Targeting of a Photosensitizer to the Mitochondrion Enhances the Potency of Photodynamic Therapy

Mahalingam, Sakkarapalayam M.; Ordaz, Josue D.; Low, Philip S.

doi:10.1021/acsomega.8b00692

Cited by 104 publications

(95 citation statements)

References 57 publications

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“…Verteporfin, an FDA-approved PS, has been conjugated with several mitochondrial targeting ligands i.e., TPP, guanidinium, and bisguanidinium which resulted in different levels of mitochondrial accumulation. Interestingly, the TPP derivative exhibited the highest mitochondrial accumulation level and the effect is correlated with the improvement in PDT cytotoxicity as opposed to the other two derivatives and its parent compound [25]. Furthermore, the conjugation of TPP into the octahedral molybdenum, which has a robust ability to produce 1 O 2 , leads to an improvement in cellular uptake efficiency and mitochondrial accumulation.…”

Section: Chemical Conjugation Of the Ps With Mitochondrial Targeting mentioning

confidence: 96%

“…The distinction in the subcellular localization of the PS constitutes a different cell death mechanism. For example, mitochondria accumulation could initiate the apoptosis pathway, while plasma membrane localization may provoke the necrotic cell death [25,26]. From the viewpoint of cancer therapy, apoptosis cell death is preferable due to the negligible inflammation effects, which would lessen the side effects on healthy cells.…”

Section: Mitochondrial Targeting Pdt For Cancer Therapymentioning

confidence: 99%

“…A more recent report suggested that mitochondrial targeting PDT could inhibit mitochondrial respiration, leading to a change in intramitochondrial oxygen levels, and further enhancing the PDT effect under hypoxic conditions Ref [28]. In addition, the overproduction of ROS in mitochondria during the PDT process causes the depolarization of the mitochondria membrane, resulting in the release of proapoptotic proteins, particularly cytochrome c, from the inner mitochondrial membrane to the cytosol, further activating apoptosis cell death [25,29,30]. These findings imply the importance of mitochondrial targeting in PDT applications.…”

Section: Figurementioning

confidence: 99%

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Therapeutic Strategies for Regulating Mitochondrial Oxidative Stress

et al. 2020

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There have been many reports on the relationship between mitochondrial oxidative stress and various types of diseases. This review covers mitochondrial targeting photodynamic therapy and photothermal therapy as a therapeutic strategy for inducing mitochondrial oxidative stress. We also discuss other mitochondrial targeting phototherapeutic methods. In addition, we discuss anti-oxidant therapy by a mitochondrial drug delivery system (DDS) as a therapeutic strategy for suppressing oxidative stress. We also describe cell therapy for reducing oxidative stress in mitochondria. Finally, we discuss the possibilities and problems associated with clinical applications of mitochondrial DDS to regulate mitochondrial oxidative stress.Biomolecules 2020, 10, 83 2 of 23 Parkinson's and Alzheimer's diseases, by the direct neutralization of ROS and by suppressing inflammation [5,6]. Furthermore, CoQ 10 , a potent ubiquinone antioxidant, has been reported to show significant protective effects on mitochondria of the pancreatic beta cells during the oxidative stress induced by the chronic use of tacrolimus [7]. Due to the highly hydrophobic characteristics and the fact that most of the antioxidant molecules accumulate in a nonspecific manner, a high dose is needed to obtain the desired effects. Thus, the selective delivery of this compound would be expected to further strengthen its effectivity.In the context of cancer therapy, mitochondrial ROS were found to play an important role as a signaling molecule in controlling cell proliferation by virtue of its ability to regulate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway [8]. Moreover, antioxidant activity, such as GSH and thioredoxin, was also reported to be essential for the initiation of and the progression of cancer. Inhibition of the antioxidant activity resulted in a significant reduction in tumor progression and metastasis [9][10][11]. These findings suggest that cancer cells are maintained under conditions of ROS stress and that antioxidant supplementation may be irrelevant for cancer therapy [12][13][14]. However, ROS interact with several major biologically active molecules such as proteins, lipids, and nucleic acids, leading to irreversible oxidative damage and the further induction of lethal effects for the cells. Therefore, promoting ROS production could be a promising strategy for treating tumors. There are numerous methods that can be employed to promote ROS levels in cancers, i.e., depleting or inhibiting antioxidant activity [15,16] and inhibiting the mitochondrial respiratory system [17], and producing an excessive amount of ROS through photochemical reactions. The latter effort shows a high selectivity for tumor cells, making it more encouraging in contrast to other efforts.This review focuses on therapeutic strategies for regulating mitochondrial oxidative stress. The main theme includes therapeutic strategies designed to induce oxidative stress and suppress mitochondrial oxidative stress (Figure 1). As ...

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Section: Chemical Conjugation Of the Ps With Mitochondrial Targeting mentioning

confidence: 96%

Section: Mitochondrial Targeting Pdt For Cancer Therapymentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Therapeutic Strategies for Regulating Mitochondrial Oxidative Stress

et al. 2020

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“…VP can be activated at a speci c wavelength of light to produce reactive oxygen species (ROS) that play an anti-cancer role, ablating breast cancer tumors. The sensitivity of tumor cells to photosensitizer mainly depends on the location of the tumor and the mitochondrial content of the cells [43]. At present, no studies have declared the effects of YAP caused by photoactivated VP.…”

Section: Discussionmentioning

confidence: 99%

Verteporfin Inhibits Cell Proliferation and Induces Apoptosis in Different Subtypes of Breast Cancer Cell Lines Without Light Activation

Wei¹,

2020

Preprint

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Abstract Background: Breast cancer (BC) can be divided into five subtypes: Lumina1A, Lumina1B, HER-2 overexpression, Basal-like and Normal breast-like subtype, based on the differently expressed genes in breast cancer tissue. The Hippo signaling pathway plays an indispensable role in BC. The YAP gene is a terminal effector of Hippo pathway, and hyperactivation of YAP mediates tumorigenesis. As an inhibitor of YAP, non-photoactivated verteporfin (VP) can inhibit YAP-mediated tumor proliferation and angiogenesis by eliminating its interaction with TEAD. This study aimed to determine the effect and molecular mechanisms of VP-mediated inhibition of YAP in different subtypes of BC.Methods: Luminal A, Luminal B and Basal-like BC cells were cultivated in vitro to study effects of VP on proliferation and apoptosis of these three molecular BC subtypes. Results: Our experimental results showed that VP inhibited cell proliferation, YAP-TEAD interaction and expression of its downstream targets. VP also induced tumor cell apoptosis, and promoted the cleavage of Caspase-9 and PARP in the cells of various molecular subtypes of BC. Conclusion: These findings provide a basis for the use of VP as a potential anti-tumor therapeutic for BC by targeting the Hippo pathway effector YAP.

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“…Finally, fluorescence microscopy demonstrated their preferential accumulation in the mitochondria over the nucleus, which is a great input in the development of photodynamic therapy agents. 100…”

Section: Dual Alkynyl Platinum-based Photosensitizers and Photoimaginmentioning

confidence: 99%