Verteporfin-photoinduced apoptosis in HepG2 cells mediated by reactive oxygen and nitrogen species intermediates

Chiou, Jeng Fong; Wang, Yu Huei; Jou, Mei Jie; Liu, Tsan Zon; Shiau, Chia Yang

doi:10.3109/10715760903380458

Cited by 17 publications

(11 citation statements)

References 35 publications

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“…C). Photoactivated verteporfin was reported to lead to the generation of reactive oxygen species in hepatocellular carcinoma . However, treatment with the antioxidant N‐acetyl cysteine (NAC) did not abrogate the verteporfin‐induced reduction of MMP in GSCs (Fig.…”

Section: Resultsmentioning

confidence: 97%

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

et al. 2020

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Glioblastoma multiforme (GBM) is the most malignant primary brain tumour in adults. Since glioma stem cells (GSCs) are associated with therapeutic resistance as well as the initiation and recurrence in GBM, therapies targeting GSCs are considered to be effective for long-term survival in GBM. Several reports suggested that oxidative phosphorylation (OXPHOS) of cancer stem cells is important for their survival; however, the requirement of OXPHOS in GSCs remains unclear. Few effective and safe agents that target GSC mitochondria are available in clinical settings.In this study, we demonstrated that GSCs had high OXPHOS activity compared with isogenic differentiated GSCs and that GSC survival depended on their OXPHOS activity. Remarkably, we showed that complexes III and IV had broad therapeutic windows and that the expression levels of mitochondrial DNA-coded components of complexes III and IV were elevated in GSCs compared with differentiated GSCs. Moreover, our search of the Food and Drug Administration-approved drugs for those targeting GSC mitochondria revealed that verteporfin (Visudyne Ò ), a drug approved for macular degeneration, was a novel GSC-specific cytotoxic compound that reduced OXPHOS activity. Importantly, the cytotoxic effect of verteporfin was specific to GSCs without any toxicity to normal cells, and the IC 50 of approximately 200 nM was ten times less than its maximum blood concentration in humans. Overall, these findings indicated that high mitochondrial OXPHOS of GSCs is a potential GSC-specific vulnerability and that clinically available drugs, such as verteporfin, might become novel GSC-specific cytotoxic agents.

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Section: Resultsmentioning

confidence: 97%

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

et al. 2020

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“…It is interesting to note that several highly active drugs identified in our screen, including verteporfin, oltipraz, pyroglutamic acid, pidolic acid ( Figure 1 ), and dextrorphan tartrate, act on the glutathione/γ-glutamyl pathway used in mammalian cells which involved in protection against intracellular damage from free radicals and peroxides. Glutathione (GSH) is a reducing agent produced in the cytoplasm and transferred to the mitochondria by glutathione-S-transferase (GST), where it protects the mitochondria from reactive oxygen species (ROS) damage and functions in amino acid transport [ 24 , 25 ]. Reduced levels of GSH have been linked to increased sensitivity to ROS damage, resulting in mitochondrial swelling and subsequent damage [ 24 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library

et al. 2015

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Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2–4 week antibiotic treatment, 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive oxygen species production are more active against the B. burgdorferi persisters than the commonly used antibiotics that inhibit macromolecule biosynthesis. Future studies are needed to evaluate and optimize the promising active hits in drug combination studies in vitro and also in vivo in animal models. These studies may have implications for developing more effective treatments of Lyme disease.

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“…Although these primary ROS are short-lived, there is ample evidence that PDT induces prolonged oxidative stress in PDT-treated cells [ 25 , 26 ]. The post-PDT oxidative stress stems from (per)oxidized reaction products such as lipids [ 26 ] and proteins [ 27 ] that have a longer lifetime and, in addition to acutely generated ROS, depletion of intracellular antioxidants [ 28 ] and, hence, further exacerbation of already perturbed intracellular redox homeostasis.…”

Section: Photodynamic and Biochemical Activation Of Survival Pathwaysmentioning

confidence: 99%

“…In other cases, the activation of the survival mechanisms is induced by PDT and may consequently translate to prolonged survival in cells that were subjected to sublethal oxidative damage. Despite the fact that the ROS produced by PDT are generally short-lived (Section 2.1 ), their secondary metabolites ( e.g ., (per)oxidized proteins, protein residues, and lipids) can sustainably disrupt cellular redox states in the tumor tissue [ 26 , 28 , 62 ]. This may cause a second wave of cell death, whereby the oxidatively stressed but still viable tumor cells ultimately perish via programmed mechanisms due to the inability to restore cell function and homeostasis [ 85 ].…”

Section: Survival Pathways Activated In Tumor Cells Post-pdtmentioning

confidence: 99%

Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies

Broekgaarden

Weijer

Gulik

et al. 2015

Cancer Metastasis Rev

197

146

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Photodynamic therapy (PDT) has emerged as a promising alternative to conventional cancer therapies such as surgery, chemotherapy, and radiotherapy. PDT comprises the administration of a photosensitizer, its accumulation in tumor tissue, and subsequent irradiation of the photosensitizer-loaded tumor, leading to the localized photoproduction of reactive oxygen species (ROS). The resulting oxidative damage ultimately culminates in tumor cell death, vascular shutdown, induction of an antitumor immune response, and the consequent destruction of the tumor. However, the ROS produced by PDT also triggers a stress response that, as part of a cell survival mechanism, helps cancer cells to cope with the PDT-induced oxidative stress and cell damage. These survival pathways are mediated by the transcription factors activator protein 1 (AP-1), nuclear factor E2-related factor 2 (NRF2), hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), and those that mediate the proteotoxic stress response. The survival pathways are believed to render some types of cancer recalcitrant to PDT and alter the tumor microenvironment in favor of tumor survival. In this review, the molecular mechanisms are elucidated that occur post-PDT to mediate cancer cell survival, on the basis of which pharmacological interventions are proposed. Specifically, pharmaceutical inhibitors of the molecular regulators of each survival pathway are addressed. The ultimate aim is to facilitate the development of adjuvant intervention strategies to improve PDT efficacy in recalcitrant solid tumors.

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Verteporfin-photoinduced apoptosis in HepG2 cells mediated by reactive oxygen and nitrogen species intermediates

Cited by 17 publications

References 35 publications

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library

Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies

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