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Induction of ferroptosis by photodynamic therapy and enhancement of antitumor effect with ferroptosis inducers

  • Original Article—Alimentary Tract
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Abstract

Background

Photodynamic therapy (PDT) is an effective tumor treatment that involves the administration of a photosensitizer to generate cytotoxic 1O2 [reactive oxygen species (ROS)] from molecular oxygen that is produced from energy absorption following tumor irradiation at specific wavelengths. Ferroptosis is induced by the disruption of the glutathione peroxidase 4 (GPX4) antioxidant system, leading to lipid peroxidation. We hypothesized that talaporfin sodium-photodynamic therapy (TS-PDT)-generated ROS would lead to ferroptosis via accumulation of lipid peroxidation.

Methods

Cell viability assay in TS-PDT-treated cells in combination with a ferroptosis inhibitor (ferrostatin-1: Fer-1) or ferroptosis inducers (imidazole ketone erastin: IKE, Ras-selective lethal 3: RSL3) was performed. Accumulation of lipid peroxidation, GPX4 antioxidant system and cystine/glutamate antiporter (system xc−) activity in TS-PDT-treated cells was investigated. In xenograft mice, the antitumor effect of TS-PDT in combination with ferroptosis inducers (IKE or sorafenib) was examined.

Results

TS-PDT-induced cell death was partly suppressed by Fer-1 and accompanied by lipid peroxidation. TS-PDT combined with IKE or RSL3 enhanced the induction of cell death. TS-PDT inhibited cystine uptake activity via system xc−. In vivo, the combination of TS-PDT and ferroptosis inducers (IKE or sorafenib) reduced tumor volume.

Conclusion

This study found that the mechanism underlying TS-PDT-induced ferroptosis constitutes direct lipid peroxidation by the generated ROS, and the inhibition of system xc−, and that the combination of a ferroptosis inducer with TS-PDT enhances the antitumor effect of TS-PDT. Our findings suggest that ferroptosis-inducing therapies combined with PDT may benefit cancer patients.

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Abbreviations

ATM:

Ataxia telangiectasia-mutated

FBS:

Fetal bovine serum

Fer-1:

Ferrostatin-1

FSP1:

Ferroptosis suppressor protein 1

GSH:

Reduced glutathione

GPX4:

Glutathione peroxidase 4

IKE:

Imidazole ketone erastin

MDA:

Malondialdehyde

NAC:

N-Acetylcysteine

NADPH:

Nicotinamide adenine dinucleotide phosphate hydrogen

Nec-1s:

Necrostatin-1s

PBS:

Phosphate-buffered saline

PDT:

Photodynamic therapy

PUFAs:

Polyunsaturated fatty acids

RIPK:

Receptor-interacting protein kinase

ROS:

Reactive oxygen species

RSL3:

Ras-selective lethal 3

SLC3A2:

Solute carrier family 3 member 2

SLC7A11:

Solute carrier family 7 member 11

TBARS:

Thiobarbituric acid-reactive substance

TS:

Talaporfin sodium

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Acknowledgements

We would like to thank Suzuka Asai and Yukimi Ito for their technical assistance. We are grateful for the assistance of the Research Equipment Sharing Center at the Nagoya City University.

Funding

This work was partially supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (2020–2022) (grant number 20K08361) (to M. Tanaka); JSPS KAKENHI (2023–2025) (grant number 23K07358) (to M. Tanaka); Toyoaki Scholarship Foundation (2022–2023) (grant number JOSE203179) (to M. Tanaka); Iketani Science and Technology Foundation (2022–2023) (grant number JOSE204007) (to M. Tanaka); JSPS KAKENHI (2022–2023) (grant number 22K20862) (to M. Sasaki); Grant from Bristol Myers Squibb (grant number JOSE202103) (to H. Kataoka) and JSPS KAKENHI (2023–2025) (grant number 23K07421) (to H. Kataoka); JSPS KAKENHI (2023–2024) (grant number 23K15019) (to M. Sasaki). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan

    Yuki Kojima, Mamoru Tanaka, Makiko Sasaki, Keiji Ozeki, Takaya Shimura, Eiji Kubota & Hiromi Kataoka

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  1. Yuki Kojima
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  2. Mamoru Tanaka
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Contributions

All the authors contributed to the study conception and design. Study design was performed by YK and MT. Material preparation, data collection, and analysis were performed by YK, MS and MT. The first draft of the manuscript was written by YK. Funding was acquired by MS, MT and HK. All the authors commented on the final manuscript and approved the final manuscript.

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Correspondence to Mamoru Tanaka.

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Our study was approved by the Animal Research Committee of the Nagoya City University (project number: 21-014).

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Kojima, Y., Tanaka, M., Sasaki, M. et al. Induction of ferroptosis by photodynamic therapy and enhancement of antitumor effect with ferroptosis inducers. J Gastroenterol 59, 81–94 (2024). https://doi.org/10.1007/s00535-023-02054-y

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