physiological characteristics of tumors, chemotherapy or gene therapy alone cannot completely kill tumor cells. Therefore, combining chemotherapy with gene therapy for combination therapy is the key to solving this problem. However, there are still significant challenges in how to simultaneously deliver and rapidly release the drugs and siRNA into cancer cells. In this work, a triblock copolymer was synthesized to co-deliver siRNA and paclitaxel to tumor cells. This system has an acid-sensitive subsurface layer, which can not only load siRNA to prevent premature drug release but also has good controlled release performance. In vitro experiments showed that polymeric vectors can efficiently deliver siRNA and paclitaxel simultaneously into tumor cells for rapid release within the tumor cells. This study reveals that this novel polymeric micelle is a suitable vector for the codelivery of chemotherapeutic drugs and siRNA to cancer cells, representing an important advance in nanotechnology, nanomedicine, drug delivery, and cancer therapy.

Novel HIF-1α inhibitor CDMP-TQZ for cancer therapy

2021 ◽  
Author(s):  
Po-Chen Chu ◽  
Yu-Chieh Wu ◽  
Chien-Yu Chen ◽  
Yu-Syuan Hung ◽  
Chih-Shiang Chang
Keyword(s):  
Transcription Factor ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Human Cancer ◽  
Proteasomal Degradation ◽  
Low Oxygen ◽  
Therapeutic Targeting ◽  
Human Cancer Cells ◽  
Unique Ability

Aim: Tumor cells adapt to hypoxic microenvironments by releasing the key transcription factor HIF-1α, which promotes angiogenesis, glycolytic phenotype, metastasis and erythropoiesis, allowing proliferation amid low oxygen levels. Therefore, therapeutic targeting of HIF-1α represents a viable strategy for cancer therapy. Methods & Results: The authors synthesized a series of novel tetrahydroquinazoline derivatives in six steps and demonstrated that their development had a unique ability to suppress HIF-1α expression through proteasomal degradation. Conclusion: Among these compounds, CDMP-TQZ (8bf) exhibited the highest antiproliferative potency in human cancer cells, in part through downregulation of HIF-1α.

scholarly journals The disubstituted adamantyl derivative LW1564 inhibits the growth of cancer cells by targeting mitochondrial respiration and reducing hypoxia-inducible factor (HIF)-1α accumulation

2020 ◽  
Vol 52 (11) ◽  
pp. 1845-1856
Author(s):  
Inhyub Kim ◽  
Minkyoung Kim ◽  
Min Kyung Park ◽  
Ravi Naik ◽  
Jae Hyung Park ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Mitochondrial Respiration ◽  
Complex I ◽  
Cancer Metabolism ◽  
Hypoxia Inducible Factor ◽  
Xenograft Model ◽  
Biological Evaluation ◽  
Atp Production ◽  
Mouse Xenograft Model

AbstractTargeting cancer metabolism has emerged as an important cancer therapeutic strategy. Here, we describe the synthesis and biological evaluation of a novel class of hypoxia-inducible factor (HIF)-1α inhibitors, disubstituted adamantyl derivatives. One such compound, LW1564, significantly suppressed HIF-1α accumulation and inhibited the growth of various cancer cell lines, including HepG2, A549, and HCT116. Measurements of the oxygen consumption rate (OCR) and ATP production rate revealed that LW1564 suppressed mitochondrial respiration, thereby increasing the intracellular oxygen concentration to stimulate HIF-1α degradation. LW1564 also significantly decreased overall ATP levels by inhibiting mitochondrial electron transport chain (ETC) complex I and downregulated mammalian target of rapamycin (mTOR) signaling by increasing the AMP/ATP ratio, which increased AMP-activated protein kinase (AMPK) phosphorylation. Consequently, LW1564 promoted the phosphorylation of acetyl-CoA carboxylase, which inhibited lipid synthesis. In addition, LW1564 significantly inhibited tumor growth in a HepG2 mouse xenograft model. Taken together, the results indicate that LW1564 inhibits the growth of cancer cells by targeting mitochondrial ETC complex I and impairing cancer cell metabolism. We, therefore, suggest that LW1564 may be a potent therapeutic agent for a subset of cancers that rely on oxidative phosphorylation for ATP generation.

scholarly journals Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism

2006 ◽  
Vol 175 (6) ◽  
pp. 913-923 ◽  
Author(s):  
Hélène Pelicano ◽  
Rui-hua Xu ◽  
Min Du ◽  
Li Feng ◽  
Ryohei Sasaki ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Mitochondrial Respiration ◽  
Warburg Effect ◽  
Survival Advantage ◽  
Mitochondrial Dna Deletion ◽  
Atp Production ◽  
Akt Activation ◽  
Survival Pathway ◽  
The Warburg Effect

Cancer cells exhibit increased glycolysis for ATP production due, in part, to respiration injury (the Warburg effect). Because ATP generation through glycolysis is less efficient than through mitochondrial respiration, how cancer cells with this metabolic disadvantage can survive the competition with other cells and eventually develop drug resistance is a long-standing paradox. We report that mitochondrial respiration defects lead to activation of the Akt survival pathway through a novel mechanism mediated by NADH. Respiration-deficient cells (ρ-) harboring mitochondrial DNA deletion exhibit dependency on glycolysis, increased NADH, and activation of Akt, leading to drug resistance and survival advantage in hypoxia. Similarly, chemical inhibition of mitochondrial respiration and hypoxia also activates Akt. The increase in NADH caused by respiratory deficiency inactivates PTEN through a redox modification mechanism, leading to Akt activation. These findings provide a novel mechanistic insight into the Warburg effect and explain how metabolic alteration in cancer cells may gain a survival advantage and withstand therapeutic agents.

scholarly journals Cancer therapy with a CRISPR-assistant telomerase-activating gene expression system

2018 ◽  
Author(s):  
Wei Dai ◽  
Xinhui Xu ◽  
Danyang Wang ◽  
Jian Wu ◽  
Jinke Wang
Keyword(s):  
Gene Expression ◽  
Side Effects ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Expression System ◽  
Telomerase Activity ◽  
Adeno Associated Virus ◽  
Ht 29

AbstractTelomerase is silent in most normal somatic cells while active in 90% of tumor cells. Various telomerase activity inhibitors have been developed to treat cancer but all failed due to side effects. Here we acted oppositely to develop a cancer therapy named telomerase-activating gene expression (Tage) by utilizing the telomerase activity in tumor cells. By using CRISPR/Cas9 functions, the Tage system can effectively kill various cancer cells, including HepG2, HeLa, PANC-1, MDA-MB-453, A549, HT-29, SKOV-3, Hepa1-6, and RAW264.7, without effecting normal cells. By using homothallic switching endonuclease and adeno-associated virus, the Tage system realizes its in vivo application. The virus-loaded Tage system can significantly and specifically kill the cancer cells in mice by intravenous drug administration without side effects or toxicity.One Sentence Summary: Killing cancer cells in body with a gene therapy missile detonated by telomerase.

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