scholarly journals Emerging approaches to target mitochondrial apoptosis in cancer cells

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1793 ◽  
Author(s):  
Andrew Gilmore ◽  
Louise King
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Tumour Cells ◽  
Mitochondrial Apoptosis ◽  
Therapeutic Approaches ◽  
Bh3 Mimetics ◽  
Novel Therapeutics ◽  
New Class ◽  
New Therapeutic Approaches

Apoptosis is a highly conserved programme for removing damaged and unwanted cells. Apoptosis in most cells is coordinated on mitochondria by the Bcl-2 family of proteins. The balance between pro- and anti-apoptotic Bcl-2 family proteins sets a threshold for mitochondrial apoptosis, a balance that is altered during cancer progression. Consequently, avoidance of cell death is an established cancer hallmark. Although there is a general perception that tumour cells are more resistant to apoptosis than their normal counterparts, the realities of cell death regulation in cancer are more nuanced. In this review we discuss how a profound understanding of this control has led to new therapeutic approaches, including the new class of BH3-mimetics, which directly target apoptosis as a vulnerability in cancer. We discuss recent findings that highlight the current limitations in our understanding of apoptosis and how these novel therapeutics work.

scholarly journals Bidirectional Interaction Between Cancer Cells and Platelets Provides Potential Strategies for Cancer Therapies

2021 ◽  
Vol 11 ◽  
Author(s):  
Liuting Yu ◽  
Yao Guo ◽  
Zhiguang Chang ◽  
Dengyang Zhang ◽  
Shiqiang Zhang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Antiplatelet Agents ◽  
Cancer Therapies ◽  
Therapeutic Approaches ◽  
Tumor Cell Adhesion ◽  
Essential Components ◽  
Tumor Growth And Metastasis ◽  
Induced Apoptosis ◽  
Adhesion And Invasion

Platelets are essential components in the tumor microenvironment. For decades, clinical data have demonstrated that cancer patients have a high risk of thrombosis that is associated with adverse prognosis and decreased survival, indicating the involvement of platelets in cancer progression. Increasing evidence confirms that cancer cells are able to induce production and activation of platelets. Once activated, platelets serve as allies of cancer cells in tumor growth and metastasis. They can protect circulating tumor cells (CTCs) against the immune system and detachment-induced apoptosis while facilitating angiogenesis and tumor cell adhesion and invasion. Therefore, antiplatelet agents and platelet-based therapies should be developed for cancer treatment. Here, we discuss the mechanisms underlying the bidirectional cancer-platelet crosstalk and platelet-based therapeutic approaches.

scholarly journals Mitochondrial apoptosis and BH3 mimetics

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2804 ◽  
Author(s):  
Haiming Dai ◽  
X. Wei Meng ◽  
Scott H. Kaufmann
Keyword(s):  
Antineoplastic Agent ◽  
Lymphocytic Leukemia ◽  
Mitochondrial Apoptosis ◽  
Acute Leukemias ◽  
Bh3 Mimetics ◽  
Bcl2 Family ◽  
New Class ◽  
Preclinical And Clinical Studies ◽  
Shed Light ◽  
Bh3 Mimetic

The BCL2-selective BH3 mimetic venetoclax was recently approved for the treatment of relapsed, chromosome 17p-deleted chronic lymphocytic leukemia (CLL) and is undergoing extensive testing, alone and in combination, in lymphomas, acute leukemias, and solid tumors. Here we summarize recent advances in understanding of the biology of BCL2 family members that shed light on the action of BH3 mimetics, review preclinical and clinical studies leading to the regulatory approval of venetoclax, and discuss future investigation of this new class of antineoplastic agent.

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 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.

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]

scholarly journals LncRNAs: New Players in Apoptosis Control

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Marianna Nicoletta Rossi ◽  
Fabrizio Antonangeli
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Noncoding Rnas ◽  
New Class ◽  
Physiological Processes ◽  
Specific Cancer ◽  
Cancer Types ◽  
Major Attention ◽  
Apoptotic Pathways ◽  
Polyadenylated Rnas

The discovery that the mammalian genome is largely transcribed and that almost half of the polyadenylated RNAs is composed of noncoding RNAs has attracted the attention of the scientific community. Growing amount of data suggests that long noncoding RNAs (lncRNAs) are a new class of regulators involved not only in physiological processes, such as imprinting and differentiation, but also in cancer progression and neurodegeneration. Apoptosis is a well regulated type of programmed cell death necessary for correct organ development and tissue homeostasis. Indeed, cancer cells often show an inhibition of the apoptotic pathways and it is now emerging that overexpression or downregulation of different lncRNAs in specific types of tumors sensitize cancer cells to apoptotic stimuli. In this review we summarize the latest studies on lncRNAs and apoptosis with major attention to those performed in cancer cells and in healthy cells upon differentiation. We discuss the new perspectives of using lncRNAs as targets of anticancer drugs. Finally, considering that lncRNA levels have been reported to have a correlation with specific cancer types, we argue the possibility of using lncRNAs as tumor biomarkers.

Emerging Therapeutic Targets in Oncologic Photodynamic Therapy

2019 ◽  
Vol 24 (44) ◽  
pp. 5268-5295 ◽  
Author(s):  
Gina Manda ◽  
Mihail E. Hinescu ◽  
Ionela V. Neagoe ◽  
Luis F.V. Ferreira ◽  
Rica Boscencu ◽  
...  
Keyword(s):  
Cell Death ◽  
Photodynamic Therapy ◽  
Singlet Oxygen ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Molecular Networks ◽  
Systems Medicine ◽  
Therapeutic Tools

Background:Reactive oxygen species sustain tumorigenesis and cancer progression through deregulated redox signalling which also sensitizes cancer cells to therapy. Photodynamic therapy (PDT) is a promising anti-cancer therapy based on a provoked singlet oxygen burst, exhibiting a better toxicological profile than chemo- and radiotherapy. Important gaps in the knowledge on underlining molecular mechanisms impede on its translation towards clinical applications.Aims and Methods:The main objective of this review is to critically analyse the knowledge lately gained on therapeutic targets related to redox and inflammatory networks underlining PDT and its outcome in terms of cell death and resistance to therapy. Emerging therapeutic targets and pharmaceutical tools will be documented based on the identified molecular background of PDT.Results:Cellular responses and molecular networks in cancer cells exposed to the PDT-triggered singlet oxygen burst and the associated stresses are analysed using a systems medicine approach, addressing both cell death and repair mechanisms. In the context of immunogenic cell death, therapeutic tools for boosting anti-tumor immunity will be outlined. Finally, the transcription factor NRF2, which is a major coordinator of cytoprotective responses, is presented as a promising pharmacologic target for developing co-therapies designed to increase PDT efficacy.Conclusion:There is an urgent need to perform in-depth molecular investigations in the field of PDT and to correlate them with clinical data through a systems medicine approach for highlighting the complex biological signature of PDT. This will definitely guide translation of PDT to clinic and the development of new therapeutic strategies aimed at improving PDT.

The Tangled Mitochondrial Metabolism in Cancer: An Innovative Pharmacological Approach

2020 ◽  
Vol 27 (13) ◽  
pp. 2106-2117 ◽  
Author(s):  
Patrizia Bottoni ◽  
Roberto Scatena
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Oxidative Metabolism ◽  
Reactive Oxygen ◽  
Mitochondrial Metabolism ◽  
Oxygen Species ◽  
Therapeutic Approaches ◽  
Fundamental Step

Background: Mitochondria are remarkably gaining significant and different pathogenic roles in cancer (i.e., to sustain specific metabolism, to activate signaling pathways, to promote apoptosis resistance, to favor cancer cell dissemination, and finally to facilitate genome instability). Interestingly, all these roles seem to be linked to the fundamental activity of mitochondria, i.e. oxidative metabolism. Intriguingly, a typical modification of mitochondrial oxidative metabolism and reactive oxygen species production/ neutralization seems to have a central role in all these tangled pathogenic roles in cancer. On these bases, a careful understanding of the molecular relationships between cancer and mitochondria may represent a fundamental step to realize therapeutic approaches blocking the typical cancer progression. The main aim of this review is to stress some neglected aspects of oxidative mitochondrial metabolism of cancer cells to promote more translational research with diagnostic and therapeutic potential. Methods: We reviewed the available literature regarding clinical and experimental studies on various roles of mitochondria in cancer, with attention to the cancer cell mitochondrial metabolism. Results: Mitochondria are an important source of reactive oxygen species. Their toxic effects seem to increase in cancer cells. However, it is not clear if damage depends on ROS overproduction and/or defect in detoxification. Failure of both these processes is likely a critical component of the cancer process and is strictly related to the actual microenvironment of cancer cells. Conclusions: Mitochondria, also by ROS production, have a fundamental pathogenetic role in promoting and maintaining cancer and its spreading. To carefully understand the tangled redox state of cancer cells mitochondria represents a fundamental step to realize therapeutic approaches blocking the typical cancer progression.

scholarly journals Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: The cellular mechanism

2010 ◽  
Vol 111 (6) ◽  
pp. 1426-1436 ◽  
Author(s):  
Ning Wang ◽  
Yibin Feng ◽  
Meifen Zhu ◽  
Chi-Man Tsang ◽  
Kwan Man ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Cellular Mechanism ◽  
Autophagic Cell Death ◽  
Mitochondrial Apoptosis ◽  
Liver Cancer Cells

scholarly journals Targeting of Prosurvival Pathways as Therapeutic Approaches against Primary Effusion Lymphomas: Past, Present, and Future

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Marisa Granato ◽  
Roberta Santarelli ◽  
Roberta Gonnella ◽  
Antonella Farina ◽  
Pankaj Trivedi ◽  
...  
Keyword(s):  
Cell Death ◽  
Dendritic Cell ◽  
B Cell ◽  
Cancer Cells ◽  
Side Effect ◽  
Cytotoxic Effect ◽  
Anticancer Therapy ◽  
Therapeutic Approaches ◽  
Potential Side Effect ◽  
Primary Effusion Lymphomas

Constitutively activated prosurvival pathways render cancer cells addicted to their effects. Consequently they turn out to be the Achilles’ heels whose inhibition can be exploited in anticancer therapy. Primary effusion lymphomas (PELs) are very aggressive non-Hodgkin’s B cell lymphomas, whose pathogenesis is strictly linked to Kaposi’s sarcoma herpesvirus (KSHV) infection. Here we summarized previous studies from our and other laboratories exploring the cytotoxic effect of drugs inhibiting the main prosurvival pathways activated in PEL cells. Moreover, the immunogenicity of cell death, in terms of dendritic cell (DC) activation and their potential side effect on DCs, is discussed.

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