Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation

Peery, Robert C.; Kyei-Baffour, Kwaku; Dong, Zizheng; Liu, Jianguo; Horn, Pedro de Andrade; Dai, Mingji; Liu, Jing-Yuan; Zhang, Jian-Ting

doi:10.1021/acs.jmedchem.0c00475

Cited by 21 publications

(28 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Degradation of the dimeric proteins can result from the interaction with the hydrophobic dimerization interface, which leads to conformational changes. This degradation can be mediated by the proteasome enzyme [ 12 ]. Since 5c and 5e were expected to inhibit survivin dimerization as shown in the docking study, we assumed that they may induce the degradation of survivin via the proteasome.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Novel 3-Cyanopyridines as Survivin Modulators and Apoptosis Inducers

et al. 2020

View full text Add to dashboard Cite

The overexpression of survivin is usually accompanied by an increased resistance of cancer cells to chemotherapeutic agents in addition to cancer aggressiveness. Consequently, survivin is considered as an attractive target to develop new promising anticancer candidates. A series of novel 3-cyanopyridine derivatives was synthesized and assessed for their cytotoxic activity against three human cancer cell lines: prostate carcinoma (PC-3), breast cancer (MDA-MB-231) and hepatocellular carcinoma (HepG2). In addition, their activities were evaluated in comparison with a standard anticancer drug 5-FU. Compounds 5c and 5e both exhibited promising cytotoxicity against all the tested cell lines; especially, 5e showed better cytotoxic effect than the reference drug 5-FU. In order to evaluate the safety of these compounds, they were tested on the normal cell line WI-38, revealing their toxic selectivity toward cancer cells over normal ones. Further studies were performed in order to understand their mechanism of action; we examined the ability of our promising compounds 5c and 5e to induce cell cycle arrest. Both resulted in a notable induction of cell cycle arrest at the G2/M phase, along with an increase in the DNA content in the pre-G1 phase, giving us an indication of the incidence of apoptosis. 5c and 5e were further subjected to additional study using Annexin V-FITC assay in order to evaluate their ability to induce apoptosis. The results showed a marked increase in the early and late apoptotic cells, as well as an increase in the percentage of necrosis. Furthermore, Western blotting assay was accomplished using different concentrations of 5c and 5e. The results revealed a striking reduction in survivin expression through proteasome-dependent survivin degradation in addition to a decrease in the expression of some other inhibitor of apoptosis proteins (IAP) family proteins: Livin, XIAP, and C-IAP1 in a concentration-dependent manner. A docking study of 5c and 5e compounds in the dimerization site of survivin was also performed, showing agreement with the in vitro anti-survivin activity.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Therefore, it is considered as a cancer-specific biomarker. Hence, targeting survivin embodies an attractive strategy for the development of more selective anticancer therapeutics [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel 3-Cyanopyridines as Survivin Modulators and Apoptosis Inducers

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Once the tumor reached 200 cm 3 , the mice were randomly divided into two groups (n = 5 per group). According to previous studies 20 , 21 , compound 3K (5 mg/kg body weight) dissolved in 1 ml of solvent (DMSO:corn oil, 1:9) was administered orally every 2 days for 31 days. The control group was treated with an equal volume of the vehicle.…”

Section: Methodsmentioning

confidence: 99%

Specific Pyruvate Kinase M2 Inhibitor, Compound 3K, Induces Autophagic Cell Death through Disruption of the Glycolysis Pathway in Ovarian Cancer Cells

Park¹,

Kundu²,

Lee³

et al. 2021

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Ovarian cancer is a common cause of death among gynecological cancers. Although ovarian cancer initially responds to chemotherapy, frequent recurrence in patients remains a therapeutic challenge. Pyruvate kinase M2 (PKM2) plays a pivotal role in regulating cancer cell survival. However, its therapeutic role remains unclear. Here, we investigated the anticancer effects of compound 3K, a specific PKM2 inhibitor, on the regulation of autophagic and apoptotic pathways in SK-OV-3 (PKM2-overexpressing human ovarian adenocarcinoma cell line). The anticancer effect of compound 3K was examined using MTT and colony formation assays in SK-OV-3 cells. PKM2 expression was positively correlated with the severity of the tumor, and expression of pro-apoptotic proteins increased in SK-OV-3 cells following compound 3K treatment. Compound 3K induced AMPK activation, which was accompanied by mTOR inhibition. Additionally, this compound inhibited glycolysis, resulting in reduced proliferation of SK-OV-3 cells. Compound 3K treatment suppressed tumor progression in an in vivo xenograft model. Our findings suggest that the inhibition of PKM2 by compound 3K affected the Warburg effect and induced autophagic cell death. Therefore, use of specific PKM2 inhibitors to block the glycolytic pathway and target cancer cell metabolism represents a promising therapeutic approach for treating PKM2-overexpressing ovarian cancer.

show abstract

“…As a central player in cell biology and a therapeutic target, STAT3 is a transcription factor that regulates cell differentiation, proliferation and apoptosis, resulting in promoting cancer progression (88). Chen et al (89) reported that ropivacaine (0.25, 0.5 and 1 mM) possessed inhibitory effects to cervical cancer SiHa, Caski cells via suppressing the expression of cyclin D1 and survivin, an anti-apoptotic protein (90,91), by abrogating the phosphorylation and transcriptional activation of STAT3 whose overexpression could reverse the cytotoxicity of ropivacaine (89). These effects were mediated by up-regulating MEG2 and down-regulating microRNA96, suggesting ropivacaine as a potential therapeutic agent for cervical cancer (89).…”

Section: Via Micro Rnas/long Non-coding Rnas (Lncrnas) and Associated...mentioning

confidence: 99%

Local Anesthetic Ropivacaine Exhibits Therapeutic Effects in Cancers

Zhang

Tan

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

Despite the significant progress in cancer treatment, new anticancer therapeutics drugs with new structures and/or mechanisms are still in urgent need to tackle many key challenges. Drug repurposing is a feasible strategy in discovering new drugs among the approved drugs by defining new indications. Recently, ropivacaine, a local anesthetic that has been applied in clinical practice for several decades, has been found to possess inhibitory activity and sensitizing effects when combined with conventional chemotherapeutics toward cancer cells. While its full applications and the exact targets remain to be revealed, it has been indicated that its anticancer potency was mediated by multiple mechanisms, such as modulating sodium channel, inducing mitochondria-associated apoptosis, cell cycle arrest, inhibiting autophagy, and/or regulating other key players in cancer cells, which can be termed as multi-targets/functions that require more in-depth studies. In this review, we attempted to summarize the research past decade of using ropivacaine in suppressing cancer growth and sensitizing anticancer drugs both in-vitro and in-vivo, and tried to interpret the underlying action modes. The information gained in these findings may inspire multidisciplinary efforts to develop/discover more novel anticancer agents via drug repurposing.

show abstract

Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation

Cited by 21 publications

References 21 publications

Discovery of Novel 3-Cyanopyridines as Survivin Modulators and Apoptosis Inducers

Discovery of Novel 3-Cyanopyridines as Survivin Modulators and Apoptosis Inducers

Specific Pyruvate Kinase M2 Inhibitor, Compound 3K, Induces Autophagic Cell Death through Disruption of the Glycolysis Pathway in Ovarian Cancer Cells

Local Anesthetic Ropivacaine Exhibits Therapeutic Effects in Cancers

Contact Info

Product

Resources

About