Novel Ferrocene Derivatives Induce Apoptosis through Mitochondria-Dependent and Cell Cycle Arrest via PI3K/Akt/mTOR Signaling Pathway in T Cell Acute Lymphoblastic Leukemia

Zeng, Liao; Tang, Mingqing; Pi, Chao; Zheng, Jia‐nan; Gao, Sanxing; Chabanne, Titaua; Chauvin, Rémi; Cheng, Wenzhao; Lin, Hongjun; Xu, Rui‐hua; Cui, Xiuling

doi:10.3390/cancers13184677

Cited by 9 publications

(6 citation statements)

References 49 publications

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“…Therefore, PI3K/AKT/mTOR signaling has become one of the main targets for the treatment of T-ALL [29]. In the present work, after PX-866 and PI-103 treatment, the apoptotic rate of CCRF-CEM and Jurkat cells was signi cantly elevated.…”

Section: Discussionsupporting

confidence: 45%

Apoptosis of T-acute lymphoblastic leukemia cells is induced by the combination of PI3K and autophagy inhibitors

DONG

Sun

YANG

et al. 2022

Preprint

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Background: The PI3K/Akt signaling pathway plays an important role in the occurrence and development of tumors, and various PI3K inhibitors have been reported in antitumor. However, PI3K inhibitors can induce autophagy and activation of autophagy can promote drug resistance of tumor cells or improve cell survival. Therefore, the present study aimed to investigate the effects of the PI3K inhibitor PX-866 or PI-103 combined with the autophagy inhibitor 3-methyladenine (3-MA) on the apoptosis of acute T-acute lymphoblastic leukemia cells lines CCRF-CEM and Jurkat cells. Methods and results: We found PX-866 and PI-103 treatment significantly reduced cell viability whilst also greatly increasing apoptosis in CCRF-CEM and Jurkat cells. The efficacy of this treatment was further enhanced when combined with 3-MA. The phosphorylation levels of AKT and mTOR in CCRF-CEM and Jurkat cells were significantly suppressed by the introduction of PX-866 or PI-103, the effects of which were reversed by co-treatment with 3-MA. In addition, the expression of LC3, ATG5, ATG12 and Beclin-1 were found to be significantly upregulated by PX-866 or PI-103 treatment and were markedly downregulated by the co-administration of 3-MA. TEM results revealed that the number of autophagic vacuoles in CCRF-CEM and Jurkat cells was increased by PX-866 and PI-103 treatment, which was reversed by 3-MA co-treatment. Conclusions: The combination of PI3K and autophagy inhibitors reduced cell viability and induced apoptosis in T-acute lymphoblastic leukemia cells. This discovery provided a new way to improve the effectiveness of anti-tumor strategies in T-cell acute lymphoblastic leukemia.

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Section: Discussionsupporting

confidence: 45%

Apoptosis of T-acute lymphoblastic leukemia cells is induced by the combination of PI3K and autophagy inhibitors

DONG

Sun

YANG

et al. 2022

Preprint

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“…Harmicene 28 , also an O-7-substituted TT-harmine derivative, had an even more pronounced effect on the HCT116 cell cycle. Furthermore, it is known that ferrocene derivatives also inhibit the proliferation of various cancer cells through the induction of G0/G1 cell cycle arrest, downregulation of cyclin D1, CDK4 [ 50 ], and CDK6 and concomitant increases in p27 and p21 expression [ 51 ].…”

Section: Resultsmentioning

confidence: 99%

Harmicens, Novel Harmine and Ferrocene Hybrids: Design, Synthesis and Biological Activity

Poje

Marinović

Pavić

et al. 2022

IJMS

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Cancer and malaria are both global health threats. Due to the increase in the resistance to the known drugs, research on new active substances is a priority. Here, we present the design, synthesis, and evaluation of the biological activity of harmicens, hybrids composed of covalently bound harmine/β-carboline and ferrocene scaffolds. Structural diversity was achieved by varying the type and length of the linker between the β-carboline ring and ferrocene, as well as its position on the β-carboline ring. Triazole-type harmicens were prepared using Cu(I)-catalyzed azide-alkyne cycloaddition, while the synthesis of amide-type harmicens was carried out by applying a standard coupling reaction. The results of in vitro biological assays showed that the harmicens exerted moderate antiplasmodial activity against the erythrocytic stage of P. falciparum (IC50 in submicromolar and low micromolar range) and significant and selective antiproliferative activity against the MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range, SI > 5.9). Cell localization experiments showed different localizations of nonselective harmicene 36 and HCT116-selective compound 28, which clearly entered the nucleus. A cell cycle analysis revealed that selective harmicene 28 had already induced G1 cell cycle arrest after 24 h, followed by G2/M arrest with a concomitant drastic reduction in the percentage of cells in the S phase, whereas the effect of nonselective compound 36 on the cell cycle was much less pronounced, which agreed with their different localizations within the cell.

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“…Cell cycle progression is tightly linked with cell proliferation [ 19 ]. The cell cycle is mainly adjusted by checkpoints which are activated by DNA damage to assure the exact progress of the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Structure Elucidation and Anti-Tumor Activities of Trichothecenes from Endophytic Fungus Fusariumsporotrichioides

Wang

et al. 2022

Biomolecules

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The secondary metabolites of Fusarium sporotrichioides, an endophytic fungus with anti-tumor activity isolated from Rauvolfia yunnanensis Tsiang, were investigated. Five trichothecenes, including one previously undescribed metabolite, were isolated and identified. Their structures were elucidated by means of extensive spectroscopic methods; the absolute configuration of compound 1 was determined by the ECD method. Surprisingly, 8-n-butyrylneosolaniol (3) exhibited stronger anti-tumor activity than T-2 toxin against Huh-7 cell line, with an IC50 value of 265.9 nM. 8-n-butyrylneosolaniol (3) promoted apoptosis induction in Huh-7 cells. Moreover, cell cycle analysis showed that cell cycle arrest caused by 8-n-butyrylneosolaniol (3) at the G2/M phase resulted in cell proliferation inhibition and pro-apoptotic activity. Further studies showed a significant decrease in mitochondrial membrane permeabilization and a significant increase in ROS generation, which led to the activation of caspase cascades and subsequent cleavage of PARP fragments. In conclusion, 8-n-butyrylneosolaniol (3) induced cell apoptosis in Huh-7 cells via the mitochondria-mediated apoptotic signaling pathway, which could be a leading compound for anti-tumor agents.

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Novel Ferrocene Derivatives Induce Apoptosis through Mitochondria-Dependent and Cell Cycle Arrest via PI3K/Akt/mTOR Signaling Pathway in T Cell Acute Lymphoblastic Leukemia

Cited by 9 publications

References 49 publications

Apoptosis of T-acute lymphoblastic leukemia cells is induced by the combination of PI3K and autophagy inhibitors

Apoptosis of T-acute lymphoblastic leukemia cells is induced by the combination of PI3K and autophagy inhibitors

Harmicens, Novel Harmine and Ferrocene Hybrids: Design, Synthesis and Biological Activity

Structure Elucidation and Anti-Tumor Activities of Trichothecenes from Endophytic Fungus Fusariumsporotrichioides

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