Novel Sulfonyl-Substituted Tetrandrine Derivatives for Colon Cancer Treatment by Inducing Mitochondrial Apoptosis and Inhibiting PI3K/AKT/mTOR Pathway DOI
Jie Ling, Xiao Li, Maolin Wang

et al.

Published: Jan. 1, 2023

Tetrandrine (TET) possesses multiple pharmacological activities and could suppress tumor proliferation via PI3K pathway inhibition. However, inferior antitumor activity potential toxicity limit its clinical application. In the present study, a series of 14-sulfonamide sulfonate TET derivatives were designed, synthesized, evaluated for biological activities. Through structural-activity relationship studies, compound 3c with α, β-unsaturated carbonyl group exhibited most potent against all tested cell lines (including Hela, HCT116, HepG2, MCF-7, SHSY5Y), as well negligible normal LO2 HEK293. Additionally, effectively inhibited HCT116 CT26 in vitro increased proportion G2/M phase, activated mitochondrial apoptosis pathway, induced colon cancer by suppressing PI3K/AKT/mTOR pathway. The further molecular docking results confirmed that is potentially bound to residues stronger binding affinity than TET. Ultimately, dramatically suppressed growth xenograft model, without noticeable visceral detected high-dose group. summary, might new insights designing inhibitors be candidate treatment.

Language: Английский

Hybridization-based discovery of novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitors DOI Creative Commons

Changqun Liu,

Yuening Cao,

Yi Y. Zuo

et al.

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: March 1, 2024

Phosphatidylinositol 3-kinases (PI3Ks) overexpression can elicit cellular homeostatic dysregulation, which further contributes to tumorigenesis, with PI3Kα emerging as the most prevalent mutant isoform kinase among PI3Ks. Therefore, selective inhibitors targeting have attracted considerable interest in recent years. Molecular hybridization, advantage of simplified pharmacokinetics and drug-drug interactions, emerged one important avenues for discovering potential drugs. This study aimed construct by hybridization investigate their antitumor activity mechanism. 26 quinazoline-2-indolinone derivatives were obtained molecular structure–activity relationship was analyzed MTT, vitro docking. The biological evaluation compound 8 performed transwell, flow cytometry, laser scanning confocal microscopy, Western blot, CTESA immunohistochemistry. Here, we employed methods a series inhibitors. Encouragingly, representative exhibited enzymatic IC50 value 9.11 nM 10.41/16.99/37.53-fold relative biochemical selectivity PI3Kβ/γ/δ, respectively. Moreover, effectively suppressed viability B16, HCT116, MCF-7, H22, PC-3, A549 cells (IC50 values: 0.2 μM ∼ 0.98 μM), dramatically inhibited proliferation migration NSCLC cells, well induced mitochondrial apoptosis through PI3K/Akt/mTOR pathway. Importantly, demonstrated potent vivo anti-tumor non-small cell lung cancer mouse models without visible toxicity. presented new avenue development provided solid foundation novel QHIDs future therapies treatment NSCLC.

Language: Английский

Citations

25
Carrier-free self-assembled nanomedicine based on celastrol and galactose for targeting therapy of hepatocellular carcinoma via inducing ferroptosis DOI
Xin Zhang, Yao Chen, Xiao Li

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 267, P. 116183 - 116183

Published: Feb. 5, 2024

Language: Английский

Citations

22
Cancer resistance and metastasis are maintained through oxidative phosphorylation DOI

Cemile Uslu,

Eda Kapan,

Alex Lyakhovich

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 587, P. 216705 - 216705

Published: Feb. 18, 2024

Language: Английский

Citations

20
Bruceine A alleviates alcoholic liver disease by inhibiting AIM2 inflammasome activation via activating FXR DOI
Li Lin,

Shuai Xu,

Wenyu Wang

et al.

Phytomedicine, Journal Year: 2024, Volume and Issue: 130, P. 155693 - 155693

Published: May 7, 2024

Language: Английский

Citations

8
A comprehensive view on the apigenin impact on colorectal cancer: Focusing on cellular and molecular mechanisms DOI Creative Commons

Siamak Daneshvar,

Mohammad Yasin Zamanian, Mehraveh Sadeghi Ivraghi

et al.

Food Science & Nutrition, Journal Year: 2023, Volume and Issue: 11(11), P. 6789 - 6801

Published: Aug. 28, 2023

Abstract Colon cancer (CC) is one of the most common and deadly cancers worldwide. Oncologists are facing challenges such as development drug resistance lack suitable options for CC treatment. Flavonoids a group natural compounds found in fruits, vegetables, other plant‐based foods. According to research, they have potential role prevention treatment cancer. Apigenin flavonoid that present many fruits vegetables. It has been used antioxidant long time considered due its anticancer effects low toxicity. The results this review study show apigenin on cells through various mechanisms. In comprehensive review, we cellular targets signaling pathways indicated date vivo vitro models. Among important modulated pathways, Wnt/β‐catenin, PI3K/AKT/mTOR, MAPK/ERK, JNK, STAT3, Bcl‐xL Mcl‐1, PKM2, NF‐kB described. Furthermore, suppresses cell cycle G2/M phase cells. cells, apigenin‐induced apoptosis increased by inhibiting formation autophagy. study, appears be promising agent therapy, but more research required field pharmacology pharmacokinetics establish dosage clinical studies.

Language: Английский

Citations

16
Advances in nanoscale carrier-based approaches to reduce toxicity and enhance efficacy of podophyllotoxin DOI Creative Commons
Chaozheng Zhang, Yi Y. Zuo, Tingting Zhang

et al.

Acta Materia Medica, Journal Year: 2023, Volume and Issue: 2(4)

Published: Jan. 1, 2023

Podophyllotoxin (PPT), an aryltetralin-type lignan isolated from Podophyllum species, exhibits a wide range of biologic and pharmacologic activities, mainly serves as antiviral agent or antitumor drug in clinical applications. However, the therapeutic potential PPT has been hindered due to its detrimental systemic toxicity, poor solubility, bioavailability. Nanoparticles, which preferentially accumulate tumors through enhanced permeability retention effects, have become useful tools for targeted delivery, thus securing niche cancer therapies. The nano-based delivery platform introduced purpose improved efficacy, reduced toxicity. For decades, extensive efforts dedicated designing developing various systems mitigate undesirable toxicity expand applicability. Herein, we briefly review latest achievements patterns pharmacodynamic concerns with expectation shedding light on future research applications PPT.

Language: Английский

Citations

11
Bruceine A: Suppressing metastasis via MEK/ERK pathway and invoking mitochondrial apoptosis in triple-negative breast cancer DOI Open Access
Xiao Li,

Changqun Liu,

Xin Zhang

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115784 - 115784

Published: Oct. 24, 2023

Triple-negative breast cancer (TNBC), as the most aggressive subtype of cancer, presents a scarcity miraculous drugs in suppressing its proliferation and metastasis. Bruceine A (BA) is functional group-rich quassin compound with extensive distinctive pharmacological activities. Within present study, we investigated capabilities BA TNBC metastasis well potential mechanisms. The results displayed that dramatically repressed MDA-MB-231 4T1 cells corresponding IC50 values 78.4 nM 524.6 nM, respectively. Concurrently, arrested G1 phase by downregulating cycle-related proteins Cyclin D1 CDK4. Furthermore, distinctly induced mitochondrial dysfunction manifested diminished membrane potential, elevated reactive oxygen species generation, minimized ATP production, Caspase-dependent activation apoptosis pathway. Additionally, restrained invasion repressing MMP9 MMP2 expression. Intriguingly, after pretreatment MEK activator C16-PAF, inhibitory effect on MEK/ERK pathway was notably diminished, while suppression repression exerted were all strikingly curtailed. Molecular docking illustrated potently combined residues MEK1 protein presence diverse intermolecular interactions. Ultimately, effectively suppressed tumor growth xenograft model no detectable visceral toxicity high-dose group and, astonishingly, 4T1-luc lung model. Collectively, our study demonstrates promising chemotherapeutic agent for treating

Language: Английский

Citations

10
Novel sulfonyl-substituted tetrandrine derivatives for colon cancer treatment by inducing mitochondrial apoptosis and inhibiting PI3K/AKT/mTOR pathway DOI
Jie Ling, Xiao Li, Maolin Wang

et al.

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 143, P. 107069 - 107069

Published: Dec. 29, 2023

Language: Английский

Citations

5
Bruceine A inhibits TGF-β1/Smad pathway in pulmonary fibrosis by blocking gal3/TGF-β1 interaction DOI
Chao Du, Chong Ma, Ruoyu Geng

et al.

Phytomedicine, Journal Year: 2024, Volume and Issue: 136, P. 156267 - 156267

Published: Nov. 21, 2024

Language: Английский

Citations

1
Bruceine A inhibited breast cancer proliferation and metastasis by inducing autophagy via targeting PI3K‐AKT signaling pathway DOI Open Access
Zhen Gao, Yan Zhang, Weixing Shen

et al.

Chemical Biology & Drug Design, Journal Year: 2023, Volume and Issue: 103(1)

Published: Nov. 27, 2023

Abstract Although there have been significant advances in cancer treatment, the urgent need to inhibit breast metastasis remained unmet. Bruceine A (BA) is a natural compound extracted from Bruceae Fructus and has long recognized antitumor effects with high safety biocompatibility. However, mechanisms and/or targets of BA for metastatic treatment are still not fully elucidated. In this study, we systematically investigated on inhibition its underlying mechanisms. We found that, addition cytotoxic effects, significantly inhibited invasion migration capabilities two types cell lines (MDA‐MB‐231 MCF‐7) while concurrently promoting apoptosis these cells. Further mechanistic studies revealed by targeting canonical PI3K‐AKT signaling pathway, initiated autophagy both vitro. vivo results further confirmed vitro findings, manifested shrinkage size weight tumor as well initiation (indicated upregulation LC3I/II) through pathway mice model. These data collectively demonstrated potential antimetastasis cells, suggesting future clinical transformation therapy.

Language: Английский

Citations

2