Lipophilic triphenylphosphonium derivatives enhance radiation-induced cell killing via inhibition of mitochondrial energy metabolism in tumor cells

Yasui, Hirofumi; Yamamoto, Kumiko; Suzuki, Motofumi; Sakai, Yoshiko; Bo, Tomoki; Nagane, Masaki; Nishimura, Eri; Yamamori, Tohru; Yamasaki, Toshihide; Yamada, Ken Ichi; Inanami, Osamu

doi:10.1016/j.canlet.2017.01.006

Cited by 26 publications

(25 citation statements)

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“…Recent studies have demonstrated that exposure to radiation in human colorectal carcinoma cell line HCT116, osteosarcoma cell line HPS11 [44], and human lung cell carcinoma A549 [21] leads to the activation of mitochondrial energy metabolism and mitochondrial ATP production. These reports suggested that the cellular switch mechanism of energy metabolism in mitochondrial respiration provides additional advantage for cell survival because several lipophilic triphenylphosphonium derivatives enhance radiation-induced cell death via inhibition of mitochondrial energy metabolism [7]. The present study also showed that radiation-induced increases in the rotenonesensitive OCR (Figures 1B and C) and oligomycin-sensitive ATP levels ( Figure 3C) were observed at 24 h after X-irradiation, whereas AEC values after X-irradiation were stable (0.76-0.86).…”

Section: Discussionmentioning

confidence: 99%

“…In our recent studies [5,6], inhibition of dynamin-related protein 1 (Drp1), which controlled mitochondrial fission, reduced mitotic catastrophe in mouse fibroblast NIH3T3 cells and mouse SV40-immortalized embryo fibroblasts exposed to X-rays. It was also demonstrated that treatment with lipophilic triphenylphosphonium cation (TPP + ) derivatives, which inhibit mitochondrial ETC, enhanced X-ray-induced cell death by increasing reactive oxygen species (ROS) release from mitochondria and loss of intracellular ATP in human cervical carcinoma HeLa cells [7]. Compared to the cytotoxicity induced by cisplatin alone, enhanced cytotoxicity was observed when cisplatin was delivered to mitochondria of chemoresistant A2780/CP70 cells by nanoparticles (NP); the cisplatin-nanoparticle combination decreased mtDNA levels and mitochondrial function [8].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of mitochondrial redox status and energy metabolism of X-irradiated HeLa cells by LC/UV, LC/MS/MS and ESR

Yamamoto

Ikenaka

Ichise

et al. 2018

Free Radical Research

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To evaluate the metabolic responses in tumour cells exposed to ionizing radiation, oxygen consumption rate (OCR), cellular lipid peroxidation, cellular energy status (intracellular nucleotide pool and ATP production), and mitochondrial reactive oxygen species (ROS), semiquinone (SQ), and iron-sulphur (Fe-S) cluster levels were evaluated in human cervical carcinoma HeLa cells at 12 and 24 h after X-irradiation. LC/MS/MS analysis showed that levels of 8-iso PGF and 5-iPF-VI, lipid peroxidation products of membrane arachidonic acids, were not altered significantly in X-irradiated cells, although mitochondrial ROS levels and OCR significantly increased in the cells at 24 h after irradiation. LC/UV analysis revealed that intracellular AMP, ADP, and ATP levels increased significantly after X-irradiation, but adenylate energy charge (adenylate energy charge (AEC) = [ATP + 0.5 × ADP]/[ATP + ADP + AMP]) remained unchanged after X-irradiation. In low-temperature electron spin resonance (ESR) spectra of HeLa cells, the presence of mitochondrial SQ at g = 2.004 and Fe-S cluster at g = 1.941 was observed and X-irradiation enhanced the signal intensity of SQ but not of the Fe-S cluster. Furthermore, this radiation-induced increase in SQ signal intensity disappeared on treatment with rotenone, which inhibits electron transfer from Fe-S cluster to SQ in complex I. From these results, it was suggested that an increase in OCR and imbalance in SQ and Fe-S cluster levels, which play a critical role in the mitochondrial electron transport chain (ETC), occur after X-irradiation, resulting in an increase in ATP production and ROS leakage from the activated mitochondrial ETC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of mitochondrial redox status and energy metabolism of X-irradiated HeLa cells by LC/UV, LC/MS/MS and ESR

Yamamoto

Ikenaka

Ichise

et al. 2018

Free Radical Research

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“…A clonogenic survival assay for determination of the radio-sensitizing effect of SAS was performed as previously described [ 14 ]. B16F10 cells were trypsinized, diluted, counted, and seeded into 60-mm dishes at densities of 100–10,000 cells/dish before being allowed to adhere in a 37°C incubator for 6 hours.…”

Section: Methodsmentioning

confidence: 99%

Sulfasalazine, an inhibitor of the cystine-glutamate antiporter, reduces DNA damage repair and enhances radiosensitivity in murine B16F10 melanoma

et al. 2018

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The sodium-independent cystine-glutamate antiporter plays an important role in extracellular cystine uptake. It comprises the transmembrane protein, xCT and its chaperone, CD98. Because glutathione is only weakly cell membrane permeable, cellular uptake of its precursor, cystine, is known to be a key step in glutathione synthesis. Moreover, it has been reported that xCT expression affects the progression of tumors and their resistance to therapy. Sulfasalazine is an inhibitor of xCT that is known to increase cellular oxidative stress, giving it anti-tumor potential. Here, we describe a radio-sensitizing effect of sulfasalazine using a B16F10 melanoma model. Sulfasalazine decreased glutathione concentrations and resistance to H2O2 in B16F10 melanoma cells, but not in mouse embryonic fibroblasts. It synergistically enhanced the cyto-killing effect of X-irradiation in B16F10 cells. It inhibited cellular DNA damage repair and prolonged cell cycle arrest after X-irradiation. Furthermore, in an in vivo transplanted melanoma model, sulfasalazine decreased intratumoral glutathione content, leading to enhanced susceptibility to radiation therapy. These results suggest the possibility of using SAS to augment the treatment of radio-resistant cancers.

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“…As a third option, mitoQ may have increased ROS production and oxidative stress due to its long alkyl linker group ( Fig. S1; Maroz et al 2009;Reily et al 2013;Trnka et al 2015;Yasui et al 2017;Gottwald et al 2018). This may have promoted the consumption of tocopherol and xanthophylls to be used as radical scavengers (Britton et al 2004;Panda and Cherian 2014).…”

Section: Discussionmentioning

confidence: 99%

Testing the shared‐pathway hypothesis in the carotenoid‐based coloration of red crossbills

et al. 2020

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The mechanisms involved in the production of red carotenoid-based ornaments of vertebrates are still poorly understood. These colorations often depend on enzymatic transformations (ketolation) of dietary yellow carotenoids, which could occur in the inner mitochondrial membrane (IMM). Thus, carotenoid ketolation and cell respiration could share biochemical pathways, favoring the evolution of ketocarotenoid-based ornaments as reliable indices of individual quality under sexual selection. Captive male red crossbills (Loxia curvirostra Linnaeus) were exposed to redox-active compounds designed to penetrate and act in the IMM: an ubiquinone (mitoQ) or a superoxide dismutase mimetic (mitoTEMPO). MitoQ can act as an antioxidant but also distort the IMM structure, increasing mitochondrial free radical production. MitoQ decreased yellow carotenoids and tocopherol levels in blood, perhaps by being consumed as antioxidants. Contrarily, mitoTEMPO-treated birds rose circulating levels of the second most abundant ketocarotenoid in crossbills (i.e., canthaxanthin). It also increased feather total red ketocarotenoid concentration and redness, but only among those birds exhibiting a redder plumage at the start of the study, that is, supposedly high-quality individuals. The fact that mitoTEMPO effects depended on original plumage color suggests that the red-ketocarotenoid-based ornaments indicate individual quality as mitochondrial function efficiency. The findings would thus support the shared pathway hypothesis.

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Lipophilic triphenylphosphonium derivatives enhance radiation-induced cell killing via inhibition of mitochondrial energy metabolism in tumor cells

Cited by 26 publications

References 31 publications

Evaluation of mitochondrial redox status and energy metabolism of X-irradiated HeLa cells by LC/UV, LC/MS/MS and ESR

Evaluation of mitochondrial redox status and energy metabolism of X-irradiated HeLa cells by LC/UV, LC/MS/MS and ESR

Sulfasalazine, an inhibitor of the cystine-glutamate antiporter, reduces DNA damage repair and enhances radiosensitivity in murine B16F10 melanoma

Testing the shared‐pathway hypothesis in the carotenoid‐based coloration of red crossbills

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