Lysosomal cathepsin initiates apoptosis, which is regulated by photodamage to Bcl-2 at mitochondria in photodynamic therapy using a novel photosensitizer, ATX-s10 (Na)

Ichinose, Shuji; Usuda, Jitsuo; Hirata, Takeshi; Inoue, Tatsuya; Ohtani, Kazuhiro; Maehara, Sachio; Kubota, Mitsuhiro; Imai, Kentarou; Tsunoda, Yoshihiko; Kuroiwa, Yukari; Yamada, Kimito; Tsutsui, Hidemitsu; Furukawa, Kinya; Okunaka, Tetsuya; Oleinick, Nancy L.; Kato, Harubumi

doi:10.3892/ijo.29.2.349

Cited by 38 publications

(45 citation statements)

References 21 publications

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“…Bcl-2, an antiapoptotic protein of the Bcl-2 family, promotes cell survival by interfering with the activation of the cytochrome c/Apaf-1 pathway through stabilization of the mitochondrial membrane (26) and is a target of some photosensitizers (27)(28)(29)(30). In the present study, Bcl-2 was down-regulated by 9-HPbD-PDT, which was prevented by pretreatment with the antioxidants (Fig.…”

Section: Discussionsupporting

confidence: 54%

Photoactivation of 9-hydroxypheophorbide α triggers apoptosis through the reactive oxygen species-mediated mitochondrial pathway and endoplasmic reticulum stress in AMC-HN-3 laryngeal cancer cells

Ahn²,

Shin³

et al. 2010

Int J Oncol

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Abstract. Photodynamic therapy (PDT) is a promising treatment modality for a variety of cancers. It utilizes lightabsorbing compounds combined with direct illumination to generate reactive oxygen species in photosensitizer-targeted tumor cells resulting in the final photodamage of tumors. Recently, we demonstrated that a combination modality of 9-hydroxypheophorbide · (9-HPbD)-based PDT and carboplatin exerts enhanced cytotoxic and apoptotic effects on AMC-HN-3 laryngeal cancer cells. The present study aimed to investigate the potential apoptotic pathways initiated by 9-HPbD-PDT-mediated reactive oxygen species (ROS) in AMC-HN-3 cells. Cytotoxicity and apoptosis induced by 9-HPbD-PDT were exhibited in a ROS-dependent manner. Mitochondria and the endoplasmic reticulum (ER) were observed as preferential sites of 9-HPbD accumulation in AMC-HN-3 cells. ROS induced by 9-HPbD-PDT directly led to downregulated expression of Bcl-2, loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, elevation of intracellular calcium due to ER stress, as well as induction of CHOP and activation of caspase-3, -8, -9 and -12. Our results demonstrated that ROS induced by 9-HPbD-PDT play a causative role in triggering mitochondrial events, ER stress and probable involvement of the extrinsic apoptotic pathway in AMC-HN-3 cells.

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Section: Discussionsupporting

confidence: 54%

Photoactivation of 9-hydroxypheophorbide α triggers apoptosis through the reactive oxygen species-mediated mitochondrial pathway and endoplasmic reticulum stress in AMC-HN-3 laryngeal cancer cells

Ahn²,

Shin³

et al. 2010

Int J Oncol

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“…Photodynamic therapy with photosensitizers that accumulate inside lysosomes may induce cell death dependent on LMP and cathepsins (Buytaert et al, 2007), as has been shown for ATX-s10 and N-aspartyl chlorin e6 (Caruso et al, 2004;Ichinose et al, 2006). In addition, antiapoptotic members of the Bcl-2 family of proteins are often degraded after photodynamic therapy, making cells more sensitive to apoptotic cell death (Xue et al, 2003;Ichinose et al, 2006).…”

Section: Lmp In Cancer Cellsmentioning

confidence: 99%

Lysosomal membrane permeabilization in cell death

2008

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Mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major checkpoint(s) of apoptotic and necrotic cell death. Recently, the permeabilization of yet another organelle, the lysosome, has been shown to initiate a cell death pathway, in specific circumstances. Lysosomal membrane permeabilization (LMP) causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol. LMP is induced by a plethora of distinct stimuli including reactive oxygen species, lysosomotropic compounds with detergent activity, as well as some endogenous cell death effectors such as Bax. LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including caspases. This latter process is usually mediated indirectly, through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D), which then induces MOMP, resulting in cytochrome c release and apoptosome-dependent caspase activation. However, massive LMP often results in cell death without caspase activation; this cell death may adopt a subapoptotic or necrotic appearance. The regulation of LMP is perturbed in cancer cells, suggesting that specific strategies for LMP induction might lead to novel therapeutic avenues.

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“…Aliquots of the cells were seeded into 25 cm 2 flasks in amounts sufficient to yield 50-150 colonies. After incubation for 10-14 days, the cells were stained with 0.1% crystal violet in 20% ethanol, and colonies containing at ≥50 cells were counted (13,23,24). The plating efficiency of the untreated cells was 30-40%.…”

Section: Methodsmentioning

confidence: 99%

High expression of GADD-45α and VEGF induced tumor recurrence via upregulation of IL-2 after photodynamic therapy using NPe6

Ohtani

Usuda²,

Ichinose³

et al. 2008

Int J Oncol

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Abstract. NPe6 is a novel second-generation photosensitizer used for photodynamic therapy (PDT). PDT using NPe6 and diode laser (664 nm) induces cell death, inflammatory reactions, immunological responses and damage to the microvasculature. In this study, we evaluated the influence of the immunological responses and of enhanced angiogenesis on the anti-tumor effect of NPe6-PDT using cytokine-overexpressing Lewis lung carcinoma (LLC), LLC-IL-2 cells both in vitro and in vivo. We showed by DNA microarray analysis in vitro that IL-2 and GADD-45α (growth arrest and DNA damage 45 alpha) mRNA expressions were induced by 3 h after NPe6-PDT applied at a dose killing 90% of the cells (LD 90 ). IL-2-overexpressing cells (LLC/IL-2 cells) were resistant to the loss of clonogenicity as compared to the parental LLC cells in vitro. Furthermore, in female C57BL/6 mice, NPe6-PDT produced a cure rate of 66.7% in LLC tumors, whereas the cure rate was only 16.6% in LLC/IL-2 tumors, and overexpression of IL-2 caused failure of NPe6-PDT, with tumor recurrence, in vivo. These results suggest that IL-2 expression may play an unfavorable role in attenuation of the antitumor effect of NPe6-PDT. It has been reported that the expression of vascular endothelial growth factor (VEGF), in particular, may cause tumor recurrence after PDT and exert unfavorable effect in relation to attenuate the anti-tumor activity of PDT. Results of immunohistochemical analysis of LLC/IL-2 tumors have revealed that the expressions of GADD-45α and VEGF are induced in these tumors after PDT, and in particular, 12 h after PDT, the expression levels were much higher as compared with those in the LLC tumors. The results of our studies using in vitro and in vivo models suggest that the cell death caused by PDT was inhibited by induction of GADD-45α expression and that tumor recurrence was promoted by the enhancement of VEGF expression mediated by IL-2 upregulation. Therefore, it is speculated that the use of an IL-2 inhibitor may improve the efficacy of NPe6-PDT.

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Lysosomal cathepsin initiates apoptosis, which is regulated by photodamage to Bcl-2 at mitochondria in photodynamic therapy using a novel photosensitizer, ATX-s10 (Na)

Cited by 38 publications

References 21 publications

Photoactivation of 9-hydroxypheophorbide α triggers apoptosis through the reactive oxygen species-mediated mitochondrial pathway and endoplasmic reticulum stress in AMC-HN-3 laryngeal cancer cells

Photoactivation of 9-hydroxypheophorbide α triggers apoptosis through the reactive oxygen species-mediated mitochondrial pathway and endoplasmic reticulum stress in AMC-HN-3 laryngeal cancer cells

Lysosomal membrane permeabilization in cell death

High expression of GADD-45α and VEGF induced tumor recurrence via upregulation of IL-2 after photodynamic therapy using NPe6

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