Salinomycin Induces Autophagy in Colon and Breast Cancer Cells with Concomitant Generation of Reactive Oxygen Species

Verdoodt, Berlinda; Vogt, Markus; Schmitz, Inge; Liffers, Sven-Thorsten; Tannapfel, Andrea; Mirmohammadsadegh, Alireza

doi:10.1371/journal.pone.0044132

Cited by 86 publications

(82 citation statements)

References 44 publications

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“…GR cells cultured in 20% oxygen and 10% FCS (hereafter called 'normoxic conditions') had a much higher expression of LC3A mRNA and autophagosome-bound LC3A-II protein as compared with those levels in the parental cells (Figures 4a-c). This was true even when GR and their parental cells were treated by salinomycin, an autophagy-inducing drug, 21 or CQ, a late-stage inhibitor of autophagy. 11 These findings indicate that GR cells have significantly higher levels of basal autophagy than their respective parental cells.…”

Section: High Basal Autophagy In Egfr-mutant Cells Y Sakuma Et Almentioning

confidence: 98%

“…A cancer tissue microenvironment was simulated with RPMI1640 media containing 1% FCS and antibiotics at 37 1C in a humidified incubator with 1% O 2 þ 5% CO 2 . Two EGFR TKIs, gefitinib (Biaffin GmbH & Co KG, Kassel, Germany) and WZ4002 (Selleck Chemicals, Houston, TX, USA), were used in this study, as well as an autophagy-inducing drug, salinomycin (Sigma-Aldrich, St Louis, MO, USA) 21 and a late-stage inhibitor of autophagy, chloroquine (CQ) diphosphate salt (Sigma-Aldrich). 11 Generation of GR HCC827 and HCC4006 Cells HCC827 and HCC4006 cells were cultured in the presence of 1 mM gefitinib until they acquired resistance.…”

Section: Cell Culture and Drugsmentioning

confidence: 99%

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Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Sakuma

Matsukuma

Nakamura

et al. 2013

Laboratory Investigation

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Lung cancers harboring epidermal growth factor receptor (EGFR) mutations depend on constitutive activation of the kinase for survival. Although most EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs) and shrink in response to treatment, acquired resistance to TKI therapy is common. We demonstrate here that two EGFRmutated lung adenocarcinoma cell lines, HCC827 and HCC4006, contain a subpopulation of cells that have undergone epithelial-to-mesenchymal transition and survive independent of activated EGFR. These EGFR-independent cancer cells, herein termed gefitinib-resistant (GR) cells, demonstrate higher levels of basal autophagy than their parental cells and thrive under hypoxic, reduced-serum conditions in vitro; this somewhat simulates the hypoxic environment common to cancerous tissues. We show that depletion of the essential autophagy gene, ATG5, by small interfering RNA (siRNA) or chloroquine, an autophagy inhibitor, markedly reduces GR cell viability under hypoxic conditions. Moreover, we show a significant elevation in caspase activity in GR cells following knockdown of ATG5. These results suggest that GR cells can evade apoptosis and survive in hostile, hypoxic environments with constant autophagic flux. We also show the presence of autophagosomes in some cancer cells from patient samples, even in untreated EGFR-mutant lung cancer tissue samples. Together, our results indicate that autophagy inhibitors alone or in combination with EGFR TKIs may be an effective approach for the treatment of EGFR-mutant lung cancers, where basal autophagy of some cancer cells is upregulated.

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Section: High Basal Autophagy In Egfr-mutant Cells Y Sakuma Et Almentioning

confidence: 98%

Section: Cell Culture and Drugsmentioning

confidence: 99%

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Sakuma

Matsukuma

Nakamura

et al. 2013

Laboratory Investigation

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“…[23] The same phenomenon was later confirmed in an independent study and also observed in colon cancer cells. [24] Salinomycin has been shown to perturb the autophagic flux in CSCs and breast cancer stem-like cells [25] and to trigger mitochondrial dysfunction in neurons. [26] Although a unified mechanism of action explaining the selectivity of salinomycin in targeting CSCs would be highly desirable, these biological studies have increased our knowledge on the phenotypic and metabolic differences in cells that can be mediated by small molecules in this biological context.…”

Section: Unbiased Screening Approaches -Case-studiesmentioning

confidence: 99%

Targeting Cancer Stem Cells with Small Molecules

Müller

Cañeque

Acevedo

et al. 2017

Israel Journal of Chemistry

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Cancers arise as a result of physiological imbalances and subsequent uncontrolled cell division. Cancer initiation requires a set of biochemical alterations, including some occurring at the genetic and epigenetic levels. Thus, tumors are heterogeneous in nature making it challenging to selectively target different cancer cells by means of small molecule intervention. The paradigm of cancer stem cells (CSCs) describes subpopulations of cells with high selfrenewal and tumor-seeding capacity. These cells, typically refractory to conventional therapies, can give rise to relapse after treatment. Combinatorial strategies, including drugs that selectively target this population of cells, have emerged in recent years. Here, we review how discovery-basedunbiased -screening approaches [1] have helped identify small molecules that specifically target CSCs. We also highlight biological pathways characteristic of CSCs that can potentially be selectively targeted in a hypothesis-driven manner by small molecules. We describe molecules that effectively target CSCs and emphasize what is known about their biological modes of action. The diversity and complexity of biochemical processes that CSCs may be addicted to, raises the question of how selective targeting of these pathways can be achieved. This challenge may be addressed by the continuing production of structurally complex and diverse small molecules using target and diversity-oriented synthesis approaches.[2]

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“…29 Sal induces not only apoptosis but also autophagy in human cancer cells, via the generation of ROS and activation of endoplasmic reticulum stress. 30,31 Silver nanoparticles (AgNPs) are one of the nanomaterials with the highest degree of commercialization. 32,33 AgNPs have been extensively used as antibacterial agents in the health industry and biomedical applications, and also as antiangiogenic 34 and anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

“…Our results are consistent with other studies stating that Sal induced apoptosis in human prostate cancer cells. 74 Verdoodt et al 30 demonstrated that Sal induces autophagy in Figure 5 effect of sal, agNPs, or both sal and agNPs on cytotoxicity in human ovarian cancer cells. Notes: (A) The cells were treated with sal (3 µM), agNPs (4 µg/ml), or the combination of sal (3 µM) and agNPs (4 µg/ml) for 24 hours.…”

mentioning

confidence: 99%

Combination of salinomycin and silver nanoparticles enhances apoptosis and autophagy in human ovarian cancer cells: an effective anticancer therapy

Zhang

Gurunathan

2016

IJN

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Ovarian cancer is one of the most important malignancies, and the origin, detection, and pathogenesis of epithelial ovarian cancer remain elusive. Although many cancer drugs have been developed to dramatically reduce the size of tumors, most cancers eventually relapse, posing a critical problem to overcome. Hence, it is necessary to identify possible alternative therapeutic approaches to reduce the mortality rate of this devastating disease. To identify alternative approaches, we first synthesized silver nanoparticles (AgNPs) using a novel bacterium called Bacillus clausii . The synthesized AgNPs were homogenous and spherical in shape, with an average size of 16–20 nm, which are known to cause cytotoxicity in various types of human cancer cells, whereas salinomycin (Sal) is able to kill cancer stem cells. Therefore, we selected both Sal and AgNPs to study their combined effect on apoptosis and autophagy in ovarian cancer cells. The cells treated with either Sal or AgNPs showed a dose-dependent effect with inhibitory concentration (IC)-50 values of 6.0 µM and 8 µg/mL for Sal and AgNPs, respectively. To determine the combination effect, we measured the IC 25 values of both Sal and AgNPs (3.0 µM and 4 µg/mL), which showed a more dramatic inhibitory effect on cell viability and cell morphology than either Sal or AgNPs alone. The combination of Sal and AgNPs had more pronounced effect on cytotoxicity and expression of apoptotic genes and also significantly induced the accumulation of autophagolysosomes, which was associated with mitochondrial dysfunction and loss of cell viability. Our data show a strong synergistic interaction between Sal and AgNPs in tested cancer cells. The combination treatment increased the therapeutic potential and demonstrated the relevant targeted therapy for the treatment of ovarian cancer. Furthermore, we provide, for the first time, a mode of action for Sal and AgNPs in ovarian cancer cells: enhanced apoptosis and autophagy.

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Salinomycin Induces Autophagy in Colon and Breast Cancer Cells with Concomitant Generation of Reactive Oxygen Species

Cited by 86 publications

References 44 publications

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Targeting Cancer Stem Cells with Small Molecules

Combination of salinomycin and silver nanoparticles enhances apoptosis and autophagy in human ovarian cancer cells: an effective anticancer therapy

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