Akt/mTOR Targeting Activity of Resveratrol Derivatives in Non-Small Lung Cancer

Innets, Bhurichaya; Thongsom, Sunisa; Petsri, Korrakod; Racha, Satapat; Yokoya, Masashi; Moriue, Sohsuke; Chaotham, Chatchai; Chanvorachote, Pithi

doi:10.3390/molecules27238268

Cited by 13 publications

(5 citation statements)

References 44 publications

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“…Finally, the resveratrol analogues 4,4′-(ethane-1,2-diyl) bis(2-methoxyphenol) and 4-(3-hydroxy-4-methoxyphenethyl)-2-methoxyphenol had very similar structures but exerted different cytotoxicity in non-small lung cancer cells. The IC50 values were 108.6 ± 10.82 and more than 200 µM in the A549 cell line and 103.5 ± 6.08 and more than 200 µM in H23 cells, respectively, while resveratrol itself exhibited more than 200 µM in both cell lines [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives

Fragopoulou,

Gkotsi,

Petsini

et al. 2023

Molecules

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Resveratrol, a naturally occurring stilbene, exhibits numerous beneficial health effects. Various studies have demonstrated its diverse biological actions, including anti-oxidant, anti-inflammatory, and anti-platelet properties, thereby supporting its potential for cardio protection, neuroprotection, and anti-cancer activity. However, a significant limitation of resveratrol is its weak bioavailability. To overcome this challenge, multiple research groups have investigated the synthesis of new resveratrol derivatives to enhance bioavailability and pharmacological activities. Nevertheless, there are limited data on the effects of resveratrol derivatives on platelet function. Therefore, the objective of this study was to synthesize resveratrol methoxy derivatives and evaluate their anti-platelet and anti-proliferative activity. Platelet-rich plasma (PRP) obtained from healthy volunteers was utilized to assess the derivatives’ ability to inhibit platelet aggregation induced by platelet activating factor (PAF), adenosine diphosphate (ADP), and thrombin receptor activating peptide (TRAP). Additionally, the derivatives’ anti-tumor activity was evaluated against the proliferation of PC-3 and HCT116 cells. The results revealed that some methoxy derivatives of resveratrol exhibited comparable or even superior anti-platelet activity compared to the original compound. The most potent derivative was the 4′-methoxy derivative, which demonstrated approximately 2.5 orders of magnitude higher anti-platelet activity against TRAP-induced platelet aggregation, indicating its potential as an anti-platelet agent. Concerning in silico studies, the 4′-methyl group of 4′-methoxy derivative is oriented similarly to the fluorophenyl–pyridyl group of Vorapaxar, buried in a hydrophobic cavity. In terms of their anti-tumor activity, 3-MRESV exhibited the highest potency in PC-3 cells, while 3,4′-DMRESV and TMRESV showed the greatest efficacy in HCT116 cells. In conclusion, methoxy derivatives of resveratrol possess similar or improved anti-platelet and anti-cancer effects, thereby holding potential as bioactive compounds in various pathological conditions.

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Section: Discussionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives

Fragopoulou,

Gkotsi,

Petsini

et al. 2023

Molecules

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“…This may suggest that targeting Trp80 residues is the most critical factor in determining activity. By contrast, numerous allosteric Akt inhibitors exhibit more favorable interactions with specific Trp80 residues [ 18 , 51 ]. In addition, DH_25 showed a similar binding pattern to miransertib, an oral allosteric Akt-1 inhibitor, by VDW interaction with Trp80.…”

Section: Discussionmentioning

confidence: 99%

Novel Synthetic Derivative of Renieramycin T Right-Half Analog Induces Apoptosis and Inhibits Cancer Stem Cells via Targeting the Akt Signal in Lung Cancer Cells

Petsri

Yokoya

Racha

et al. 2023

IJMS

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Akt is a key regulatory protein of cancer stem cells (CSCs) and is responsible for cancer aggressiveness and metastasis. Targeting Akt is beneficial for the development of cancer drugs. renieramycin T (RT) has been reported to have Mcl-1 targeting activity, and the study of the structure-activity relationships (SARs) demonstrated that cyanide and the benzene ring are essential for its effects. In this study, novel derivatives of the RT right-half analog with cyanide and the modified ring were synthesized to further investigate the SARs for improving the anticancer effects of RT analogs and evaluate CSC-suppressing activity through Akt inhibition. Among the five derivatives, a compound with a substituted thiazole structure (DH_25) exerts the most potent anticancer activity in lung cancer cells. It has the ability to induce apoptosis, which is accompanied by an increase in PARP cleavage, a decrease in Bcl-2, and a diminishment of Mcl-1, suggesting that residual Mcl-1 inhibitory effects exist even after modifying the benzene ring to thiazole. Furthermore, DH_25 is found to induce CSC death, as well as a decrease in CSC marker CD133, CSC transcription factor Nanog, and CSC-related oncoprotein c-Myc. Notably, an upstream member of these proteins, Akt and p-Akt, are also downregulated, indicating that Akt can be a potential target of action. Computational molecular docking showing a high-affinity interaction between DH_25 and an Akt at the allosteric binding site supports that DH_25 can bind and inhibit Akt. This study has revealed a novel SAR and CSC inhibitory effect of DH_25 via Akt inhibition, which may encourage further development of RT compounds for cancer therapy.

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“…Ginsenoside is a natural steroid that enhances and regulates the immune function, which not only inhibits the proliferation of lung adenocarcinoma, induces apoptosis of cancer cells, inhibits the inflammatory response of the body, but also plays a role in lung protection ( 36 ). Resveratrol is a natural polyphenolic compound with anti-free radical and antioxidant properties, which exerts anti-lung adenocarcinoma effects by modulating anti-inflammatory and hormonal effects ( 37 ). Therefore, the advantage of immunotherapy is that it allows tumors to achieve sustained remission and the adverse effects produced are relatively mild; as a popular treatment modality, immunotherapy, especially combination therapy, is widely used in the treatment of patients with lung adenocarcinoma, which creates more possibilities for the improvement of patients’ quality of survival.…”

Section: Overview Of Lung Adenocarcinoma Treated By Western Medicinementioning

confidence: 99%

Progress in the treatment of lung adenocarcinoma by integrated traditional Chinese and Western medicine

Jiang,

2024

Front. Med.

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Non-small cell lung cancer (NSCLC) overwhelmingly represents the predominant histological subtype of lung cancer, with lung adenocarcinoma emerging as the most prevalent form. Conventional Western medical treatments encompass a spectrum of modalities, including surgical interventions, cytotoxic chemotherapy, radiotherapy, targeted pharmacotherapy, and immunotherapy. In contrast, Traditional Chinese Medicine (TCM) methodologies encompass traditional Chinese medicine treatments, acupuncture therapies, and tuina treatments. While conventional Western medicine has made remarkable strides in the treatment of lung cancer, it is important to acknowledge the limitations inherent in singular treatment approaches. Consequently, the quest for a more comprehensive and integrative therapeutic paradigm becomes imperative. A deficiency of evaluation criteria specific to lung adenocarcinoma treatment in the realm of TCM represents an outstanding challenge in need of resolution. Nonetheless, in the backdrop of the continuous evolution of lung adenocarcinoma treatment modalities, the amalgamation of Chinese and Western medical approaches for treating this condition has exhibited a promising trajectory. It not only contributes to mitigating toxicity and augmenting efficacy but also serves to reduce a spectrum of postoperative complications, thereby enhancing the quality of patients’ survival and extending life expectancy. This article furnishes a comprehensive survey of the research advancements in the integration of Chinese and Western medical approaches for treating lung adenocarcinoma. It elucidates the merits and demerits of individual and combined therapeutic strategies, surmounts current limitations, underscores the virtues of amalgamating Chinese and Western medical paradigms, and offers a more holistic, integrated, and efficacious treatment blueprint.

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Akt/mTOR Targeting Activity of Resveratrol Derivatives in Non-Small Lung Cancer

Cited by 13 publications

References 44 publications

Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives

Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives

Novel Synthetic Derivative of Renieramycin T Right-Half Analog Induces Apoptosis and Inhibits Cancer Stem Cells via Targeting the Akt Signal in Lung Cancer Cells

Progress in the treatment of lung adenocarcinoma by integrated traditional Chinese and Western medicine

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