Hinokiflavone induces apoptosis in melanoma cells through the ROS-mitochondrial apoptotic pathway and impairs cell migration and invasion

Yang, Shuping; Zhang, Yange; Luo, Yi; Xu, Bocheng; Yao, Yuqin; Deng, Yuanle; Yang, Fangfang; Ye, Tinghong; Wang, Gang; Cheng, Zhiqiang; Zheng, Yu; Xie, Yongmei

doi:10.1016/j.biopha.2018.02.076

Cited by 35 publications

(22 citation statements)

References 41 publications

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“…This cycle of mitochondrial dysfunction, ER stress, and increasing ROS levels, ultimately results in apoptosis. Similar to our findings, numerous ROS‐inducing natural compounds have been developed to target a variety of cancers, which are also shown to induce S‐phase arrest due to oxidative stress and DNA damage from high levels of free radicals . These effects appear to be cancer‐specific due to existing oxidative stress.…”

Section: Discussionsupporting

confidence: 87%

The novel capsazepine analog, CIDD‐99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV1‐independent induction of ER stress, mitochondrial dysfunction, and apoptosis

Chapa

Singha

Self

et al. 2019

J Oral Pathology Medicine

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Background Oral squamous cell carcinoma (OSCC) is a deadly disease with a mere 40% five‐year survival rate for patients with advanced disease. Previously, we discovered that capsazepine (CPZ), a transient receptor potential channel, Vanilloid subtype 1 (TRPV1) antagonist, has significant anti‐tumor effects against OSCC via a unique mechanism‐of‐action that is independent of TRPV1. Thus, we developed novel CPZ analogs with more potent anti‐proliferative effects (CIDD‐24, CIDD‐99, and CIDD‐111). Methods Using OSCC xenograft models, we determined the efficacy of these analogs in vivo. TRPV1 interactions were evaluated using calcium imaging and a rat model of orofacial pain. Anti‐cancer mechanism(s)‐of‐action were assessed by cell cycle analysis and mitochondrial depolarization assays. Results CIDD‐99 was the most potent analog demonstrating significant anti‐tumor effects in vivo (P < 0.001). CIDD‐24 was equipotent to the parent compound CPZ, but less potent than CIDD‐99. CIDD‐111 was the least efficacious analog. Calcium imaging studies confirmed that CIDD‐99 neither activates nor inhibits TRPV1 confirming that TRPV1 activity is not involved in its anti‐cancer effects. All analogs induced an S‐phase block, dose‐dependent mitochondrial depolarization, and apoptosis. Histological analyses revealed increased apoptosis and reduced cell proliferation in tumors treated with these analogs. Importantly, CIDD‐99 had the most dramatic anti‐tumor effects with 85% of tumors resolving leaving only minute traces of viable tissue. Additionally, CIDD‐99 was non‐noxious and demonstrated no observable adverse reactions Conclusion This study describes a novel, highly efficacious, CPZ analog, CIDD‐99, with dramatic anti‐tumor effects against OSCC that may be efficacious as a lone therapy or in combination with standard therapies.

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Section: Discussionsupporting

confidence: 87%

The novel capsazepine analog, CIDD‐99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV1‐independent induction of ER stress, mitochondrial dysfunction, and apoptosis

Chapa

Singha

Self

et al. 2019

J Oral Pathology Medicine

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“…These differences between A375 and B16 cells may have occurred due to the varying sensitivities of the two cell types. The different responses to pectolinarigenin in A375 and B16 melanoma cells from different species are supported by a previous study Yang et al (33) have demonstrated that the ROS level in A375 cells treated with hinokiflavone was notably increased, whereas that in B16 cells was first increased and then decreased, and loss of ΔΨm and unbalanced the level of ROS in both A375 and B16 cells was observed. Therefore, it is possible that the ROS-mediated mitochondrial apoptotic pathway is involved in melanoma cell death induced by pectolinarigenin.…”

Section: Discussionsupporting

confidence: 77%

Pectolinarigenin inhibits cell viability, migration and invasion and induces apoptosis via a ROS‑mitochondrial apoptotic pathway in melanoma cells

Deng

Zhang

et al. 2020

Oncol Lett

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Pectolinarigenin a plant secondary metabolite that has various biological effects, including the inhibition of melanogenesis and tumor growth. Melanoma has a high degree of malignancy, with rapid metastasis and severe drug resistance, explaining the need for new candidate drugs that inhibit tumor growth and metastasis. However, the pharmacological action and mechanism of pectolinarigenin on the growth and metastasis of melanoma remain elusive. Thus, the present study aimed to investigate the role of pectolinarigenin in melanoma cell proliferation, apoptosis, migration and invasion. Apoptotic and metastasis-associated proteins were analyzed using western blotting. The results demonstrated that pectolinarigenin treatment resulted in growth inhibition and apoptosis induction in melanoma cells, arising from the loss of mitochondrial transmembrane potential, reactive oxygen species and the altered expression of apoptosis-associated proteins. In addition, wound-healing and Transwell assays demonstrated the potential of pectolinarigenin to impair the migration and invasion of melanoma cells in accordance with the changes in the expression of the associated proteins. Therefore, the results of the present study suggested that pectolinarigenin may serve a pivotal role in promoting melanoma cell apoptosis and reducing metastasis, and may thus be a promising potential candidate for an anti-melanoma treatment strategy.

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“…Hinokiflavone is a naturally derived bioflavanoid known to possess anti-inflammatory, antioxidant and antitumour activity. Several mechanisms have been proposed for the pharmacological activities of Hinokiflavone including inhibition of mRNA spliceosome, activation of mitochondrial ROS/JNK/caspase signaling pathway, as well as inhibition of Matrix Metalloproteinase 9 [17][18][19][20]. This study presented a novel mechanism for Hinokiflavone mediated anti-cancer potential through inhibition and destabilization of MDM2 to promote cancer cell apoptosis and growth arrest.…”

Section: Discussionmentioning

confidence: 89%

An Integrated Structure-based Approach for the Development of MDM2 inhibitors

Sheng

2021

Proceedings of the 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Dam

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MDM2 is an oncogenic RING domain E3 ubiquitin ligase found to be overexpressed in a number of human cancers, leading to poor prognosis. MDM2 negatively regulates the tumour suppressor p53 through ubiquitination of p53 and tagging it for proteasomal degradation. MDM2 also exhibits p53-independent oncogenic. Thus, inhibition of MDM2 in cancer cells could be a desired strategy in anti-cancer therapeutic development. Bioflavonoid Hinokiflavone was identified through an in silico screening targeting the MDM2 catalytic RING domain. Hinokiflavone was shown to physically bind the recombinant MDM2: MDMX RING domain heterodimer, and inhibit MDM2-mediated ubiquitination. This study provided biochemical and cellular evidence suggesting Hinokiflavone is a promising small molecule with anti-cancer effects through targeting MDM2.

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Hinokiflavone induces apoptosis in melanoma cells through the ROS-mitochondrial apoptotic pathway and impairs cell migration and invasion

Cited by 35 publications

References 41 publications

The novel capsazepine analog, CIDD‐99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV1‐independent induction of ER stress, mitochondrial dysfunction, and apoptosis

The novel capsazepine analog, CIDD‐99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV1‐independent induction of ER stress, mitochondrial dysfunction, and apoptosis

Pectolinarigenin inhibits cell viability, migration and invasion and induces apoptosis via a ROS‑mitochondrial apoptotic pathway in melanoma cells

An Integrated Structure-based Approach for the Development of MDM2 inhibitors

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