Design, Synthesis, and Anticancer Activity of Triptycene–Peptide Hybrids that Induce Paraptotic Cell Death in Cancer Cells

Yamaguchi, Kohei; Yokoi, Kenta; Umezawa, Masakazu; Tsuchiya, Koji; Yamada, Yasuyuki; Aoki, Shin

doi:10.1021/acs.bioconjchem.2c00076

Cited by 9 publications

(8 citation statements)

References 71 publications

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“…Induction of paraptosis by cyclometalated iridium (Ir) complex-peptide hybrid (IPH) and CGP37157 (an inhibitor of a mitochondrial Na + /Ca 2+ exchanger) is also reported to be associated with membrane fusion between mitochondria and the ER, followed by Ca 2+ influx from the ER to mitochondria, and a decrease in the mitochondrial membrane potential ( ΔΨ m) ( Yokoi et al, 2022 ). It has been reported that paraptosis induced by iridium complex-peptide hybrids and triptycene-peptide hybrids are inhibited by carbonyl cyanide 3-chloroophenylhydrazone (CCCP), while paraptosis induced by a natural product such as celastrol is not inhibited by CCCP ( Yamaguchi et al, 2022 ; Yokoi et al, 2022 ).…”

Section: Recent Trends In Paraptosis Researchmentioning

confidence: 99%

“…Paraptosis was induced in MCF-7 cells upon treatment with both diethyldithiocarbamate and B12b and if there is short exposure of DSFoxy along with this, it led to lysosomal cell death ( Solovieva et al, 2022 ). A triptycene-peptide hybrid: syn-6 and anti-6 is capable of inducing paraptosis in Jurkat cells by the loss of mitochondrial membrane potential and cytoplasmic vacuolation ( Yamaguchi et al, 2022 ). The membrane interaction between the poorly differentiated gastric adenocarcinoma, and tumour-associated tissue eosinophilia can result in the activation and degranulation of Eosinophil sombrero vesicles towards the tumour cells, which induced paraptosis in the tumour cells due to the formation of cytoplasmic vacuoles, and mitochondrial swelling ( Caruso et al, 2022 ).…”

Section: Recent Trends In Paraptosis Researchmentioning

confidence: 99%

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Paraptosis: a unique cell death mode for targeting cancer

Hanson,

Dharan,

P. V.

et al. 2023

Front. Pharmacol.

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Programmed cell death (PCD) is the universal process that maintains cellular homeostasis and regulates all living systems’ development, health and disease. Out of all, apoptosis is one of the major PCDs that was found to play a crucial role in many disease conditions, including cancer. The cancer cells acquire the ability to escape apoptotic cell death, thereby increasing their resistance towards current therapies. This issue has led to the need to search for alternate forms of programmed cell death mechanisms. Paraptosis is an alternative cell death pathway characterized by vacuolation and damage to the endoplasmic reticulum and mitochondria. Many natural compounds and metallic complexes have been reported to induce paraptosis in cancer cell lines. Since the morphological and biochemical features of paraptosis are much different from apoptosis and other alternate PCDs, it is crucial to understand the different modulators governing it. In this review, we have highlighted the factors that trigger paraptosis and the role of specific modulators in mediating this alternative cell death pathway. Recent findings include the role of paraptosis in inducing anti-tumour T-cell immunity and other immunogenic responses against cancer. A significant role played by paraptosis in cancer has also scaled its importance in knowing its mechanism. The study of paraptosis in xenograft mice, zebrafish model, 3D cultures, and novel paraptosis-based prognostic model for low-grade glioma patients have led to the broad aspect and its potential involvement in the field of cancer therapy. The co-occurrence of different modes of cell death with photodynamic therapy and other combinatorial treatments in the tumour microenvironment are also summarized here. Finally, the growth, challenges, and future perspectives of paraptosis research in cancer are discussed in this review. Understanding this unique PCD pathway would help to develop potential therapy and combat chemo-resistance in various cancer.

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Section: Recent Trends In Paraptosis Researchmentioning

confidence: 99%

Section: Recent Trends In Paraptosis Researchmentioning

confidence: 99%

Paraptosis: a unique cell death mode for targeting cancer

Hanson,

Dharan,

P. V.

et al. 2023

Front. Pharmacol.

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“…Unrestrained proliferation is a hallmark of tumor cells, which evade growth inhibition by resisting cell death and evading immune-mediated killing. Induction of programmed cell death is an effective strategy in tumor therapy [20]. Studies have shown that programmed cell death has several modes, including apoptosis, neuroapoptosis, cell necrosis and ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value and immune infiltration analyses of cuproptosis-related genes in hepatocellular carcinoma

Li,

Ma,

Zheng

et al. 2023

Acta Materia Medica

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The role of cuproptosis, a newly discovered form of programmed cell death, remains poorly understood in hepatocellular carcinoma (HCC). This study was aimed at constructing a novel cuproptosis model for analyzing the clinical features, mutation characteristics and immune profile of HCC associated with cuproptosis-related genes (CRG), and to analyze the prognostic value of CRGs in HCC. We comprehensively evaluated HCC datasets containing clinicopathological information from The Cancer Genome Atlas and GEO, on the basis of 19 CRGs. The prognostic value of the cuproptosis-related risk score was established. Our results revealed two clusters associated with cuproptosis. Cluster B exhibited pronounced isolated innate immune cell infiltration and poor prognosis, and significant differences in prognosis and immune infiltration were observed between the groups with high and low cuproptosis risk. High copper mortality risk scores were associated with an elevated tumor mutational burden (TMB) and poor prognosis. Our findings suggest that evaluating copper-death subtypes provides insights into CRGs. Moreover, the copper mortality risk score model aids in characterizing prognosis and immune infiltration independently of the TMB.

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“…We previously reported that hybrid compounds of cyclometalated iridium(III) (Ir(III)) complexes with cyclic peptides that bind to death receptors (DRs) expressed on the cancer cells, which detect Jurkat cells and induce their apoptosis and necrosis-type cell death. , In addition, Ir(III) complexes and triptycene compounds conjugated with cationic peptides such as KK(K)GG (K: lysine, G: glycine) sequences, which induce paraptosis, a non-apoptotic programmed cell death, in Jurkat cells and other cancer cell lines, were designed and synthesized. − Therefore, our future efforts will be directed to the design and synthesis of hybrid compounds of poly(bpy) ligands with DR-binding peptides and/or cationic peptide units, which would give the answers to the following question, which will be the dominant type of cell death, apoptosis and/or paraptosis, or other types.…”

Section: Discussionmentioning

confidence: 99%

Design and Synthesis of Poly(2,2′-Bipyridyl) Ligands for Induction of Cell Death in Cancer Cells: Control of Anticancer Activity by Complexation/Decomplexation with Biorelevant Metal Cations

Balachandran,

Hirose,

Tanaka

et al. 2023

Inorg. Chem.

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Chelation therapy is a medical procedure for removing toxic metals from human organs and tissues and for the treatment of diseases by using metal-chelating agents. For example, iron chelation therapy is designed not only for the treatment of metal poisoning but also for some diseases that are induced by iron overload, cancer chemotherapy, and related diseases. However, the use of such metal chelators needs to be generally carried out very carefully, because of the side effects possibly due to the non-specific complexation with intracellular metal cations. Herein, we report on the preparation and characterization of some new poly(bpy) ligands (bpy: 2,2′-bipyridyl) that contain one–three bpy ligand moieties and their anticancer activity against Jurkat, MOLT-4, U937, HeLa S3, and A549 cell lines. The results of MTT assays revealed that the tris(bpy) and bis(bpy) ligands exhibit potent activity for inducing the cell death in cancer cells. Mechanistic studies suggest that the main pathway responsible for the cell death by these poly(bpy) ligands is apoptotic cell death. It was also found that the anticancer activity of the poly(bpy) ligands could be controlled by the complexation (anticancer activity is turned OFF) and decomplexation (anticancer activity is turned ON) with biorelevant metal cations. In this paper, these results will be described.

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Design, Synthesis, and Anticancer Activity of Triptycene–Peptide Hybrids that Induce Paraptotic Cell Death in Cancer Cells

Cited by 9 publications

References 71 publications

Paraptosis: a unique cell death mode for targeting cancer

Paraptosis: a unique cell death mode for targeting cancer

Prognostic value and immune infiltration analyses of cuproptosis-related genes in hepatocellular carcinoma

Design and Synthesis of Poly(2,2′-Bipyridyl) Ligands for Induction of Cell Death in Cancer Cells: Control of Anticancer Activity by Complexation/Decomplexation with Biorelevant Metal Cations

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