Hypocrellins and Hypericin induced apoptosis in human tumor cells: A possible role of hydrogen peroxide

Ali-Seyed, Mohamed; Chee, Soo Khee; Yuen, Gan Yik; Olivo, Malini

doi:10.3892/ijmm.9.5.461

Cited by 15 publications

(23 citation statements)

References 59 publications

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“…The biological effect of PDT depends on singlet oxygen or other oxygen species induced cell death (15,26,27) and our results have supported the hypothesis of mitochondria and lysosomal based photodynamic anti-cancer therapy (28). Therefore, the present study aimed to determine whether ROS production is involved in Photolon-Pdt induced apoptosis.…”

Section: Photolon-pdt Induced H 2 O 2 Productionmentioning

confidence: 61%

“…Cells were washed twice with PBS, resuspended in 0.5 ml of PBS + 1% FBS and analyzed by flow cytometry with the excitation wavelength set at 488 nm and the emission set at 525 nm (green). Flow cytometry data were analyzed as described (15). Confocal scanning laser microscopy (CLSM) further verified morphologically and confirmed the above findings.…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Mitochondrial localized photosensitizers are able to induce apoptosis very rapidly and cytochrome c release is triggered by mitochondrial depolarization following photosensitization (15,20). The present study assessed the involvement of permeability transition pore (MPT) and related mechanism of cytochrome c release upon light irradiation at different time points.…”

Section: Mitochondria Localized Photolon and Pdt Associated Drop In Mmentioning

confidence: 99%

“…Therefore, the present study aimed to determine whether ROS production is involved in Photolon-Pdt induced apoptosis. in this regard, H 2 O 2 was chosen because H 2 O 2 was implicated in PDT-mediated cell death (15,29). dCFH-da was used to detect the amount of intracellular H 2 O 2 .…”

Section: Photolon-pdt Induced H 2 O 2 Productionmentioning

confidence: 99%

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Photolon™ - Photosensitization induces apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes

Olivo

2011

Int J Oncol

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Abstract. The localization of photosensitizers in the subcellular compartments during photodynamic therapy (PDT) plays a major role in the cell destruction; therefore, the aim of this study was to investigate the intracellular localization of Chlorin e6-PVP (Photolon™) in malignant and normal cells. Our study involves the characterization of the structural determinants of subcellular localization of Photolon, and how subcellular localization affects the selective toxicity of Photolon towards tumor cells. Using confocal laser scanning microscopy (CLSM) and fluorescent organelle probes; we examined the subcellular localization of Photolon™ in the murine colon carcinoma CT-26 and normal fibroblast (NHLC) cells. Our results demonstrated that after 30 min of incubation, the distribution of Photolon was localized mainly in the cytoplasmic organelles including the mitochondria, lysosomes, Golgi apparatus, around the nuclear envelope and also in the nucleus but not in the endoplasmic reticulum whereas in NHLC cells, Photolon was found to be localized minimally only in the nucleus not in other organelles studied. The relationship between subcellular localization of Photolon and PDT-induced apoptosis was investigated. Apoptotic cell death was judged by the formation of known apoptotic hallmarks including, the phosphatidylserine externalization (PS), PARP cleavage, a substrate for caspase-3 and the formation of apoptotic nuclei. At the irradiation dose of 1 J/cm 2 , the percentage of apoptotic cells was 80%, respectively. This study provided substantial evidence that Photolon preferentially localized in the subcellular organelles in the following order: nucleus, mitochondria, lysosomes and the Golgi apparatus and subsequent photodamage of the mitochondria and lysosomes played an important role in PDT-mediated apoptosis CT-26 cells. Our results based on the cytoplasmic organelles and the intranuclear localization extensively enhance the efficacy of PDT with appropriate photosensitizer and light dose and support the idea that PDT can contribute to elimination of malignant cells by inducing apoptosis, which is of physiological significance.

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Section: Photolon-pdt Induced H 2 O 2 Productionmentioning

confidence: 61%

Section: Flow Cytometrymentioning

confidence: 99%

Section: Mitochondria Localized Photolon and Pdt Associated Drop In Mmentioning

confidence: 99%

Section: Photolon-pdt Induced H 2 O 2 Productionmentioning

confidence: 99%

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Photolon™ - Photosensitization induces apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes

Olivo

2011

Int J Oncol

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“…Geldanamycin, a benzoquinone found in a strain of Streptomyces hygroscopicus, that is able to induce arrest of the cell cycle and apoptosis in tumor cells (22). Illudins, a class of quinone antibiotics, have been shown to induce apoptosis in animal tumor models (23); and hypocrelins, polycyclic quinones derived from Hypocrella bambusae, fungi used in Chinese traditional medicine, are able to induce caspase-3 activity and apoptosis (24). The molecular details of how angucyclinone 5-aza-analogues and arylaminopyrimido [4,5-c]isoquinoline-7,10-quinones, exert the inhibition of TOP1 remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of human topoisomerase I and activation of caspase-3 by aza-angucyclinones and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones

et al. 2012

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Abstract.Cancer is the second cause of death in the world after cardiovascular diseases. Cancer cells acquire capacities not present in normal cells, such as self-sufficiency, resistance to antiproliferative stimuli, evasion of apoptosis, unlimited replication, invasiveness and metastasis. Consequently, it is of major interest to explore and develop molecules with anticancer activity directed to specific targets. In this study, we aimed to evaluate two series of polycyclic quinones: aza-angucyclinone and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones, in their capacity to inhibit human topoisomerase I (TOP1) and to trigger apoptosis through activation of caspase-3. We evaluated the capacity of the two series of polycyclic quinones to inhibit TOP1, using a DNA supercoiled relaxation assay and their capacity to induce apoptosis through the activation of caspase-3 in HL60 cells. Both series of quinones inhibited TOP1 activity over 50%. When we evaluated the pro-apoptotic capacity of both series of quinones, at therapeutically relevant concentrations, the arylaminoquinones ADPA-1CC (methyl 7-(4-methoxyphenyl)amino-1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate), P4 (9-phenylamino-3,4-dihydrophenanthridine-1,7,10(2H)-trione) and the aza-angucyclinone OH-6H (8-hydroxy-2,4-dimethyl-2H,4H-benzo[g]pyrimido [4,5-c]isoquinoline-1,3,7,12-tetraone) increased the caspase-3 activity by approximately 2-fold over the control. The series of the arylaminoquinones and aza-angucyclinones showed differential antiproliferative capacity. We further identified a group of them that showed antiproliferative capacity possibly through inhibition of TOP1 and by activation of caspase-3. This group of molecules may represent a potential pharmacological tool in the treatment against cancer.

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Glutathione S-transferase P1-1 expression modulates sensitivity of human kidney 293 cells to photodynamic therapy with hypericin

Dabrowski

Maeda

Zebala

et al. 2006

Archives of Biochemistry and Biophysics

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Photodynamic therapy (PDT) relies on light-dependent, tissue-targeted, oxidative stress in tumors that have accumulated a photosensitizing drug. Glutathione S-transferases (GSTs) are often up-regulated in tumors and they modulate oxidative stress by several isoform-dependent mechanisms. GSTs, therefore, are potential confounding factors in PDT. Therefore, we examined this possibility in human kidney 293 cells transfected with a plasmid encoding either green fluorescent protein alone (pIRES-GFP) or both GFP and GSTP1-1 (pIRES-GFP-GSTP). Cells were cultured and treated with light alone, the sensitizer hypericin (HYP) alone, or light and HYP. Cells harboring pIRES-GFP-GSTP exhibited a modest 2-fold increase in GSTP1-1 expression over control cells. On the basis of flow cytometry and microscopy, the light-dependent toxicity of HYP was reduced in cells over-expressing GSTP1-1. Paradoxically, the decreased toxicity in the cells with GSTP1-1 over-expression occurred concomitantly with a modest approximately 2-fold increase in cellular uptake of the drug. Immunoprecipitation of HYP and Western analysis indicated that GSTP1-1 is a major intracellular-binding site for HYP. These results are the first to demonstrate GST expression as a confounding variable of photodynamic therapy. Further, a high-affinity GST inhibitor reversed the GSTP1-1-dependent resistance, suggesting the possible utility of pharmacological strategies to optimize PDT.

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Hypocrellins and Hypericin induced apoptosis in human tumor cells: A possible role of hydrogen peroxide

Cited by 15 publications

References 59 publications

Photolon™ - Photosensitization induces apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes

Photolon™ - Photosensitization induces apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes

Inhibition of human topoisomerase I and activation of caspase-3 by aza-angucyclinones and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones

Glutathione S-transferase P1-1 expression modulates sensitivity of human kidney 293 cells to photodynamic therapy with hypericin

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