Melatonin and hyperbaric oxygen therapies suppress colorectal carcinogenesis through pleiotropic effects and multifaceted mechanisms

Li, Yi‐Chen; Chen, Chih‐Hung; Chang, Chia-Lo; Chiang, John Y.; Chu, Chi-Hsiang; Chen, Hong‐Hwa; Yip, Hon‐Kan

doi:10.7150/ijbs.62280

Cited by 15 publications

(9 citation statements)

References 63 publications

(67 reference statements)

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“…1,3 Notably, the effects of HBO exposures on Oct4 expression may vary depending on the cell types, as a 90-min HBO treatment has been reported to increase Oct4 mRNA expression in vitro in gingival mesenchymal stem cells within 24 h of the first exposure whereas decrease Oct4 protein levels in colorectal cancer cells after three times of the 90-min HBO exposures in vivo. 77,78 In contrast to the previous findings indicating that Oct4 promotes the upregulation of Nrf2 and antioxidant enzymes in mouse testicular and embryonic stem cells, 79,80 our study revealed an increase in Nrf2 expression in spite of a decrease in Oct4 expression at both the mRNA and protein levels in the preimplantation mouse blastocysts exposed to HBO for 3 days in vivo (Figures 3-5). This observation aligns with a previous study conducted in bovine embryos, which reported elevated NFE2L2 (Nrf2) and reduced POU5F1 (Oct4) mRNA levels in expanded blastocysts cultured under 20% O 2 in vitro for 7 days compared to those cultured under 5% O 2 .…”

Section: Discussioncontrasting

confidence: 99%

“…84,85 Both chronic HBO exposures in vivo and Nf2/Merlin-knockdown meningioma cells in vitro have shown a significant decrease in the phosphorylation and activation levels of Akt. 77,86 In light of these findings, it remains to be investigated whether HBO exposures lead to reduced Oct4 mRNA levels and percentages of Oct4 + ICM cells in mouse blastocysts by downregulating Akt phosphorylation due to Nf2 deficiency. This suggests a potential link between Nf2-associated Akt signaling and the regulation of Oct4 expression in response to HBO exposure, highlighting the need for further studies in this area.…”

Section: Discussionmentioning

confidence: 99%

“…It is well‐established that the Akt serine/threonine protein kinase plays a critical role in the self‐renewal of embryonic stem cells by phosphorylating Oct4 84,85 . Both chronic HBO exposures in vivo and Nf2/Merlin‐knockdown meningioma cells in vitro have shown a significant decrease in the phosphorylation and activation levels of Akt 77,86 . In light of these findings, it remains to be investigated whether HBO exposures lead to reduced Oct4 mRNA levels and percentages of Oct4 + ICM cells in mouse blastocysts by downregulating Akt phosphorylation due to Nf2 deficiency.…”

Section: Discussionmentioning

confidence: 99%

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Maternal exposure to hyperbaric oxygen at the preimplantation stages increases apoptosis and ectopic Cdx2 expression and decreases Oct4 expression in mouse blastocysts via Nrf2‐Notch1 upregulation and Nf2 downregulation

Li,

Chung,

et al. 2023

Developmental Dynamics

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BackgroundThe environmental oxygen tension has been reported to impact the blastocyst quality and cell numbers in the inner cell mass (ICM) during human and murine embryogenesis. While the molecular mechanisms leading to increased ICM cell numbers and pluripotency gene expression under hypoxia have been deciphered, it remains unknown which regulatory pathways caused the underweight fetal body and overweight placenta after maternal exposure to hyperbaric oxygen (HBO).ResultsThe blastocysts from the HBO‐exposed pregnant mice revealed significantly increased signals of reactive oxygen species (ROS) and nuclear Nrf2 staining, decreased Nf2 and Oct4 expression, increased nuclear Tp53bp1 and active caspase‐3 staining, and ectopic nuclear signals of Cdx2, Yap, and the Notch1 intracellular domain (N1ICD) in the ICM. In the ICM of the HBO‐exposed blastocysts, both Nf2 cDNA microinjection and Nrf2 shRNA microinjection significantly decreased the ectopic nuclear expression of Cdx2, Tp53bp1, and Yap whereas increased Oct4 expression, while Nrf2 shRNA microinjection also significantly decreased Notch1 mRNA levels and nuclear expression of N1ICD and active caspase‐3.ConclusionWe show for the first time that maternal exposure to HBO at the preimplantation stage induces apoptosis and impairs ICM cell specification via upregulating Nrf2‐Notch1‐Cdx2 expression and downregulating Nf2‐Oct4 expression.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Maternal exposure to hyperbaric oxygen at the preimplantation stages increases apoptosis and ectopic Cdx2 expression and decreases Oct4 expression in mouse blastocysts via Nrf2‐Notch1 upregulation and Nf2 downregulation

Li,

Chung,

et al. 2023

Developmental Dynamics

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“…Hyperbaric oxygen therapy and melatonin can alter the hypoxic microenvironment, resulting in decreased HIF-1α expression and diminished immune evasion in CRC. 170 Employing metformin as a method to improve hypoxic TME could increase TILs and enhance T-cell cytotoxicity activity, thus improving sensitivity to anti-PD-1 immunotherapy. 171 , 173 …”

Section: Targeting Hypoxia To Enhance the Efficacy Of Immunotherapy F...mentioning

confidence: 99%

Prediction of immunotherapy efficacy and immunomodulatory role of hypoxia in colorectal cancer

et al. 2022

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Immunotherapy has been used in the clinical treatment of colorectal cancer (CRC); however, most patients fail to achieve satisfactory survival benefits. Biomarkers with high specificity and sensitivity are being increasingly developed to predict the efficacy of CRC immunotherapy. In addition to DNA alteration markers, such as microsatellite instability/mismatch repair and tumor mutational burden, immune cell infiltration and immune checkpoints (ICs), epigenetic changes and no-coding RNA, and gut microbiomes all show potential predictive ability. Recently, the hypoxic tumor microenvironment (TME) has been identified as a key factor mediating CRC immune evasion and resistance to treatment. Hypoxia-inducible factor-1α is the central transcription factor in the hypoxia response that drives the expression of a vast number of survival genes by binding to the hypoxia response element in cancer and immune cells in the TME. Hypoxia regulates angiogenesis, immune cell infiltration and activation, expression of ICs, and secretion of various immune molecules in the TME and is closely associated with the immunotherapeutic efficacy of CRC. Currently, various agents targeting hypoxia have been found to improve the TME and enhance the efficacy of immunotherapy. We reviewed current markers commonly used in CRC to predict therapeutic efficacy and the mechanisms underlying hypoxia-induced angiogenesis and tumor immune evasion. Exploring the mechanisms by which hypoxia affects the TME will assist the discovery of new immunotherapeutic predictive biomarkers and development of more effective combinations of agents targeting hypoxia and immunotherapy.

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“…Melatonin (N-acetyl-5-methoxytryptamine) has been shown to have oncostatic effects in different types of cancers [4,7,8]. Previous studies have reported that melatonin regulates mitochondrial function [9] and drives apoptosis by increasing mitochondrial reactive oxygen species (ROS) in HNSCC [9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stress

Martínez-Ruiz

Florido

Rodríguez-Santana

et al. 2023

Preprint

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The prognosis of head and neck squamous cell carcinoma (HNSCC) remains poor, with a high mortality rate. Melatonin has been shown to have oncostatic effects in different types of cancers. However, inconsistent results have been reported for in vivo applications, which may depend on the low bioavailability of melatonin to the tumor. Consequently, an alternative administration route is needed to improve bioavailability and establish the optimal dosage of melatonin for cancer treatment. On the other hand, the use of patient-derived tumor tissues has transformed the field of drug research because they reflect the heterogeneity of patient tumor tissues. In the present study, we explore mechanisms for increasing melatonin bioavailability in tumors and investigate its potential as an adjuvant to improve the therapeutic efficacy of cisplatin (CDDP) in the setting of both xenotransplanted cell lines and primary human HNSCC. We analyzed the effect of two different formulations of melatonin administered subcutaneously or intratumorally in Cal-27 and SCC-9 xenografts and in patient-derived xenografts, which more closely resemble real tumors. In contrast to the results obtained with the subcutaneous administration of melatonin, intratumoral injection of melatonin drastically inhibited tumor progression in HNSCC-derived xenografts, as well as in patient-derived xenografts, suggesting that high doses of melatonin are necessary to exert its oncostatic effect. Interestingly, intratumoral injection of melatonin potentiated CDDP effects, decreasing Cal-27 tumor growth. Specifically, we demonstrated that melatonin increases ROS production and apoptosis in tumors, targeting tumor mitochondria, which had a more elongated morphology and cytoplasmic distribution than mitochondria in control tumors. Melatonin also reduces migration capacities and metastasis markers. These results illustrate the great clinical potential of intratumoral melatonin treatment and encourage a future clinical trial in cancer patients to establish a new melatonin treatment with proper clinical applications.

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Melatonin and hyperbaric oxygen therapies suppress colorectal carcinogenesis through pleiotropic effects and multifaceted mechanisms

Cited by 15 publications

References 63 publications

Maternal exposure to hyperbaric oxygen at the preimplantation stages increases apoptosis and ectopic Cdx2 expression and decreases Oct4 expression in mouse blastocysts via Nrf2‐Notch1 upregulation and Nf2 downregulation

Maternal exposure to hyperbaric oxygen at the preimplantation stages increases apoptosis and ectopic Cdx2 expression and decreases Oct4 expression in mouse blastocysts via Nrf2‐Notch1 upregulation and Nf2 downregulation

Prediction of immunotherapy efficacy and immunomodulatory role of hypoxia in colorectal cancer

Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stress

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