2017
DOI: 10.18632/aging.101351
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Abstract: Here, we performed high-throughput drug-screening to identify new non-toxic mitochondrial inhibitors. This screening platform was specifically designed to detect compounds that selectively deplete cellular ATP levels, but have little or no toxic side effects on cell viability. Using this approach, we identified DPI (Diphenyleneiodonium chloride) as a new potential therapeutic agent. Mechanistically, DPI potently blocks mitochondrial respiration by inhibiting flavin-containing enzymes (FMN and FAD-dependent), w… Show more

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Cited by 40 publications
(45 citation statements)
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References 35 publications
(27 reference statements)
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“…Another original approach has been developed to trigger cell death signaling pathways in colorectal cancer cells [101], such as ROS-dependent apoptosis and autophagy [102]. The recent improvement of high-throughput drug-screening platforms allowed the identification of novel non-toxic mitochondrial inhibitors, as in the case of diphenyleneiodonium chloride (DPI), a strong inhibitor of mitochondrial complex I and II flavin-containing enzymes, which effectively depletes cancer stem-like cells (CSCs), one of the main drivers of poor clinical outcome in a wide variety of tumor types and especially in advanced disease states [103]. Interestingly, mitochondrial inhibition with VLX600 has also been proposed in combination with imatinib in the treatment of drug-resistant gastrointestinal stromal tumors (GISTs) [104].…”
Section: Targeting Mitochondria For Cancer Therapymentioning
confidence: 99%
“…Another original approach has been developed to trigger cell death signaling pathways in colorectal cancer cells [101], such as ROS-dependent apoptosis and autophagy [102]. The recent improvement of high-throughput drug-screening platforms allowed the identification of novel non-toxic mitochondrial inhibitors, as in the case of diphenyleneiodonium chloride (DPI), a strong inhibitor of mitochondrial complex I and II flavin-containing enzymes, which effectively depletes cancer stem-like cells (CSCs), one of the main drivers of poor clinical outcome in a wide variety of tumor types and especially in advanced disease states [103]. Interestingly, mitochondrial inhibition with VLX600 has also been proposed in combination with imatinib in the treatment of drug-resistant gastrointestinal stromal tumors (GISTs) [104].…”
Section: Targeting Mitochondria For Cancer Therapymentioning
confidence: 99%
“…The uptake of riboflavin detected by autofluorescence has been shown to correlate with the presence of tumor stem cells [24,25]. We used this method as published to detect the concentration of TIC in H727 and H720 derived spheroids.…”
Section: Fluorescence and Immunofluorescence Staining Methodsmentioning
confidence: 99%
“…To initially characterize the TIC phenotype of cells within the spheroids, we exploited the reported finding that stem cells show a remarkable uptake of riboflavin [24,25]. Thus, spheroids were incubated in riboflavin and showed strong autofluorescence that increased significantly from the very low levels in parental cells compared to the 3rd gen SP ( Fig.…”
Section: Bronchial Carcinoid Cell Line Derived Spheroids Exhibit Charmentioning
confidence: 99%
“…By targeting the mitochondrial enzymes OXCT1 and ACAT1, we also developed new mitochondrial inhibitors that interfere with ketone metabolism, by mimicking the structure of CoA [24], (Figures 5 and 6). In addition, we identified a novel approach to acutely induce a Vitamin B2 (riboflavin) deficiency, that potently inhibits CSC propagation, with an IC-50 of ~ 3 nM [25], (Figure 7, Upper). Thus, this drug is approximately 30 times more potent than Palbociclib for targeting CSCs.
10.1080/15384101.2018.1515551-F0002Figure 2.Natural products used for targeting CSCs.
…”
Section: Mitochondrial-based Therapeutic Strategies For Eradicating Cmentioning
confidence: 99%