Pentamethinium salts suppress key metastatic processes by regulating mitochondrial function and inhibiting dihydroorotate dehydrogenase respiration

Fialova, Jindriska Leischner; Hönigová, Kateřina; Raudenská, Martina; Miksatkova, Lucie; Zobalova, Renata; Navrátil, Jiří; Šmigová, Jana; Moturu, Taraka Ramji; Vičar, Tomáš; Veselá, Kateřina; Abramenko, Nikita; Kejík, Zdeněk; Kaplánek, Robert; Gumulec, Jaromír; Rösel, Daniel; Martásek, Pavel; Brábek, Jan; Jakubek, Milan; Neužil, Jiřı́; Masařík, Michal

doi:10.1016/j.biopha.2022.113582

Cited by 6 publications

(3 citation statements)

References 58 publications

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“…However, their structural motif can be used as an appropriate starting point in the design of these novel dual inhibitors. It is interesting to note that suitably designed pentamethimium salts display very strong inhibition activity against dihydroorotate dehydrogenase [ 129 ], which catalyses the mitochondrial step of de novo pyrimidine synthesis (conversion of dihydroorotate to orotate) [ 130 ]. Because the enzyme prosthetic group flavin mononucleotide serves as an acceptor of a dihydroorotate electron, its inhibition can cause disturbance of mitochondrial respiration [ 131 ].…”

Section: Inhibition Of Il-6 Signalling In Combination Therapymentioning

confidence: 99%

“…Because the enzyme prosthetic group flavin mononucleotide serves as an acceptor of a dihydroorotate electron, its inhibition can cause disturbance of mitochondrial respiration [ 131 ]. In prostate cancer cells, pentamethinium application led to the imbalance of the mitochondrial metabolism, which is strongly associated with the repression of cell migration and invasiveness [ 129 ].…”

Section: Inhibition Of Il-6 Signalling In Combination Therapymentioning

confidence: 99%

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The Role of IL-6 in Cancer Cell Invasiveness and Metastasis—Overview and Therapeutic Opportunities

Rašková

Lacina

Kejík

et al. 2022

Cells

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Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role of IL-6 signalling pathways in cancer biology, with particular emphasis on cancer cell invasiveness and metastasis formation. Targeting principal components of IL-6 signalling (e.g., IL-6Rs, gp130, STAT3, NF-κB) is an intensively studied approach in preclinical cancer research. It is of significant translational potential; numerous studies strongly imply the remarkable potential of IL-6 signalling inhibitors, especially in metastasis suppression.

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Section: Inhibition Of Il-6 Signalling In Combination Therapymentioning

confidence: 99%

Section: Inhibition Of Il-6 Signalling In Combination Therapymentioning

confidence: 99%

The Role of IL-6 in Cancer Cell Invasiveness and Metastasis—Overview and Therapeutic Opportunities

Rašková

Lacina

Kejík

et al. 2022

Cells

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“…This contrasts to some previously published literature; however, this may be explained by the fact that other studies have used a different class of compounds to inhibit DHODH, which binds the active site of the enzyme. 68 We hypothesize that inhibition of DHODH causes cells to upregulate the expression of other genes, which allow the cell to increase its mitochondrial membrane potential to try to maximize mitochondrial energy production because DHODH-dependent respiration is inhibited. Additional experiments with BRQ in combination with specific mitochondrial complex inhibitors are underway to better elucidate the role of DHODH inhibition in mitochondrial respiration.…”

Section: Discussionmentioning

confidence: 99%

DHODH: a promising target in the treatment of T-cell acute lymphoblastic leukemia

Sexauer,

Alexe,

Gustafsson

et al. 2023

Blood Advances

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Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify DHODH (dihydroorotate dehydrogenase) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, cell cycle arrest, and ultimately death. T lymphoblasts appear to be specifically and exquisitely sensitive to nucleotide starvation following DHODHi. We have confirmed this sensitivity in vitro as well as in vivo in three murine models of T ALL. We identified that certain subsets of T-ALL seem to have an increased reliance on oxidative phosphorylation when treated with DHODHi. Through a series of metabolic assays, we show that leukemia cells, in the setting of nucleotide starvation, have changes in their mitochondrial membrane potential and may be more highly dependent on alternative fuel sources. The effect on normal T cell development in young mice was also examined to show that DHODH inhibition does not permanent damage the developing thymus. These changes suggest a new metabolic vulnerability that may distinguish these cells from normal T-cells and other normal hematopoietic cells and offer an exploitable therapeutic opportunity. The availability of clinical-grade DHODH inhibitors currently in human clinical trials speaks to the potential for rapidly advancing this work into the clinic.-

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Combination of quinoxaline with pentamethinium system: Mitochondrial staining and targeting

Kejík,

Koubková,

Krčová

et al. 2023

Bioorganic Chemistry

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Pentamethinium salts suppress key metastatic processes by regulating mitochondrial function and inhibiting dihydroorotate dehydrogenase respiration

Cited by 6 publications

References 58 publications

The Role of IL-6 in Cancer Cell Invasiveness and Metastasis—Overview and Therapeutic Opportunities

The Role of IL-6 in Cancer Cell Invasiveness and Metastasis—Overview and Therapeutic Opportunities

DHODH: a promising target in the treatment of T-cell acute lymphoblastic leukemia

Combination of quinoxaline with pentamethinium system: Mitochondrial staining and targeting

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