Small-molecule compounds target paraptosis to improve cancer therapy

Wang, Yujia; Wen, Xiang; Zhang, Nan; Lian, Wang; Hao, Dan; Jiang, Xian; He, Gu

doi:10.1016/j.biopha.2019.109203

Cited by 51 publications

(43 citation statements)

References 106 publications

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“…A prior study demonstrated that paraptosis was impaired by MAPK antagonists after low but not high levels of photodamage (13). This corresponds to the "canonical" route described previously (1)(2)(3)(4). As the level of ER photodamage increases to a level that can eradicate~90% of the cell population, paraptosis becomes independent of MAPK activity and does not require an interval of protein synthesis.…”

Section: Discussionsupporting

confidence: 65%

“…This can occur after a variety of external stimuli including chemotherapy (1)(2)(3)(4)(5)(6)(7) and ER photodamage (8)(9)(10). The potential relevance of paraptosis as a route to cancer control is indicated by studies showing that cell lines with an impaired apoptotic program can be eradicated by paraptosis (2,3). "Canonical" paraptosis is associated with activation of MAP kinases and requires a brief period of new protein synthesis (1).…”

Section: Introductionmentioning

confidence: 99%

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Paraptosis and Photodynamic Therapy: A Progress Report

Kessel

2020

Photochem & Photobiology

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Photodamage to the endoplasmic reticulum (ER) can initiate a death pathway termed paraptosis. The “canonical” model of paraptosis, initiated by certain drugs and other stimuli, requires a brief interval of protein synthesis, involves the action of MAP kinases and can be followed by biochemical markers. The latter include changes in expression of AIP‐1/Alix and IGF‐1R proteins and translocation of HMGB‐1 from nucleus to plasma membrane. There is also a report indicating that an enhanced level of autophagy can impair death by paraptosis. The pathway to paraptosis follows the canonical pathway when ER photodamage is minor (

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Paraptosis and Photodynamic Therapy: A Progress Report

Kessel

2020

Photochem & Photobiology

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“…In particular, a key role is played by mitochondria-associated ER membranes (MAMs), which facilitate the Ca 2+ flux from the ER to mitochondria, leading to the oxidative metabolism impairment and the following ROS overproduction frequently observed in case of pro-paraptotic Ca 2+ overload [11,13,14]. Intriguingly, paraptosis-inducing compounds have been shown to overcome cancer multi-drug resistance to apoptosis [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

et al. 2021

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Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for paraptosis induction. Additionally, δ-TT caused Ca2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated paraptosis. Graphic Abstract δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.

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“…Paraptosis is initiated with the dilation of ER and mitochondria in response to misfolded proteins (Figs 4c and 4e) [86,107,108]. This form of cell death can occur due to an exposure to chemotherapeutic agents [109][110][111] or photodamage [69,87,112,113] leading to the accumulation of multiple vacuoles that gradually fill the cytoplasm. Relatively little is known regarding the molecular basis of paraptosis, however, the underlying mechanism clearly differs from that of apoptosis.…”

Section: Subcellular Localization and Cell Death Pathways Associated mentioning

confidence: 99%

Photodynamic therapy, priming and optical imaging: Potential co-conspirators in treatment design and optimization — a Thomas Dougherty Award for Excellence in PDT paper

Silva

Saad

Thomsen

et al. 2020

J. Porphyrins Phthalocyanines

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Photodynamic therapy is a photochemistry-based approach, approved for the treatment of several malignant and non-malignant pathologies. It relies on the use of a non-toxic, light activatable chemical, photosensitizer, which preferentially accumulates in tissues/cells and, upon irradiation with the appropriate wavelength of light, confers cytotoxicity by generation of reactive molecular species. The preferential accumulation however is not universal and, depending on the anatomical site, the ratio of tumor to normal tissue may be reversed in favor of normal tissue. Under such circumstances, control of the volume of light illumination provides a second handle of selectivity. Singlet oxygen is the putative favorite reactive molecular species although other entities such as nitric oxide have been credibly implicated. Typically, most photosensitizers in current clinical use have a finite quantum yield of fluorescence which is exploited for surgery guidance and can also be incorporated for monitoring and treatment design. In addition, the photodynamic process alters the cellular, stromal, and/or vascular microenvironment transiently in a process termed photodynamic priming, making it more receptive to subsequent additional therapies including chemo- and immunotherapy. Thus, photodynamic priming may be considered as an enabling technology for the more commonly used frontline treatments. Recently, there has been an increase in the exploitation of the theranostic potential of photodynamic therapy in different preclinical and clinical settings with the use of new photosensitizer formulations and combinatorial therapeutic options. The emergence of nanomedicine has further added to the repertoire of photodynamic therapy’s potential and the convergence and co-evolution of these two exciting tools is expected to push the barriers of smart therapies, where such optical approaches might have a special niche. This review provides a perspective on current status of photodynamic therapy in anti-cancer and anti-microbial therapies and it suggests how evolving technologies combined with photochemically-initiated molecular processes may be exploited to become co-conspirators in optimization of treatment outcomes. We also project, at least for the short term, the direction that this modality may be taking in the near future.

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Small-molecule compounds target paraptosis to improve cancer therapy

Cited by 51 publications

References 106 publications

Paraptosis and Photodynamic Therapy: A Progress Report

Paraptosis and Photodynamic Therapy: A Progress Report

Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

Photodynamic therapy, priming and optical imaging: Potential co-conspirators in treatment design and optimization — a Thomas Dougherty Award for Excellence in PDT paper

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