Cyclometalated Ru(II) β-carboline complexes induce cell cycle arrest and apoptosis in human HeLa cervical cancer cells via suppressing ERK and Akt signaling

Chen, Jincan; Deng, Yuanyuan; Wang, Jie; Chen, Suxiang; Peng, Fa; He, Xuerong; Liu, Meijun; Luo, Hui; Zhang, Jingjing; Chen, Lanmei

doi:10.1007/s00775-021-01894-4

Cited by 9 publications

(4 citation statements)

References 69 publications

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“…Interestingly, Noureldeen et al [ 37 ] demonstrated that a Ru(III)-pyrimidine Schiff base interferes with Akt/mTOR and NF-κB signaling in HepG2 cells. Moreover, cyclometalated Ru(II) β-carboline complexes inhibited ERK and Akt signaling in HeLa cervical cancer cells [ 38 ]. Ru(II)-cyclopentadienyl-derived complexes have been reported to inhibit the MEK/ERK and PI3K/Akt signaling pathways in the colorectal cancer cell lines RKO and SW480 [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Ru(II)-based complexes containing 2-thiouracil derivatives suppress liver cancer stem cells by targeting NF-κB and Akt/mTOR signaling

Bomfim,

Neves,

Coelho

et al. 2024

Cell Death Discov.

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Cancer stem cells (CSCs) are defined as a rare population of cancer cells related to tumor initiation and maintenance. These cells are primarily responsible for tumor growth, invasion, metastasis, recurrence, and resistance to chemotherapy. In this paper, we demonstrated the ability of Ru(II)-based complexes containing 2-thiouracil derivatives with the chemical formulas trans-[Ru(2TU)(PPh3)2(bipy)]PF6 (1) and trans-[Ru(6m2TU)(PPh3)2(bipy)]PF6 (2) (where 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil) to suppress liver CSCs by targeting NF-κB and Akt/mTOR signaling. Complexes 1 and 2 displayed potent cytotoxic effects on cancer cell lines and suppressed liver CSCs from HepG2 cells. Increased phosphatidylserine exposure, loss of mitochondrial transmembrane potential, increased PARP (Asp214) cleavage, DNA fragmentation, chromatin condensation and cytoplasmic shrinkage were detected in HepG2 cells treated with these complexes. Mechanistically, complexes 1 and 2 target NF-κB and Akt/mTOR signaling in HepG2 cells. Cell motility inhibition was also detected in HepG2 cells treated with these complexes. Complexes 1 and 2 also inhibited tumor progression in mice with HepG2 cell xenografts and exhibited tolerable systemic toxicity. Taken together, these results indicate that these complexes are new anti-HCC drug candidates that can suppress liver CSCs.

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Section: Discussionmentioning

confidence: 99%

Ru(II)-based complexes containing 2-thiouracil derivatives suppress liver cancer stem cells by targeting NF-κB and Akt/mTOR signaling

Bomfim,

Neves,

Coelho

et al. 2024

Cell Death Discov.

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“…Ruthenium(II)-cyclopentadienyl-derived complexes were reported to induce apoptosis in CRC RKO and SW480 cell lines via inhibition of the MEK/ERK and PI3K/Akt signaling pathways [ 20 ]. Likewise, cyclometalated Ru(II) β-carboline complexes led to apoptotic cell death in HeLa cervical cancer cells through the inhibition of ERK and Akt signaling [ 21 ]. Cyclometalated Ru(II)-isoquinoline complexes caused apoptosis in cisplatin-resistant lung cancer A549/DDP cells by modulating Akt/GSK-3β/Fyn signaling [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

A novel ruthenium complex with 5-fluorouracil suppresses colorectal cancer stem cells by inhibiting Akt/mTOR signaling

Silva,

Santos,

de Castro

et al. 2023

Cell Death Discov.

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Abstract[Ru(5-FU)(PPh3)2(bipy)]PF6 (Ru/5-FU) is a novel ruthenium complex with 5-fluorouracil with promising potential against colorectal cancer (CRC). In the present study, we investigated the molecular mechanism of Ru/5-FU action in HCT116 CRC cells. Ru/5-FU exhibited potent cytotoxicity on a panel of cancer cell lines and on primary cancer cells and induced apoptosis in HCT116 CRC cells. Ru/5-FU reduced AKT1 gene transcripts, as well as the expression of Akt1 and Akt (pS473) and downstream Akt proteins mTOR (pS2448), S6 (pS235/pS236), 4EBP1 (pT36/pT45), GSK-3β (pS9) and NF-κB p65 (pS529), but not Akt upstream proteins Hsp90 and PI3K p85/p55 (pT458/pT199), indicating an inhibitory action of Akt/mTOR signaling. Ru/5-FU increased LC3B expression and reduced p62/SQSTM1 levels, indicating autophagy induction. Curiously, the autophagy inhibitors 3-methyladenine and chloroquine increased Ru/5-FU-induced cell death, indicating an induction of cytoprotective autophagy by this compound. Ru/5-FU also reduced clonogenic survival, as well as the percentage of CD133+ cells and colonosphere formation, indicating that Ru/5-FU can suppress stem cells in HCT116 cells. Ru/5-FU inhibited cell migration and invasion in wound healing assays and Transwell cell invasion assays, along with a reduction in vimentin expression and an increase in E-cadherin levels, indicating that Ru/5-FU can interfere with epithelial-mesenchymal transition. Ru/5-FU also inhibited in vivo HCT116 cell development and experimental lung metastases in mouse xenograft models. Altogether, these results indicate that Ru/5-FU is an anti-CRC chemotherapy drug candidate with the ability to suppress stemness in CRC cells by inhibiting Akt/mTOR signaling.

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“…Among these compounds, Compound 3 has higher antitumor activity than cisplatin. Based on this study, Lanmei Chen et al 75 synthesized two new Ru(II)- and Ru2 (Fig. 6C).…”

Section: Development Of Ruthenium Complex Moleculesmentioning

confidence: 97%

“…Among these compounds, Compound 3 has higher antitumor activity than cisplatin. Based on this study, Lanmei Chen et al 75 synthesized two new Ru( ii )-β-carboline complexes (RuβC-3 and RuβC-4) by introducing halogens into the carboline structure. The IC 50 values of the compounds against HeLa cells were 3.2 ± 0.4 μM (compound 4 , RuβC-3) and 4.1 ± 0.6 μM (compound 5 , RuβC-4), respectively.…”

Section: Development Of Ruthenium Complex Moleculesmentioning

confidence: 99%

Ruthenium-based antitumor drugs and delivery systems from monotherapy to combination therapy

Zhu

et al. 2022

Nanoscale

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Cyclometalated Ru(II) β-carboline complexes induce cell cycle arrest and apoptosis in human HeLa cervical cancer cells via suppressing ERK and Akt signaling

Cited by 9 publications

References 69 publications

Ru(II)-based complexes containing 2-thiouracil derivatives suppress liver cancer stem cells by targeting NF-κB and Akt/mTOR signaling

Ru(II)-based complexes containing 2-thiouracil derivatives suppress liver cancer stem cells by targeting NF-κB and Akt/mTOR signaling

A novel ruthenium complex with 5-fluorouracil suppresses colorectal cancer stem cells by inhibiting Akt/mTOR signaling

Ruthenium-based antitumor drugs and delivery systems from monotherapy to combination therapy

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