Nelfinavir, an HIV protease inhibitor, induces apoptosis and cell cycle arrest in human cervical cancer cells via the ROS-dependent mitochondrial pathway

Xiang, Tong; Du, Lanying; Pham, Petra; Zhu, Bo; Jiang, Shibo

doi:10.1016/j.canlet.2015.04.027

Cited by 59 publications

(51 citation statements)

References 42 publications

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“…These findings support earlier evidence in the literature where increased ROS levels or mitochondrial dysfunction were also observed individually upon treatment with type 1 HIV protease inhibitors (Estaquier et al 2002;Matarrese et al 2003;Roumier et al 2006;Chandra et al 2009;Touzet and Philips 2010;Bociąga-Jasik et al 2013;Xiang et al 2015), but it is the first time these parameters were measured simultaneously. The major advantage is that an unambiguous determination of both factors together in space and time allows pinpointing causal relationships.…”

Section: Discussionsupporting

confidence: 91%

“…7C). A specific increase in this localized ROS variant aligns well with earlier findings showing that SQV induces lower expression of the mitochondrial enzyme SOD2 (Xiang et al 2015).…”

Section: Biological Applicationssupporting

confidence: 91%

“…HIV protease inhibitors (HIV PI) have been shown to induce increased basal ROS levels (Chandra et al 2009;Touzet and Philips 2010), and lowered antioxidant defenses (represented by lowered expression of SOD2 (Xiang et al 2015)). Independently, other reports have linked HIV PI to changed mitochondrial morphofunction (Estaquier et al 2002;Matarrese et al 2003;Roumier et al 2006;Bociąga-Jasik et al 2013;Xiang et al 2015). As a case study, we have used the established workflow to assess the effect of HIV PI on both parameters.…”

Section: Biological Applicationsmentioning

confidence: 99%

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Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

Sieprath

Corne

Willems

et al. 2016

Advances in Anatomy, Embryology and Cell Biology

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Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and their removal by cellular antioxidant systems. Especially under pathological conditions, mitochondria constitute a relevant source of cellular ROS. These organelles harbor the electron transport chain, bringing electrons in close vicinity to molecular oxygen. Although a full understanding is still lacking, intracellular ROS generation and mitochondrial function are also linked to changes in mitochondrial morphology. To study the intricate relationships between the different factors that govern cellular redox balance in living cells, we have developed a high-content microscopy-based strategy for simultaneous quantification of intracellular ROS levels and mitochondrial morphofunction. Here, we summarize the principles of intracellular ROS generation and removal, and we explain the major considerations for performing quantitative microscopy analyses of ROS and mitochondrial morphofunction in living cells. Next, we describe our workflow and finally, we illustrate that a multiparametric readout enables the unambiguous classification of chemically perturbed cells as well as laminopathy patient cells. Principles of intracellular ROS generation and removalReactive oxygen species (ROS) are small, short-lived derivatives of molecular oxygen (O 2 ) of radical and non-radical nature (Halliwell and Gutteridge 2007 • ), nitrate radical (NO 3 • ) and many other nitrogen derivatives. ROS were originally described as molecular constituents of the defense system of phagocytic cells, but it has become clear that besides their damaging properties, they also function as signaling molecules and mediate a variety of other cellular responses including cell proliferation, differentiation, gene expression and migration (Lambeth 2004;Bartz and Piantadosi 2010). Intracellular ROS metabolismROS can be generated at various sites in the cell (Fig. 1A). This can be either deliberately, e.g. by NADPH oxidases (NOX), or as a byproduct, e.g. during normal cellular respiration in mitochondria (Babior 1999;Turrens 2003;Murphy 2009). The NOX family of NADPH oxidases (NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2) are proteins that transport electrons (e -) from NADPH across biological membranes (plasma or endomembranes) (Bedard and Krause 2007;Dupre-Crochet et al. 2013). The activation mechanisms and tissue distribution of the isoforms differ but they all use O 2 as e --acceptor, producing O 2•-. Through ROS generation, they play a role in many cellular processes including host defense, regulation of gene expression and cell differentiation (Bedard and Krause 2007). Despite their sometimes significant contribution to the global ROS pools, NOX are not the predominant source of intracellular ROS. Mitochondria are considered the major culprit, in particular under pathological conditions. Mitochondrial ROS are generated as a byproduct of the oxidative phosphorylation (OXPHOS, cf. below). Irrespective of its source, ROS production generally sta...

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Section: Discussionsupporting

confidence: 91%

“…7C). A specific increase in this localized ROS variant aligns well with earlier findings showing that SQV induces lower expression of the mitochondrial enzyme SOD2 (Xiang et al 2015).…”

Section: Biological Applicationssupporting

confidence: 91%

Section: Biological Applicationsmentioning

confidence: 99%

See 1 more Smart Citation

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

Sieprath

Corne

Willems

et al. 2016

Advances in Anatomy, Embryology and Cell Biology

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“…It has been reported that cervical carcinoma may be associated with dietary factors, and certain studies have suggested that micronutrients, including folic acid, vitamin A, vitamin C, β-carotene and vitamin E, may have a role in the prevention of human malignant tumors, including cervical carcinoma (7). These above-mentioned elements are antioxidants (8). During the process of cervical carcinoma occurrence, reactive oxygen species (ROS) may cause dysregulation of the chemical properties of the body, leading to the damaging of DNA and proteins, eventually causing cancer.…”

Section: Introductionmentioning

confidence: 99%

Alantolactone induces apoptosis of human cervical cancer cells via reactive oxygen species generation, glutathione depletion and inhibition of the Bcl-2/Bax signaling pathway

Jiang

Wang

2016

Oncology Letters

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Abstract.Alantolactone is the active ingredient in frankincense, and is extracted from the dry root of elecampane. It has a wide variety of uses, including as an insect repellent, antibacterial, antidiuretic, analgesic and anticancer agent. In addition, alantolactone induces apoptosis of human cervical cancer cells, however, its mechanism of action remains to be elucidated. Therefore, the present study investigated whether alantolactone was able to induce apoptosis of human cervical cancer cells, and its potential mechanisms of action were analyzed. Treatment of HeLa cells with alantolactone (0, 10, 20, 30, 40, 50 and 60 µM) for 12 h significantly inhibited growth in a dose-dependent manner. Cells treated with 30 µM of alantolactone for 0, 3, 6 and 12 h demonstrated marked induction of apoptosis in a time-dependent manner. Treatment of HeLa cells with 30 µM of alantolactone for 0, 3, 6 and 12 h significantly induced the generation of reactive oxygen species (ROS) and inhibited glutathione (GSH) production in HeLa cells in a dose-dependent manner. Alantolactone additionally markedly inhibited the Bcl-2/Bax signaling pathway in HeLa cells. Therefore, administration of alantolactone induced apoptosis of human cervical cancer cells via ROS generation, GSH depletion and inhibition of the Bcl-2/Bax signaling pathway.

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“…As a comparator for clinically relevant plasma levels, the table also includes the typical drug levels obtained from HIV dosing regimens for each of the corresponding PIs. Boxes have been color-coded according to presumed feasibility of achieving that level in the plasma based on current HIV dosing regimens 25,26. Overall, the PIs with the most consistent activity across cell lines was NFV.…”

Section: Resultsmentioning

confidence: 99%

The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia

Meier-Stephenson¹,

Riemer²,

Narendran³

2017

OTT

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PurposeRefractory pediatric leukemia remains one of the leading causes of death in children. Intensification of current chemotherapy regimens to improve the outcome in these children is often limited by the effects of drug resistance and cumulative toxicity. Hence, the search for newer agents and novel therapeutic approaches are urgently needed to formulate the next-generation early-phase clinical trials for these patients.Materials and methodsA comprehensive library of antimicrobials, including eight HIV protease inhibitors (nelfinavir [NFV], saquinavir, indinavir, ritonavir, amprenavir, atazanavir, lopinavir, and darunavir), was tested against a panel of pediatric leukemia cells by in vitro growth inhibition studies. Detailed target modulation studies were carried out by Western blot analyses. In addition, drug synergy experiments with conventional and novel antitumor agents were completed to identify effective treatment regimens for future clinical trials.ResultsSeveral of the HIV protease inhibitors showed cytotoxicity at physiologically relevant concentrations (half-maximal inhibitory concentration values ranging from 1–24 µM). In particular, NFV was found to exhibit the most potent antileukemic properties across all cell lines tested. Mechanistic studies show that NFV leads to the induction of autophagy and apoptosis possibly through the induction of endoplasmic reticulum stress. Furthermore, interference with cell signaling pathways, including Akt and mTOR, was also noted. Finally, drug combination studies have identified agents with potential for synergy with NFV in its antileukemic activity. These include JQ1 (BET inhibitor), AT101 (Bcl-2 family inhibitor), and sunitinib (TK inhibitor).ConclusionHere, we show data demonstrating the potential of a previously unexplored group of drugs to address an unmet therapeutic need in pediatric oncology. The data presented provide preclinical supportive evidence and rationale for future studies of these agents for refractory leukemia in children.

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Nelfinavir, an HIV protease inhibitor, induces apoptosis and cell cycle arrest in human cervical cancer cells via the ROS-dependent mitochondrial pathway

Cited by 59 publications

References 42 publications

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

Alantolactone induces apoptosis of human cervical cancer cells via reactive oxygen species generation, glutathione depletion and inhibition of the Bcl-2/Bax signaling pathway

The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia

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