Targeting ROS-AMPK pathway by multiaction Platinum(IV) prodrugs containing hypolipidemic drug bezafibrate

Qiao, Xin; Gao, Ying; Zheng, Lianfang; Ding, Xin; Xu, Ling-Wen; Hu, Juanjuan; Gao, Weizhen; Xu, Jing‐Yuan

doi:10.1016/j.ejmech.2021.113730

Cited by 21 publications

(22 citation statements)

References 60 publications

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“…γ-H2AX (a marker of DNA lesions) is responsible for recruiting DNA repair effectors, and its expression is considered to be positively related to DNA lesions . Therefore, to further study the DNA damage effects of 17a toward A549/CDDP cells, the expression of γ-H2AX was assessed by western blotting assays, using 16a (5 μM), a combination of 16a and CDDP (5 + 5 μM), and indole–chalcone derivatives 3 (5 μM) and 14 (5 μM) as references.…”

Section: Resultsmentioning

confidence: 99%

“…Complexes 9 and 10 were prepared according to the previous report. , Briefly, a solution of N -chlorosuccinimide (587.4 mg, 4.4 mmol) in deionized water (30.0 mL) was added dropwise to a suspension of cisplatin (4.0 mmol) or oxaliplatin (4.0 mmol) in deionized water (100.0 mL) at room temperature. Then, the solution was heated to 55 °C for 12 h. After completion of the reaction, the solvent was removed under reduced pressure to give a pale-yellow solid.…”

Section: Methodsmentioning

confidence: 99%

“…γ-H2AX (a marker of DNA lesions) is responsible for recruiting DNA repair effectors, and its expression is considered to be positively related to DNA lesions. 40 Therefore, to further study the DNA damage effects of 17a toward A549/CDDP cells, the expression of γ-H2AX was assessed by western blotting assays, using 16a (5 μM), a combination of 16a and CDDP (5 + 5 μM), and indole− chalcone derivatives 3 (5 μM) and 14 (5 μM) as references. Compared with the control group, a moderate increase in the expression of γ-H2AX was found in the CDDP-treated group, illustrating that CDDP cannot induce severe DNA damage in A549/CDDP cells at 5 μM (Figure 5G−H).…”

Section: Intracellular Accumulation Of Compoundsmentioning

confidence: 99%

See 2 more Smart Citations

Novel Indole–Chalcone Derivative-Ligated Platinum(IV) Prodrugs Attenuate Cisplatin Resistance in Lung Cancer through ROS/ER Stress and Mitochondrial Dysfunction

et al. 2023

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Developing multifunctional platinum(IV) prodrugs via integrating bioactive pharmacophores into one entity is an attractive strategy to ameliorate the defects of platinum(II) drugs. Herein, a series of indole–chalcone derivative-ligated platinum(IV) complexes were synthesized and evaluated for their anticancer activities. Among them, optimal complex 17a exerted superior activity compared to that of cisplatin (CDDP) against the tested cells but showed lower cytotoxicity toward human normal lung cells. Detailed mechanisms demonstrated that 17a significantly enhanced intracellular accumulation, induced DNA damage, and inhibited migration in A549/CDDP cells. Furthermore, 17a efficiently disturbed the tubulin–microtubule system, initiated reactive oxygen species (ROS)-mediated endoplasmic reticulum stress, and activated a mitochondrion-dependent apoptosis signaling pathway. Besides, 17a was superior to free drugs or their combination in inhibiting cancer growth in A549/CDDP xenografts without inducing obvious side effects. The physical mixture of 16a and CDDP was almost identical to 17a but showed apparent systematic side effects. In summary, our studies may provide an efficient treatment regimen for CDDP resistance.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Intracellular Accumulation Of Compoundsmentioning

confidence: 99%

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Novel Indole–Chalcone Derivative-Ligated Platinum(IV) Prodrugs Attenuate Cisplatin Resistance in Lung Cancer through ROS/ER Stress and Mitochondrial Dysfunction

et al. 2023

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“…Most metal-based drugs can damage MMP and activate mitochondria-related apoptotic pathways. 39,40 The SK-OV-3CR cells coincubated with DQ6 (2.25 μM) for 24 h, even at concentrations as low as IC 50 values (Fig. 23), exhibited higher green fluorescence emission intensities ( ca .…”

Section: Resultsmentioning

confidence: 98%

Synthesis and anticancer mechanisms of zinc(ii)-8-hydroxyquinoline complexes with 1,10-phenanthroline ancillary ligands

Zhang

Huang

et al. 2023

Dalton Trans.

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“…Moreover, the precursors-induced cellular DNA ICLs generate DNA double-strand breaks (DSB) during repair, which rapidly trigger the formation of phosphorylated histone variant H2AX (γH2AX). [46,47] The γH2AX foci levels can be visualized by immunofluorescence microscopy and quantified using ImageJ. The control cells treated with 0.5 % DMSO exhibited low level of γH2AX foci.…”

Section: Cell Cytotoxicity Assaymentioning

confidence: 99%

Phenyl Selenide‐Based Precursors as Hydrogen Peroxide Inducible DNA Interstrand Cross‐Linkers

Fan

Sun

et al. 2022

ChemBioChem

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DNA interstrand crosslinks (ICLs) are highly toxic DNA lesions, and induce cell death by blocking DNA strand separation. Most ICL agents aiming to kill cancer cells, also generate adverse side effects to normal cells. H 2 O 2 -inducible DNA ICL agents are highly selective for targeting cancer cells, as the concentration of H 2 O 2 is higher in cancer cells than normal cells. Previous studies have focused on arylboronate-based precursors, reacting with H 2 O 2 to generate reactive quinone methides (QMs) crosslinking DNA. Here we explore phenyl selenide-based precursors 1-3 as H 2 O 2 -inducible DNA ICL agents. The precursors 1-3 can be activated by H 2 O 2 to generate the good benzylic leaving group and promote production of reactive QMs to crosslink DNA. Moreover, the DNA cross-linking ability is enhanced by the introduction of substituents in the paraposition of the phenolic hydroxyl group. From the substituents explored (H, OMe, F), the introduction of electron donating group (OMe) shows a pronounced elevating effect. Further mechanistic studies at the molecular and DNA levels confirm alkylation sites located mainly at dAs, dCs and dGs in DNA. Additionally, cellular experiments reveal that agents 1-3 exhibit higher cytotoxicity toward H1299 human lung cancer cells compared to clinically used drugs, by inducing cellular DNA damage, apoptosis and G0/G1 cell cycle arrest. This study provides a strategy to develop H 2 O 2 -inducible DNA interstrand cross-linkers.

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Targeting ROS-AMPK pathway by multiaction Platinum(IV) prodrugs containing hypolipidemic drug bezafibrate

Cited by 21 publications

References 60 publications

Novel Indole–Chalcone Derivative-Ligated Platinum(IV) Prodrugs Attenuate Cisplatin Resistance in Lung Cancer through ROS/ER Stress and Mitochondrial Dysfunction

Novel Indole–Chalcone Derivative-Ligated Platinum(IV) Prodrugs Attenuate Cisplatin Resistance in Lung Cancer through ROS/ER Stress and Mitochondrial Dysfunction

Synthesis and anticancer mechanisms of zinc(ii)-8-hydroxyquinoline complexes with 1,10-phenanthroline ancillary ligands

Phenyl Selenide‐Based Precursors as Hydrogen Peroxide Inducible DNA Interstrand Cross‐Linkers

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