Induction of EnR stress by Melatonin enhances the cytotoxic effect of Lapatinib in HER2-positive breast cancer

Sang, Xiaolin; Li, Li; Rui, Chunhua; Liu, Yichao; Liu, Zundong; Zhou, Tao; Cheng, Hai‐Ling Margaret; Liu, Pixu

doi:10.1016/j.canlet.2021.06.011

Cited by 19 publications

(17 citation statements)

References 37 publications

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“…In oral squamous cell carcinomas (OSCCs), melatonin enhances ROS production and DNA damage to prevent OSCCs’ initiation and progression [ 78 ]. Similar functions were verified in colorectal cancer [ 79 ] and breast cancer [ 80 ]. These two studies further illustrate that ROS-mediated endoplasmic reticulum stress (EnR) is involved in the apoptosis caused by ROS overaccumulation.…”

Section: Anticancer Effect Of Melatoninsupporting

confidence: 61%

Use of Melatonin in Cancer Treatment: Where Are We?

Wang

Choi

2022

IJMS

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Cancer represents a large group of diseases accounting for nearly 10 million deaths each year. Various treatment strategies, including surgical resection combined with chemotherapy, radiotherapy, and immunotherapy, have been applied for cancer treatment. However, the outcomes remain largely unsatisfying. Melatonin, as an endogenous hormone, is associated with the circadian rhythm moderation. Many physiological functions of melatonin besides sleep–wake cycle control have been identified, such as antioxidant, immunomodulation, and anti-inflammation. In recent years, an increasing number of studies have described the anticancer effects of melatonin. This has drawn our attention to the potential usage of melatonin for cancer treatment in the clinical setting, although huge obstacles still exist before its wide clinical administration is accepted. The exact mechanisms behind its anticancer effects remain unclear, and the specific characters impede its in vivo investigation. In this review, we will summarize the latest advances in melatonin studies, including its chemical properties, the possible mechanisms for its anticancer effects, and the ongoing clinical trails. Importantly, challenges for the clinical application of melatonin will be discussed, accompanied with our perspectives on its future development. Finally, obstacles and perspectives of using melatonin for cancer treatment will be proposed. The present article will provide a comprehensive foundation for applying melatonin as a preventive and therapeutic agent for cancer treatment.

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Section: Anticancer Effect Of Melatoninsupporting

confidence: 61%

Use of Melatonin in Cancer Treatment: Where Are We?

Wang

Choi

2022

IJMS

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“…In addition, when co-administered with estradiol-progesterone therapy or Metformin, Melatonin reduced tumor incidence and metastatic burden in the animal model of HER2 + breast cancer [ 36 – 38 ]. However, while these and our findings have reported the potential therapeutic effects of Melatonin in the setting of HER2 + breast cancer [ 34 – 39 ], the impact of Melatonin on HER2 expression per se has not been previously reported.…”

Section: Discussionmentioning

confidence: 54%

“…We recently deposited the RNA-seq dataset to the Gene Expression Omnibus (GEO) with accession number GSE175906 [ 39 ]. Heatmap showing the expression of leading-edge subsets of gene sets using Omicshare ( https://www.omicshare.com/tools/Home/Soft/heatmap ).…”

Section: Methodsmentioning

confidence: 99%

Melatonin potentiates the cytotoxic effect of Neratinib in HER2+ breast cancer through promoting endocytosis and lysosomal degradation of HER2

et al. 2021

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Complete blockade of the HER2 protein itself and HER signaling network is critical to achieving effective HER2-targeted therapies. Despite the success of HER2-targeted therapies, the diseases will relapse in a significant fraction of patients with HER2+ breast cancers. How to improve the therapeutic efficacy of existing HER2-targeted agents remains an unmet clinical need. Here, we uncover a role of Melatonin in diminishing HER2-mediated signaling by destruction of HER2 protein. Mechanistically, Melatonin treatment attenuated the protective effect of the HSP90 chaperone complex on its client protein HER2, triggering ubiquitylation and subsequent endocytic lysosomal degradation of HER2. The inhibitory effect of Melatonin on HER2 signaling substantially enhanced the cytotoxic effects of the pan-HER inhibitor Neratinib in HER2+ breast cancer cells. Lastly, we demonstrate that dual inhibition of HER2 by combined use of Melatonin and Neratinib effectively blocked the growth of HER2+ breast tumor xenografts in vivo. Our findings shed light on the potential use of Melatonin in a novel dual HER2 blockade strategy for HER2+ breast cancer treatment.

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“…In this sense, melatonin has been previously shown to synergistically enhance antitumor function in tunicamycin-challenged MDA-MB-231 cells [ 32 ], which is in line with the results reported in this paper. The potentiating actions of melatonin on apoptosis induction by classical drugs, such as doxorubicin, lapatinib, and arsenic trioxide, has been also documented in breast cancer cell lines [ 33 , 34 , 35 , 36 ] and may be related to its pro-oxidant capacity in tumor cells [ 36 ]. To corroborate the combinatorial effect of PtDPhPzTn and melatonin in MDA-MB-231 cells, 5, 10, and 25 µM of the platinum(II) complex and 0.5, 1, and 2 mM of the indoleamine were combined and cell death was determined after 24 h to calculate the CI values ( Figure S1 ).…”

Section: Resultsmentioning

confidence: 99%

Pro-Apoptotic and Anti-Migration Properties of a Thiazoline-Containing Platinum(II) Complex in MDA-MB-231 Breast Cancer Cells: The Role of Melatonin as a Synergistic Agent

et al. 2022

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Triple-negative breast cancer (TNBC) is an aggressive cancer insensitive to hormonal and human epidermal growth factor receptor 2 (HER2)-targeted therapies and has a poor prognosis. Therefore, there is a need for the development of convenient anticancer strategies for the management of TNBC. In this paper, we evaluate the antitumoral potential of a platinum(II) complex coordinated with the ligand 2-(3,5-diphenylpyrazol-1-yl)-2-thiazoline (DPhPzTn), hereafter PtDPhPzTn, against the TNBC cell line MDA-MB-231, and compared its effect with both cisplatin and its less lipophilic counterpart PtPzTn, the latter containing the ligand 2-(pyrazol-1-yl)-2-thiazoline (PzTn). Then, the putative potentiating actions of melatonin, a naturally occurring antioxidant with renowned antitumor properties, on the tumor-killing ability of PtDPhPzTn were also checked in TNBC cells. Our results show that PtDPhPzTn presented enhanced cytotoxicity compared to both the classical drug cisplatin and PtPzTn. In addition, PtDPhPzTn was able to induce apoptosis, being more selective for MDA-MB-231 cells when compared to non-tumor breast epithelial MCF10A cells. Likewise, PtDPhPzTn produced moderate S phase arrest and greatly impaired the migration ability of MDA-MB-231 cells. Most importantly, the co-stimulation of TNBC cells with PtDPhPzTn and melatonin substantially enhanced apoptosis and markedly improved the anti-migratory action compared to PtDPhPzTn alone. Altogether, our findings provide evidence that PtDPhPzTn and melatonin could be potentially applied to breast cancer treatment as powerful synergistic agents.

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Induction of EnR stress by Melatonin enhances the cytotoxic effect of Lapatinib in HER2-positive breast cancer

Cited by 19 publications

References 37 publications

Use of Melatonin in Cancer Treatment: Where Are We?

Use of Melatonin in Cancer Treatment: Where Are We?

Melatonin potentiates the cytotoxic effect of Neratinib in HER2+ breast cancer through promoting endocytosis and lysosomal degradation of HER2

Pro-Apoptotic and Anti-Migration Properties of a Thiazoline-Containing Platinum(II) Complex in MDA-MB-231 Breast Cancer Cells: The Role of Melatonin as a Synergistic Agent

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