Melatonin synergizes BRAF‐targeting agent dabrafenib for the treatment of anaplastic thyroid cancer by inhibiting AKT/hTERT signalling

Liao, Yun; Gao, Yao; Chang, An‐Chen; Li, Zongjuan; Wang, Huayu; Cao, Jing; Gu, Wei; Tang, Ranran

doi:10.1111/jcmm.15854

Cited by 14 publications

(8 citation statements)

References 49 publications

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“…As expected, both the apoptotic rate and G0/G1 cell cycle arrest were increased in cells that received combinatorial treatment of melatonin and thapsigargin via triggering ER stress. In fact, melatonin has been shown to exhibit more promising antitumour effect when combining with a wide range of drugs, including dabrafenib, 32 shikonin, 33 valproic acid 17 and cisplatin 34 . These evidences suggested that combinatorial treatment is an effective approach to enhance the capability of melatonin to combat cancer.…”

Section: Discussionmentioning

confidence: 99%

Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras‐Raf‐MAPK signalling

Huang

Yuan

Tang

et al. 2020

J Cellular Molecular Medi

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Melatonin exhibits antitumour activities in the treatment of many human cancers. In the present study, we aimed to improve the therapeutic potential of melatonin in gastric cancer. Our results confirmed that melatonin dose‐dependently suppressed the proliferation and necrosis, and increased G0/G1 phase arrest, apoptosis, autophagy and endoplasmic reticulum (ER) stress. The Ras‐Raf‐MAPK signalling pathway was activated in cells after melatonin treatment. RNA‐seq was performed and GSEA analysis further confirmed that many down‐regulated genes in melatonin‐treated cells were associated with proliferation. However, GSEA analysis also indicated that many pathways related to metastasis were increased after melatonin treatment. Subsequently, combinatorial treatment was conducted to further investigate the therapeutic outcomes of melatonin. A combination of melatonin and thapsigargin increased the apoptotic rate and G0/G1 cell cycle arrest when compared to treatment with melatonin alone. Melatonin in combination with thapsigargin triggered the increased expression of Bip, LC3‐II, phospho‐Erk1/2 and phospho‐p38 MAPK. In addition, STF‐083010, an IRE1a inhibitor, further exacerbated the decrease in survival rate induced by combinatorial treatment with melatonin and thapsigargin. Collectively, melatonin was effective in gastric cancer treatment by modifying ER stress.

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Section: Discussionmentioning

confidence: 99%

Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras‐Raf‐MAPK signalling

Huang

Yuan

Tang

et al. 2020

J Cellular Molecular Medi

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show abstract

“…There is a large amount of evidence on the benefits of melatonin in anticancer properties including its pro-apoptotic, anti-proliferative, anti-angiogenic, and anti-metastatic properties [ 11 , 12 , 13 ]. Melatonin also has a synergistic effect with different chemotherapeutic drugs [ 14 , 15 , 16 ]. In the clinical study, NSCLC patients concomitantly treated with melatonin exhibited better survival outcomes compared to those treated with chemotherapy alone [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Downregulates PD-L1 Expression and Modulates Tumor Immunity in KRAS-Mutant Non-Small Cell Lung Cancer

Chao

Lee

et al. 2021

IJMS

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Non-small cell lung cancer (NSCLC) patients harboring a KRAS mutation have unfavorable therapeutic outcomes with chemotherapies, and the mutation also renders tolerance to immunotherapies. There is an unmet need for a new strategy for overcoming immunosuppression in KRAS-mutant NSCLC. The recently discovered role of melatonin demonstrates a wide spectrum of anticancer impacts; however, the effect of melatonin on modulating tumor immunity is largely unknown. In the present study, melatonin treatment significantly reduced cell viability accompanied by inducing cell apoptosis in KRAS-mutant NSCLC cell lines including A549, H460, and LLC1 cells. Mechanistically, we found that lung cancer cells harboring the KRAS mutation exhibited a higher level of programmed death ligand 1 (PD-L1). However, treatment with melatonin substantially downregulated PD-L1 expressions in both the presence and absence of interferon (IFN)-γ stimulation. Moreover, KRAS-mutant lung cancer cells exhibited higher Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) levels, and PD-L1 expression was positively correlated with YAP and TAZ in lung cancer cells. Treatment with melatonin effectively suppressed YAP and TAZ, which was accompanied by downregulation of YAP/TAZ downstream gene expressions. The combination of melatonin and an inhibitor of YAP/TAZ robustly decreased YAP and PD-L1 expressions. Clinical analysis using public databases revealed that PD-L1 expression was positively correlated with YAP and TAZ in patients with lung cancer, and PD-L1 overexpression suggested poor survival probability. An animal study further revealed that administration of melatonin significantly inhibited tumor growth and modulated tumor immunity in a syngeneic mouse model. Together, our data revealed a novel antitumor mechanism of melatonin in modulating the immunosuppressive tumor microenvironment by suppressing the YAP/PD-L1 axis and suggest the therapeutic potential of melatonin for treating NSCLC.

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“…Moreover, co-administration of BRAF-directed agents with other drugs, like check point inhibitors (pembrolizumab), may prolong survival of patients [ 152 ]. In in vitro studies, exposure of BRAF V600E-positive ATC cell lines to dabrafenib and melatonin showed synergistic inhibition of hTERT, and in consequence, cell arrest in the G1 phase and decreased cell viability [ 153 ]. Similarly, usage of another SKI, vemurafenib with a STAT3 pathway inhibitor on ATC-derived cell lines (sphere and monolayer) and mouse xenografts resulted in decreased viability and increased rate of cell apoptosis.…”

Section: Currently Used and Investigated Targeted Therapies In Tcsmentioning

confidence: 99%

Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

Ratajczak

Gawel

Godlewska

2021

IJMS

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Thyroid cancers (TCs) are the most common tumors of the endocrine system and a constant rise in the number of TC cases has been observed for the past few decades. TCs are one of the most frequent tumors in younger adults, especially in women, therefore early diagnosis and effective therapy are especially important. Ultrasonography examination followed by fine needle biopsy have become the gold standard for diagnosis of TCs, as these strategies allow for early-stage detection and aid accurate qualification for further procedures, including surgical treatment. Despite all the advancements in detection and treatment of TCs, constant mortality levels are still observed. Therefore, a novel generation line of targeted treatment strategies is being developed, including personalized therapies with kinase inhibitors. Recent molecular studies on TCs demonstrate that kinase inhibitor-based therapies might be considered as the most promising. In the past decade, new kinase inhibitors with different mechanisms of action have been reported and approved for clinical trials. This review presents an up-to-date picture of new approaches and challenges of inhibitor-based therapies in treatment of TCs, focusing on the latest findings reported over the past two years.

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Melatonin synergizes BRAF‐targeting agent dabrafenib for the treatment of anaplastic thyroid cancer by inhibiting AKT/hTERT signalling

Cited by 14 publications

References 49 publications

Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras‐Raf‐MAPK signalling

Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras‐Raf‐MAPK signalling

Melatonin Downregulates PD-L1 Expression and Modulates Tumor Immunity in KRAS-Mutant Non-Small Cell Lung Cancer

Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

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