bims-almceb 2022-05-29 papers

Cancers (Basel). 2022 May 18. pii: 2485. [Epub ahead of print]14(10):

Diphenyleneiodonium Triggers Cell Death of Acute Myeloid Leukemia Cells by Blocking the Mitochondrial Respiratory Chain, and Synergizes with Cytarabine.

Hassan Dakik, Maya El Dor, Jérôme Bourgeais, Farah Kouzi, Olivier Herault, Fabrice Gouilleux, Kazem Zibara, Frédéric Mazurier.

Acute myeloid leukemia (AML) is characterized by the accumulation of undifferentiated blast cells in the bone marrow and blood. In most cases of AML, relapse frequently occurs due to resistance to chemotherapy. Compelling research results indicate that drug resistance in cancer cells is highly dependent on the intracellular levels of reactive oxygen species (ROS). Modulating ROS levels is therefore a valuable strategy to overcome the chemotherapy resistance of leukemic cells. In this study, we evaluated the efficiency of diphenyleneiodonium (DPI)-a well-known inhibitor of ROS production-in targeting AML cells. Results showed that although inhibiting cytoplasmic ROS production, DPI also triggered an increase in the mitochondrial ROS levels, caused by the disruption of the mitochondrial respiratory chain. We also demonstrated that DPI blocks mitochondrial oxidative phosphorylation (OxPhos) in a dose-dependent manner, and that AML cells with high OxPhos status are highly sensitive to treatment with DPI, which synergizes with the chemotherapeutic agent cytarabine (Ara-C). Thus, our results suggest that targeting mitochondrial function with DPI might be exploited to target AML cells with high OxPhos status.

Keywords: Ara-C; DPI; OxPhos; leukemia; mitochondria; oxidative stress

DOI: https://doi.org/10.3390/cancers14102485

Front Oncol. 2022 ;12 906421

Editorial: Metabolism Meets Function: The Multifaced Role of Metabolism in Cancer.

Isabella Giacomini, Monica Montopoli.

Keywords: cancer; cancer metabolism; drug resistance; metabolic reprogramming; targeting metabolism; tumor microenviroment (TME)

DOI: https://doi.org/10.3389/fonc.2022.906421

Int J Mol Sci. 2022 May 16. pii: 5572. [Epub ahead of print]23(10):

Targeting Energy Metabolism in Cancer Treatment.

Joanna Kubik, Ewelina Humeniuk, Grzegorz Adamczuk, Barbara Madej-Czerwonka, Agnieszka Korga-Plewko.

Cancer is the second most common cause of death worldwide after cardiovascular diseases. The development of molecular and biochemical techniques has expanded the knowledge of changes occurring in specific metabolic pathways of cancer cells. Increased aerobic glycolysis, the promotion of anaplerotic responses, and especially the dependence of cells on glutamine and fatty acid metabolism have become subjects of study. Despite many cancer treatment strategies, many patients with neoplastic diseases cannot be completely cured due to the development of resistance in cancer cells to currently used therapeutic approaches. It is now becoming a priority to develop new treatment strategies that are highly effective and have few side effects. In this review, we present the current knowledge of the enzymes involved in the different steps of glycolysis, the Krebs cycle, and the pentose phosphate pathway, and possible targeted therapies. The review also focuses on presenting the differences between cancer cells and normal cells in terms of metabolic phenotype. Knowledge of cancer cell metabolism is constantly evolving, and further research is needed to develop new strategies for anti-cancer therapies.

Keywords: cancer metabolism; cancer treatment; glycolysis; oxidative phosphorylation

DOI: https://doi.org/10.3390/ijms23105572

Nucl Med Commun. 2022 May 30.

CD133 increases oxidative glucose metabolism of HT29 cancer cells by mitochondrial uncoupling and its inhibition enhances reactive oxygen species-inducing therapy.

Jin Hee Lee, Eun Ji Lee, Jin Won Park, Mina Kim, Kyung-Ho Jung, Young Seok Cho, Kyung-Han Lee.

OBJECTIVE: A better understanding of the metabolic phenotype of stem-like cancer cells could provide targets to help overcome chemoresistance. In this study, we hypothesized that colon cancer cells with the stem cell feature of CD133 expression have increased proton leakage that influences glucose metabolism and offers protection against reactive oxygen species (ROS)-inducing treatment.
METHODS AND RESULTS: In HT29 colon cancer cells, 18F-fluorodeoxyglucose (FDG) uptake was increased by CD133 selection and decreased by CD133 silencing. In CD133(+) cells, greater 18F-FDG uptake was accompanied by increased oxygen consumption rate (OCR) and reduced mitochondrial membrane potential and mitochondrial ROS, indicating increased proton leakage. The uncoupling protein inhibitor genipin reversed the increased 18F-FDG uptake and greater OCR of CD133(+) cells. The ROS-inducing drug, piperlongumine, suppressed CD133(-) cell survival by stimulating mitochondrial ROS generation but was unable to influence CD133(+) cells when used alone. However, cotreatment of CD133(+) cells with genipin and piperlongumine efficiently stimulated mitochondrial ROS for an enhanced antitumor effect with substantially reduced CD133 expression.
CONCLUSION: These results demonstrate that mitochondrial uncoupling is a metabolic feature of CD133(+) colon cancer cells that provides protection against piperlongumine therapy by suppressing mitochondrial ROS generation. Hence, combining genipin with ROS-inducing treatment may be an effective strategy to reverse the metabolic feature and eliminate stem-like colon cancer cells.

DOI: https://doi.org/10.1097/MNM.0000000000001587

Front Immunol. 2022 ;13 884024

Bone Marrow Niches and Tumour Cells: Lights and Shadows of a Mutual Relationship.

Valentina Granata, Laura Crisafulli, Claudia Nastasi, Francesca Ficara, Cristina Sobacchi.

The bone marrow (BM) niche is the spatial structure within the intra-trabecular spaces of spongious bones and of the cavity of long bones where adult haematopoietic stem cells (HSCs) maintain their undifferentiated and cellular self-renewal state through the intervention of vascular and nervous networks, metabolic pathways, transcriptional and epigenetic regulators, and humoral signals. Within the niche, HSCs interact with various cell types such as osteoblasts, endothelial cells, macrophages, and mesenchymal stromal cells (MSCs), which maintain HSCs in a quiescent state or sustain their proliferation, differentiation, and trafficking, depending on body needs. In physiological conditions, the BM niche permits the daily production of all the blood and immune cells and their admittance/ingress/progression into the bloodstream. However, disruption of this delicate microenvironment promotes the initiation and progression of malignancies such as those included in the spectrum of myeloid neoplasms, also favouring resistance to pharmacological therapies. Alterations in the MSC population and in the crosstalk with HSCs owing to tumour-derived factors contribute to the formation of a malignant niche. On the other hand, cells of the BM microenvironment cooperate in creating a unique milieu favouring metastasization of distant tumours into the bone. In this framework, the pro-tumorigenic role of MSCs is well-documented, and few evidence suggest also an anti-tumorigenic effect. Here we will review recent advances regarding the BM niche composition and functionality in normal and in malignant conditions, as well as the therapeutic implications of the interplay between its diverse cellular components and malignant cells.

Keywords: JAK2; MSCs; RANKL; bone marrow niches; hematopoietic stem cells (HSCs); metastasis; myeloid neoplasms; targeted therapy

DOI: https://doi.org/10.3389/fimmu.2022.884024

Front Physiol. 2022 ;13 859820

Low Cancer Incidence in Naked Mole-Rats May Be Related to Their Inability to Express the Warburg Effect.

Pedro Freire Jorge, Matthew L Goodwin, Maurits H Renes, Maarten W Nijsten, Matthew Pamenter.

Metabolic flexibility in mammals enables stressed tissues to generate additional ATP by converting large amounts of glucose into lactic acid; however, this process can cause transient local or systemic acidosis. Certain mammals are adapted to extreme environments and are capable of enhanced metabolic flexibility as a specialized adaptation to challenging habitat niches. For example, naked mole-rats (NMRs) are a fossorial and hypoxia-tolerant mammal whose metabolic responses to environmental stressors markedly differ from most other mammals. When exposed to hypoxia, NMRs exhibit robust hypometabolism but develop minimal acidosis. Furthermore, and despite a very long lifespan relative to other rodents, NMRs have a remarkably low cancer incidence. Most advanced cancers in mammals display increased production of lactic acid from glucose, irrespective of oxygen availability. This hallmark of cancer is known as the Warburg effect (WE). Most malignancies acquire this metabolic phenotype during their somatic evolution, as the WE benefits tumor growth in several ways. We propose that the peculiar metabolism of the NMR makes development of the WE inherently difficult, which might contribute to the extraordinarily low cancer rate in NMRs. Such an adaptation of NMRs to their subterranean environment may have been facilitated by modified biochemical responses with a stronger inhibition of the production of CO2 and lactic acid by a decreased extracellular pH. Since this pH-inhibition could be deeply hard-wired in their metabolic make-up, it may be difficult for malignant cells in NMRs to acquire the WE-phenotype that facilitates cancer growth in other mammals. In the present commentary, we discuss this idea and propose experimental tests of our hypothesis.

Keywords: Warburg effect; cancer metabolism; hypoxic metabolic response; hypoxic ventilatory response (HVR); metabolic fuel switching; metabolism; naked mole-rat; thermoregulation

DOI: https://doi.org/10.3389/fphys.2022.859820