Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells

Gupta, Nehal; Kaushik, Itishree; Wright, Stephen E.; Markiewski, Maciej M.; Srivastava, Sanjay

doi:10.3390/ijms22105150

Cited by 25 publications

(7 citation statements)

References 69 publications

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“…Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, switched the phenotype of MDSC into mature DC and turned the response into Th1 type promoting cytotoxic activity of T cells [ 174 ]. Moreover, atovaquone, an antimalarial drug inhibiting the expression of ribosomal protein S19 (RPS19), induced the MDSC maturation, Tregs reduction, and decreased synthesis of TGF-β and IL-10 [ 175 ]. Artemisinin, another antiplasmodial drug demonstrated similar activity and evoked an increase of T-bet, IFN-γ, and TNFα levels [ 176 ].…”

Section: Strategies To Overcome Immunotherapy Resistance Of Breast Cancermentioning

confidence: 99%

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Retecki

Seweryn

Graczyk-Jarzynka

et al. 2021

Cancers

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Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted.

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Section: Strategies To Overcome Immunotherapy Resistance Of Breast Cancermentioning

confidence: 99%

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Retecki

Seweryn

Graczyk-Jarzynka

et al. 2021

Cancers

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show abstract

“…TNBC is one of the most fatal cancers and is more aggressive than other breast cancer types owing to lack of effective drugs and approved targets [ 4 , 17 , 30 ]. Although cytotoxic chemotherapy has been suggested for the treatment of TNBC, it eventually induces drug resistance and toxicity.…”

Section: Discussionmentioning

confidence: 99%

Isobavachalcone Induces Multiple Cell Death in Human Triple-Negative Breast Cancer MDA-MB-231 Cells

Gao

Chen

et al. 2022

Molecules

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Standardized treatment guidelines and effective drugs are not available for human triple-negative breast cancer (TNBC). Many efforts have recently been exerted to investigate the efficacy of natural compounds as anticancer agents owing to their low toxicity. However, no study has examined the effects of isobavachalcone (IBC) on the programmed cell death (PCD) of human triple-negative breast MDA-MB-231 cancer cells. In this study, IBC substantially inhibited the proliferation of MDA-MB-231 cells in concentration- and time-dependent manners. In addition, we found that IBC induced multiple cell death processes, such as apoptosis, necroptosis, and autophagy in MDA-MB-231 cells. The initial mechanism of IBC-mediated cell death in MDA-MB-231 cells involves the downregulation of Akt and p-Akt-473, an increase in the Bax/Bcl-2 ratio, and cleaved caspases-3 induced apoptosis; the upregulation of RIP3, p-RIP3 and MLKL induced necroptosis; as well as a simultaneous increase in LC3-II/I ratio induced autophagy. In addition, we observed that IBC induced mitochondrial dysfunction, thereby decreasing cellular ATP levels and increasing reactive oxygen species accumulation to induce PCD. These results suggest that IBC is a promising lead compound with anti-TNBC activity.

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“…Migrastatic drugs have been defined as selective inhibitors of metastatic abilities with non-cytotoxic effect ( Gandalovičová et al, 2017 ). Although some migrastatic actions of cytotoxic compounds are reported, those effects can be attributed to the induced cell death, because the direct link between migration and mitochondrial dysfunction has been not established ( Song et al, 2017 ; Yan et al, 2017 ; Dong et al, 2018 ; Yang et al, 2018 ; Cheng et al, 2019 ; Luo et al, 2019 ; Gupta et al, 2021 ; Liu et al, 2021 ). Table 1 shows recent compounds reported with migrastatic effects by induction of mitochondrial dysfunction at non-cytotoxic concentrations.…”

Section: Migrastatic Agents That Promote Mitochondrial-extracellular Matrix Disruption In Cancer Cellsmentioning

confidence: 99%

Extracellular Matrix Signals as Drivers of Mitochondrial Bioenergetics and Metabolic Plasticity of Cancer Cells During Metastasis

Urra

Fuentes-Retamal

Palominos

et al. 2021

Front. Cell Dev. Biol.

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The role of metabolism in tumor growth and chemoresistance has received considerable attention, however, the contribution of mitochondrial bioenergetics in migration, invasion, and metastasis is recently being understood. Migrating cancer cells adapt their energy needs to fluctuating changes in the microenvironment, exhibiting high metabolic plasticity. This occurs due to dynamic changes in the contributions of metabolic pathways to promote localized ATP production in lamellipodia and control signaling mediated by mitochondrial reactive oxygen species. Recent evidence has shown that metabolic shifts toward a mitochondrial metabolism based on the reductive carboxylation, glutaminolysis, and phosphocreatine-creatine kinase pathways promote resistance to anoikis, migration, and invasion in cancer cells. The PGC1a-driven metabolic adaptations with increased electron transport chain activity and superoxide levels are essential for metastasis in several cancer models. Notably, these metabolic changes can be determined by the composition and density of the extracellular matrix (ECM). ECM stiffness, integrins, and small Rho GTPases promote mitochondrial fragmentation, mitochondrial localization in focal adhesion complexes, and metabolic plasticity, supporting enhanced migration and metastasis. Here, we discuss the role of ECM in regulating mitochondrial metabolism during migration and metastasis, highlighting the therapeutic potential of compounds affecting mitochondrial function and selectively block cancer cell migration.

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Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells

Cited by 25 publications

References 69 publications

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Isobavachalcone Induces Multiple Cell Death in Human Triple-Negative Breast Cancer MDA-MB-231 Cells

Extracellular Matrix Signals as Drivers of Mitochondrial Bioenergetics and Metabolic Plasticity of Cancer Cells During Metastasis

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