Cited by 173Antioxidant Activity and Oxidative StressCancer and biochemical researchCell death mechanisms and regulation

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Pro-oxidant Actions of Carotenoids in Triggering Apoptosis of Cancer Cells: A Review of Emerging Evidence

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Shin, Juhyun, Song, Min-Ho, Oh, Jae-Wook, Keum, Young-Soo, Saini, Ramesh Kumar·2020·Antioxidants

Abstract

Carotenoids are well known for their potent antioxidant function in the cellular system. However, in cancer cells with an innately high level of intracellular reactive oxygen species (ROS), carotenoids may act as potent pro-oxidant molecules and trigger ROS-mediated apoptosis. In recent years, the pro-oxidant function of several common dietary carotenoids, including astaxanthin, β-carotene, fucoxanthin, and lycopene, has been investigated for their effective killing effects on various cancer cell lines. Besides, when carotenoids are delivered with ROS-inducing cytotoxic drugs (e.g., anthracyclines), they can minimize the adverse effects of these drugs on normal cells by acting as antioxidants without interfering with their cytotoxic effects on cancer cells as pro-oxidants. These dynamic actions of carotenoids can optimize oxidative stress in normal cells while enhancing oxidative stress in cancer cells. This review discusses possible mechanisms of carotenoid-triggered ROS production in cancer cells, the activation of pro-apoptotic signaling by ROS, and apoptotic cell death. Moreover, synergistic actions of carotenoids with ROS-inducing anti-cancer drugs are discussed, and research gaps are suggested.

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Crossref · 10.3390/antiox9060532

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Figure 1 An outline of major differences in cellular metabolism between normal and cancer cells. Under pre-existence conditions of high oxidative stress in cancer cells, carotenoids predominantly function as pro-oxidants, resulting in the ROS-triggered apoptosis of cancer cells.
Figure 1 An outline of major differences in cellular metabolism between normal and cancer cells. Under pre-existence conditions of high oxidative stress in cancer cells, carotenoids predominantly function as pro-oxidants, resulting in the ROS-triggered apoptosis of cancer cells.CC BY · PubMed Central
Figure 2 Possible routes of carotenoids-triggered reactive oxygen species (ROS) production in cancer cells.
Figure 2 Possible routes of carotenoids-triggered reactive oxygen species (ROS) production in cancer cells.CC BY · PubMed Central
Figure 3 Key pro-apoptotic and anti-apoptotic factors regulated by enhanced reactive oxygen species (ROS) levels, mediated by pro-oxidant effects of carotenoids. Bcl-2: B-cell lymphoma 2; Bak: Bcl-2 homologous antagonist/killer; Bax: Bcl-2-associated X protein; Bcl-xL: Bcl-extra-large; Bim: Bcl-2-like protein 11; NF-kB: Nuclear factor-κB; PARP: poly (ADP-ribose) polymerase.
Figure 3 Key pro-apoptotic and anti-apoptotic factors regulated by enhanced reactive oxygen species (ROS) levels, mediated by pro-oxidant effects of carotenoids. Bcl-2: B-cell lymphoma 2; Bak: Bcl-2 homologous antagonist/killer; Bax: Bcl-2-associated X protein; Bcl-xL: Bcl-extra-large; Bim: Bcl-2-like protein 11; NF-kB: Nuclear factor-κB; PARP: poly (ADP-ribose) polymerase.CC BY · PubMed Central
Figure 4 Major routes of p53 activation triggered by carotenoids-mediated reactive oxygen species (ROS)-induced. (A) E3 ubiquitin ligases MDM2 and MDM4 mediated proteasomal degradation in non-stress cells; (B) Kinases-mediated activation in cancer cells, and (C) Direct redox activation by S-glutathionylation of redox-sensitive cysteine residues at 124, 135, 141, and 277 of DNA-binding domain. ATM: ataxia telangiectasia mutated; ATR: ataxia telangiectasia and Rad3 related (a serine/threonine-protein kinase); DNA-PK: DNA-dependent protein kinase.
Figure 4 Major routes of p53 activation triggered by carotenoids-mediated reactive oxygen species (ROS)-induced. (A) E3 ubiquitin ligases MDM2 and MDM4 mediated proteasomal degradation in non-stress cells; (B) Kinases-mediated activation in cancer cells, and (C) Direct redox activation by S-glutathionylation of redox-sensitive cysteine residues at 124, 135, 141, and 277 of DNA-binding domain. ATM: ataxia telangiectasia mutated; ATR: ataxia telangiectasia and Rad3 related (a serine/threonine-protein kinase); DNA-PK: DNA-dependent protein kinase.CC BY · PubMed Central
Figure 5 Mechanisms of the carotenoids-mediated p53-induced apoptosis of cancer cells. Bcl-2: B-cell lymphoma 2; Bad: Bcl-2-associated agonist of cell death; Bak: Bcl-2 homologous antagonist/killer; Bax: Bcl-2-associated X protein; Bcl-xL: Bcl-extra-large; Bid: BH3 interacting-domain death agonist; Bim: Bcl-2-like protein 11; Noxa: Latin for damage, also known as phorbol-12-myristate-13-acetate-induced protein PMAIP1; PARP: poly (ADP-ribose) polymerase.
Figure 5 Mechanisms of the carotenoids-mediated p53-induced apoptosis of cancer cells. Bcl-2: B-cell lymphoma 2; Bad: Bcl-2-associated agonist of cell death; Bak: Bcl-2 homologous antagonist/killer; Bax: Bcl-2-associated X protein; Bcl-xL: Bcl-extra-large; Bid: BH3 interacting-domain death agonist; Bim: Bcl-2-like protein 11; Noxa: Latin for damage, also known as phorbol-12-myristate-13-acetate-induced protein PMAIP1; PARP: poly (ADP-ribose) polymerase.CC BY · PubMed Central

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Metadata

Authors
Shin, J., Song, M.-H., Oh, J.-W., Keum, Y.-S., & Saini, R. K.
Affiliations
  • Konkuk University (KR)
  • Department of Crop Science, Konkuk University, Seoul 143-701, Korea
Corresponding author
Saini, Ramesh Kumar
Venue
Antioxidants
Publisher
MDPI AG
Published
2020-06-17
Volume
9
Issue
6
Pages
532
ISSN
2076-3921 (ISSN-L)
OpenAlex
W3036006354
Cited by
173
References
67
Citations by year
2026: 18 · 2025: 25 · 2024: 30 · 2023: 32 · 2022: 33 · 2021: 28 · 2020: 7
FWCI
2.19
Type
journal article
Language
en
Open access
Locations
  • Antioxidants (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Research Foundation of Korea (2019R1G1A1006815)
Topics
  • Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
carotenoids, pro-oxidant activity, reactive oxygen species, apoptosis, cancer cells, astaxanthin, beta-carotene, fucoxanthin, lycopene, anthracyclines, oxidative stress, pro-apoptotic signaling, drug synergy, dietary carotenoids

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