The role of the microbiome in ovarian cancer: mechanistic insights into oncobiosis and to bacterial metabolite signaling

Sipos, Áron; Ujlaki, Gyula; Mikó, Edit; Maka, Eszter; Szabó, Judit; Uray, Karen; Krasznai, Zoltán; Bai, Péter

doi:10.1186/s10020-021-00295-2

Cited by 93 publications

(77 citation statements)

References 331 publications

(236 reference statements)

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“…We assessed breast cancer (modelled by MCF7 cells) as prior data [ 22 ] suggested the potential effectiveness of ruthenium complexes. Pancreatic adenocarcinoma (modelled by Capan2 cells) and glioblastoma (modelled by U251 cells), similar to ovarian cancer, are usually malign diseases where treatment options are limited [ 54 , 55 , 56 ]. All complexes exerted cytostatic effects on all cell lines in proliferation assays (SRB) ( Figure 11 ).…”

Section: Resultsmentioning

confidence: 99%

Ruthenium Half-Sandwich Type Complexes with Bidentate Monosaccharide Ligands Show Antineoplastic Activity in Ovarian Cancer Cell Models through Reactive Oxygen Species Production

Kacsir

Sipos

Ujlaki

et al. 2021

IJMS

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Ruthenium complexes are developed as substitutes for platinum complexes to be used in the chemotherapy of hematological and gynecological malignancies, such as ovarian cancer. We synthesized and screened 14 ruthenium half-sandwich complexes with bidentate monosaccharide ligands in ovarian cancer cell models. Four complexes were cytostatic, but not cytotoxic on A2780 and ID8 cells. The IC50 values were in the low micromolar range (the best being 0.87 µM) and were similar to or lower than those of the clinically available platinum complexes. The active complexes were cytostatic in cell models of glioblastoma, breast cancer, and pancreatic adenocarcinoma, while they were not cytostatic on non-transformed human skin fibroblasts. The bioactive ruthenium complexes showed cooperative binding to yet unidentified cellular target(s), and their activity was dependent on reactive oxygen species production. Large hydrophobic protective groups on the hydroxyl groups of the sugar moiety were needed for biological activity. The cytostatic activity of the ruthenium complexes was dependent on reactive species production. Rucaparib, a PARP inhibitor, potentiated the effects of ruthenium complexes.

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Section: Resultsmentioning

confidence: 99%

Ruthenium Half-Sandwich Type Complexes with Bidentate Monosaccharide Ligands Show Antineoplastic Activity in Ovarian Cancer Cell Models through Reactive Oxygen Species Production

Kacsir

Sipos

Ujlaki

et al. 2021

IJMS

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“…We propose the use of these newly identified compounds in neoplasias where other metal-based cytostatic agents are in use but therapeutic options are limited, as in ovarian cancer [ 65 ] or pancreatic adenocarcinoma [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Reactive Oxygen Species Production Is Responsible for Antineoplastic Activity of Osmium, Ruthenium, Iridium and Rhodium Half-Sandwich Type Complexes with Bidentate Glycosyl Heterocyclic Ligands in Various Cancer Cell Models

Kacsir

Sipos

Bényei

et al. 2022

IJMS

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Platinum complexes are used in chemotherapy, primarily as antineoplastic agents. In this study, we assessed the cytotoxic and cytostatic properties of a set of osmium(II), ruthenium(II), iridium(III) and rhodium(III) half-sandwich-type complexes with bidentate monosaccharide ligands. We identified 5 compounds with moderate to negligible acute cytotoxicity but with potent long-term cytostatic activity. These structure-activity relationship studies revealed that: 1) osmium(II) p-cymene complexes were active in all models, while rhodium(III) and iridium(III) Cp* complexes proved largely inactive; 2) the biological effect was influenced by the nature of the central azole ring of the ligands—1,2,3-triazole was the most effective, followed by 1,3,4-oxadiazole, while the isomeric 1,2,4-oxadiazole abolished the cytostatic activity; 3) we found a correlation between the hydrophobic character of the complexes and their cytostatic activity: compounds with O-benzoyl protective groups on the carbohydrate moiety were active, compared to O-deprotected ones. The best compound, an osmium(II) complex, had an IC50 value of 0.70 µM. Furthermore, the steepness of the inhibitory curve of the active complexes suggested cooperative binding; cooperative molecules were better inhibitors than non-cooperative ones. The cytostatic activity of the active complexes was abolished by a lipid-soluble antioxidant, vitamin E, suggesting that oxidative stress plays a major role in the biological activity of the complexes. The complexes were active on ovarian cancer, pancreatic adenocarcinoma, osteosarcoma and Hodgkin’s lymphoma cells, but were inactive on primary, non-transformed human fibroblasts, indicating their applicability as potential anticancer agents.

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“…Bioactive metabolites, synthesized by the microbiome or the oncobiome, can act in a similar fashion to hormones and can link up the microbiome and the distantly located cancer cells [2][3][4]125]. As the gut microbiome is the biggest in the body in terms of the number of bacteria, its metabolic capacity is considerable.…”

Section: Bacterial Metabolite Signaling and The Oncobiosis Of The Gastrointestinal Tract And Urinary Tractmentioning

confidence: 99%

“…The microbiome metabolizes chemotherapeutic drugs, including those used in the (neoadjuvant) chemotherapy of breast cancer [ 270 ]. Hence, the microbiome can fundamentally change the pharmacokinetics and pharmacodynamics of these drugs (reviewed in [ 3 , 4 , 270 , 271 ]). Not surprisingly, antibiotics modulate the pharmacokinetic and pharmacodynamic properties of chemotherapeutic drugs and the therapeutic outcome [ 272 ].…”

Section: The Role Of the Breast Cancer Oncobiome In Chemotherapymentioning

confidence: 99%

“…The microbiome that is undergoing oncobiotic transformation is termed the oncobiome. Oncobiosis occurs in multiple neoplasias, including breast cancer, and oncobiosis may have a pathogenic role in these cancers [2][3][4][5][6][7][8]. In this review, we will dissect the microbiome-elicited pathways and discuss how these pathways protect against metastasis formation in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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The involvement of oncobiosis and bacterial metabolite signaling in metastasis formation in breast cancer

Kovàcs

Mikó

Ujlaki

et al. 2021

Cancer Metastasis Rev

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Breast cancer, the most frequent cancer in women, is characterized by pathological changes to the microbiome of breast tissue, the tumor, the gut, and the urinary tract. Changes to the microbiome are determined by the stage, grade, origin (NST/lobular), and receptor status of the tumor. This year is the 50th anniversary of when Hill and colleagues first showed that changes to the gut microbiome can support breast cancer growth, namely that the oncobiome can reactivate excreted estrogens. The currently available human and murine data suggest that oncobiosis is not a cause of breast cancer, but can support its growth. Furthermore, preexisting dysbiosis and the predisposition to cancer are transplantable. The breast’s and breast cancer’s inherent microbiome and the gut microbiome promote breast cancer growth by reactivating estrogens, rearranging cancer cell metabolism, bringing about a more inflammatory microenvironment, and reducing the number of tumor-infiltrating lymphocytes. Furthermore, the gut microbiome can produce cytostatic metabolites, the production of which decreases or blunts breast cancer. The role of oncobiosis in the urinary tract is largely uncharted. Oncobiosis in breast cancer supports invasion, metastasis, and recurrence by supporting cellular movement, epithelial-to-mesenchymal transition, cancer stem cell function, and diapedesis. Finally, the oncobiome can modify the pharmacokinetics of chemotherapeutic drugs. The microbiome provides novel leverage on breast cancer that should be exploited for better management of the disease.

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The role of the microbiome in ovarian cancer: mechanistic insights into oncobiosis and to bacterial metabolite signaling

Cited by 93 publications

References 331 publications

Ruthenium Half-Sandwich Type Complexes with Bidentate Monosaccharide Ligands Show Antineoplastic Activity in Ovarian Cancer Cell Models through Reactive Oxygen Species Production

Ruthenium Half-Sandwich Type Complexes with Bidentate Monosaccharide Ligands Show Antineoplastic Activity in Ovarian Cancer Cell Models through Reactive Oxygen Species Production

Reactive Oxygen Species Production Is Responsible for Antineoplastic Activity of Osmium, Ruthenium, Iridium and Rhodium Half-Sandwich Type Complexes with Bidentate Glycosyl Heterocyclic Ligands in Various Cancer Cell Models

The involvement of oncobiosis and bacterial metabolite signaling in metastasis formation in breast cancer

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