Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with Chloroquine

Ke, Xiangyu; Qin, Qingsong; Deng, Tianyi; Liao, Yueyan; Gao, Shou‐Jiang

doi:10.3390/cancers12020365

Cited by 14 publications

(6 citation statements)

References 57 publications

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“…Tenovin-6 is a potent activator of p53; interestingly, the sensitivity of Tenovin-6 to gastric cancer cell lines and the initiation of autophagy were not correlated with TP53 gene status. Meanwhile, CQ increased Tenovin-6-induced cell death also in a p53-independent manner [115].…”

Section: Gastric Cancermentioning

confidence: 98%

Triangular Relationship between p53, Autophagy, and Chemotherapy Resistance

Patel

Gewirtz

2020

IJMS

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Chemotherapy and radiation often induce a number of cellular responses, such as apoptosis, autophagy, and senescence. One of the major regulators of these processes is p53, an essential tumor suppressor that is often mutated or lost in many cancer types and implicated in early tumorigenesis. Gain of function (GOF) p53 mutations have been implicated in increased susceptibility to drug resistance, by compromising wildtype anti-tumor functions of p53 or modulating key p53 processes that confer chemotherapy resistance, such as autophagy. Autophagy, a cellular survival mechanism, is initially induced in response to chemotherapy and radiotherapy, and its cytoprotective nature became the spearhead of a number of clinical trials aimed to sensitize patients to chemotherapy. However, increased pre-clinical studies have exemplified the multifunctional role of autophagy. Additionally, compartmental localization of p53 can modulate induction or inhibition of autophagy and may play a role in autophagic function. The duality in p53 function and its effects on autophagic function are generally not considered in clinical trial design or clinical therapeutics; however, ample pre-clinical studies suggest they play a role in tumor responses to therapy and drug resistance. Further inquiry into the interconnection between autophagy and p53, and its effects on chemotherapeutic responses may provide beneficial insights on multidrug resistance and novel treatment regimens for chemosensitization.

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Section: Gastric Cancermentioning

confidence: 98%

Triangular Relationship between p53, Autophagy, and Chemotherapy Resistance

Patel

Gewirtz

2020

IJMS

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“…34 Among the 30 drugs screened in this study, the p53 transcriptional activity agonist Tenovin-6 exerts an antitumor effect by inhibiting the protein deacetylation activity of SirT1 and SirT2. 35 In addition, the activation of p53 also leads to proteasomal degradation of Mcl-1 through activation of GSK3, 29 perhaps inhibiting any Mcl-1 upregulation that may occur as a consequence of exposure to ABT-199 and may further confer the synergy seen in these experiments.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Drug Screen for Potential Combinations With Venetoclax Guides the Treatment of Transformed Follicular Lymphoma

Pan

Zhong

et al. 2023

Int J Toxicol

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Transformed follicular lymphoma (t-FL) is an aggressive malignancy that is refractory and rapidly progressing with poor prognosis. There is currently no effective treatment. High-throughput screening (HTS) platforms are used to profile the sensitivity or toxicity of hundreds of drug molecules, and this approach is applied to identify potential effective treatments for t-FL. We randomly selected a compound panel from the School of Pharmaceutical Sciences Xiamen University, tested the effects of the panel on the activity of t-FL cell lines using HTS and the CCK-8 assay, and identified compounds showing synergistic anti-proliferative activity with the Bcl-2 inhibitor venetoclax (ABT-199). Bioinformatics tools were used to analyze the potential synergistic mechanisms. The single-concentration compound library demonstrated varying degrees of activity across the t-FL cell lines evaluated, of which the Karpas422 cells were the most sensitive, but it was the cell line with the least synergy with ABT-199. We computationally identified 30 drugs with synergistic effects in all cell lines. Molecularly, we found that the targets of these 30 drugs didn’t directly regulate Bcl-2 and identified 13 medications with high evidence value above .9 of coordination with ABT-199, further confirming TP53 may play the largest role in the synergistic effect. Collectively, these findings identified the combined regimens of ABT-199 and further suggested that the mechanism is far from directly targeting Bcl-2, but rather through the regulation and synergistic action of p53 and Bcl-2. This study intended to reveal the best synergistic scheme of ABT-199 through HTS to more quickly inform the treatment of t-FL.

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“…Tenovin-1 and -6 inhibit SIRT-1 and SIRT-2 and decrease cell growth in Burkitt’s lymphoma and melanoma cells [ 193 ], gastric cancer cells [ 194 ], and NSCLC [ 195 ]. In addition, promising results were obtained in decreasing tumor growth in leukemia and melanoma [ 113 , 196 ].…”

Section: Sirtuins As Targets In Different Pathologiesmentioning

confidence: 99%

Virtual Screening in the Identification of Sirtuins’ Activity Modulators

et al. 2022

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Sirtuins are NAD+-dependent deac(et)ylases with different subcellular localization. The sirtuins’ family is composed of seven members, named SIRT-1 to SIRT-7. Their substrates include histones and also an increasing number of different proteins. Sirtuins regulate a wide range of different processes, ranging from transcription to metabolism to genome stability. Thus, their dysregulation has been related to the pathogenesis of different diseases. In this review, we discussed the pharmacological approaches based on sirtuins’ modulators (both inhibitors and activators) that have been attempted in in vitro and/or in in vivo experimental settings, to highlight the therapeutic potential of targeting one/more specific sirtuin isoform(s) in cancer, neurodegenerative disorders and type 2 diabetes. Extensive research has already been performed to identify SIRT-1 and -2 modulators, while compounds targeting the other sirtuins have been less studied so far. Beside sections dedicated to each sirtuin, in the present review we also included sections dedicated to pan-sirtuins’ and to parasitic sirtuins’ modulators. A special focus is dedicated to the sirtuins’ modulators identified by the use of virtual screening.

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Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with Chloroquine

Cited by 14 publications

References 57 publications

Triangular Relationship between p53, Autophagy, and Chemotherapy Resistance

Triangular Relationship between p53, Autophagy, and Chemotherapy Resistance

High-Throughput Drug Screen for Potential Combinations With Venetoclax Guides the Treatment of Transformed Follicular Lymphoma

Virtual Screening in the Identification of Sirtuins’ Activity Modulators

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