Imidazoacridinone-dependent lysosomal photodestruction: a pharmacological Trojan horse approach to eradicate multidrug-resistant cancers

Adar, Y. Y.; Stark, Michal; Bram, Eran; Nowak-Śliwińska, Patrycja; Bergh, Hubert van den; Szewczyk, Grzegorz; Sarna, Tadeusz; Składanowski, Andrzej; Griffioen, Arjan W.; Assaraf, Yehuda G.

doi:10.1038/cddis.2012.30

Cited by 81 publications

(71 citation statements)

References 28 publications

(33 reference statements)

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“…The results obtained point out that accumulation of C1330 in particular structures is crucial for the effective photokilling of C. albicans cells. In accordance with observations made by others (3,26,29), we observed that the nucleus is not the only structure where C1330 accumulates (30 min at 100 M) (Fig. 6A).…”

Section: Discussionsupporting

confidence: 93%

“…Imidazoacridinones accumulate effectively in lysosomes of tumor cells, due to their weak base nature. Alkalization of the cells with bafilomycin or ammonium chloride abolished selective accumulation of IA in cell lysosomes and promoted accumulation in the nucleus (26). Under our experimental conditions, we observed that in C. albicans cells, C1330 accumulated efficiently in the nucleus.…”

Section: Discussionmentioning

confidence: 48%

“…Dark toxicity toward human cells in our experimental model was not observed, in contrast to previously published results, where some dark toxicity was noticed. Cells incubated with C1330 at a concentration of 10 M, upon illumination, decreased their survival to 30% and 50% of the controls (nonilluminated cells) for the human cancer cell line A549 and its multidrug resistance phenotype counterpart, A549/K1.5 (26). Under our experimental conditions, the studied HaCaT cell line survived the dark treatment, even at a C1330 concentration of 50 M (Fig.…”

Section: Discussionmentioning

confidence: 60%

“…Here, we present data concerning a novel representative of a group of photosensitizing agents that so far have been studied as anticancer drugs exhibiting their mechanism of action through DNA binding and trapping the DNA-topoisomerase II-cleavable complexes. It was only recently found that the compounds from the imidazoacridinone group, exemplified by C1330, are also able to act through the light-dependent lysosome-destructive pathway, thus overcoming the MDR (multidrug resistance) phenotype in several cancer cell lines (26). This light-dependent action encouraged us to study the potential fungicidal action of imidazoacridinone agents against C. albicans in a light-dependent way.…”

Section: Discussionmentioning

confidence: 99%

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Imidazoacridinone Derivatives as Efficient Sensitizers in Photoantimicrobial Chemotherapy

Taraszkiewicz

Grinholc

Bielawski

et al. 2013

Appl Environ Microbiol

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The objective of this study was to investigate a new potential photosensitizer (PS) in the photodynamic inactivation (PDI) of microorganisms in vitro (11 reference strains and 13 clinical isolates, representing common Gram-positive and Gram-negative human pathogens), with special emphasis on Candida albicans. We studied the light-induced cytotoxicity of the imidazoacridinone derivative C1330 toward fungal cells grown in planktonic form. We examined the influence of various parameters (time of incubation, PDI quencher effect, and C1330 accumulation in C. albicans cells) on the efficacy of light-dependent cytotoxicity. Additionally, we checked for the potential cyto-and phototoxic activity of C1330 against human dermal keratinocytes. In our research, we used a broadband incoherent blue light source (380 to 470 nm) with an output power of 100 mW/cm 2 . In vitro studies showed that the C1330 action against C. albicans was a light-dependent process. C1330 was an efficient photosensitizer in the photodynamic inactivation of C. albicans, which reduced the growth of planktonic cells by 6.1 log 10 units. Efficient accumulation of PS in the nucleus and vacuoles was observed after 30 min of incubation, which correlated with the highest photokilling efficacy. Significant changes in intracellular structure were observed upon illumination of C1330-incubated C. albicans cells. In the case of the human HaCaT cell line, approximately 40% of cells survived the treatment, which indicates the potential benefit of further study of the application of C1330 in photoantimicrobial chemotherapy. These data suggest that PDI may be a viable approach for the treatment of localized C. albicans infections.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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Imidazoacridinone Derivatives as Efficient Sensitizers in Photoantimicrobial Chemotherapy

Taraszkiewicz

Grinholc

Bielawski

et al. 2013

Appl Environ Microbiol

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“…Vesicles that reside intracellularly have also been implicated in resistance to antiangiogenic therapy. This relates to the sequestration and accumulation of therapeutic compounds in the lysosomes and endocytic vesicles, a phenomenon that has already been described for chemotherapeutics Adar et al, 2012) and photosensitizing compounds . We recently showed that this also applies to one of the antiangiogenic TKIs, i.e., sunitinib.…”

Section: F Emerging Mechanisms Of Resistancementioning

confidence: 97%

The Great Escape; the Hallmarks of Resistance to Antiangiogenic Therapy

et al. 2015

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Mitochondria‐ and Lysosomes‐Targeted Synergistic Chemo‐Photodynamic Therapy Associated with Self‐Monitoring by Dual Light‐Up Fluorescence

Chen

et al. 2018

Adv Funct Materials

104

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The current cancer therapy faces great challenges on improving the treatment efficiency and overcoming the drug resistance. To tackle these challenges, herein dual-organelle-targeted nanoparticles (NPs) are developed with synergistic chemo-photodynamic therapy functions through self-assembly of mitochondria-targeted chemotherapeutic agent AIE-Mito-TPP and lysosomes-targeted photosensitizer AlPcSNa 4 . The dual-organelle-targeted NPs can be quickly taken up by cancer cells through endocytosis and gradually decompose to release AIE-Mito-TPP and AlPcSNa 4 , which, respectively, accumulate in mitochondria and lysosomes. The AIE-Mito-TPP can efficiently destroy mitochondrial functions, while the AlPcSNa 4 can efficiently destroy lysosomes via reactive oxygen species generation under NIR light irradiation. The dual-organelle-targeted drug delivery process can also be self-monitored by the dual light-up fluorescence of green-emissive AIE-Mito-TPP and red-emissive AlPcSNa 4 . With A375 cells and A375-bearing nude mice as a model, the theranostic potential of the AIE-Mito-TPP/AlPcSNa 4 NPs is systematically investigated both in vitro and in vivo. Under NIR light irradiation, the AIE-Mito-TPP/AlPcSNa 4 NPs show a remarkable cytotoxicity against A375 cells and efficiently inhibit the in vivo tumor growth. Therefore, the theranostic NPs with dual-organelle-targeted and synergistic chemo-photodynamic therapy functions associated with self-monitoring ability are expected to have promising applications in imaging-guided precise cancer therapy. Synthesis of AIE-Mito-TPP/AlPcSNa 4 NPs:The DMSO solutions of AlPcSNa 4 (75 µL, 4 × 10 −3 m) and AIE-Mito-TPP (600 µL, 1.0 × 10 −3 m) were first mixed at room temperature, and then 67.5 µL of the mixture solution was added into water solution (2.9325 mL) under stirring for 2 h to yield the stock solution of AIE-Mito-TPP/AlPcSNa 4 NPs (20 × 10 −6 m of AIE-Mito-TPP and 10 × 10 −6 m of AlPcSNa 4 ).Intracellular Release Monitoring: The A375 cells were seeded in glass-bottom cell culture dishes (10 × 10 4 per dish). After incubation for 24 h, the cells were rinsed with PBS and further treatment with AIE-Mito-TPP (2.5 × 10 −6 m), AlPcSNa 4 (1.25 × 10 −6 m), or AIE-Mito-TPP/AlPcSNa 4 NPs (2.5 × 10 −6 m of AIE-Mito-TPP and 1.25 × 10 −6 m of AlPcSNa 4 ) for 0.5 h. The cells were then rinsed three times with PBS and fresh culture media was added. After further incubation at 37 °C for 0, 2, 4, and 6 h, the fluorescence images were taken under confocal laser scanning microscope (CLSM). For AIE-Mito-TPP, λ ex = 405 nm, λ em = 450-600 nm. For AlPcSNa 4 , λ ex = 633 nm, λ em = 640-750 nm.Colocalization Experiment with LysoTracker Red: The A375 cells were seeded in glass-bottom cell culture dishes (10 × 10 4 per dish). After incubation for 24 h, the cells were rinsed with PBS and 1.0 mL of DMEM containing LysoTracker Red (100 × 10 −9 m) was added. After further incubation at 37 °C for 45 min, the cells were rinsed with PBS and then treated with AIE-Mito-TPP/AlPcSNa 4 NPs (2.5 × 10 −6 m of AIE-Mito-TPP an...

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Imidazoacridinone-dependent lysosomal photodestruction: a pharmacological Trojan horse approach to eradicate multidrug-resistant cancers

Cited by 81 publications

References 28 publications

Imidazoacridinone Derivatives as Efficient Sensitizers in Photoantimicrobial Chemotherapy

Imidazoacridinone Derivatives as Efficient Sensitizers in Photoantimicrobial Chemotherapy

The Great Escape; the Hallmarks of Resistance to Antiangiogenic Therapy

Mitochondria‐ and Lysosomes‐Targeted Synergistic Chemo‐Photodynamic Therapy Associated with Self‐Monitoring by Dual Light‐Up Fluorescence

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