Targeting Energy Metabolism in Cancer Stem Cells: Progress and Challenges in Leukemia and Solid Tumors

Jones, Courtney L.; Inguva, Anagha; Jordan, Craig T.

doi:10.1016/j.stem.2021.02.013

Cited by 89 publications

(59 citation statements)

References 175 publications

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“…4c). The remarkable degree of efficacy seen for ammocidin A monotherapy in leukemia is consistent with recent studies that suggest that leukemia cells, and in particular therapy resistant leukemia stem cells (LSCs), are exquisitely sensitive to OXPHOS inhibition 8,51–55 .…”

Section: Resultssupporting

confidence: 82%

“…Although Warburg metabolism predominates in many cancers, there is increasing recognition that some cancers and subsets of cancer cells are dependent on mitochondrial oxidative phosphorylation (OXPHOS) to serve both bioenergetic and biosynthetic needs 5–7 . Notably, OXPHOS dependence appears to be a recurrent vulnerability of cancer stem cells (CSCs) and leukemia stem cells (LSCs), which are often responsible for treatment failure 8–11 . Despite these vulnerabilities, outside of a small group of genetically defined tumor subsets 12 , therapeutics designed for metabolic targets in cancer have largely fallen short of their great promise 13 .…”

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confidence: 99%

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A Family of Glycosylated Macrolides Selectively Target Energetic Vulnerabilities in Leukemia

Reisman

Guo

et al. 2021

Preprint

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Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1 subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. CryoEM of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence define the mechanism of action of apoptolidin family glycomacrolides and establish a path to address OXPHOS-dependent cancers.

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Section: Resultssupporting

confidence: 82%

mentioning

confidence: 99%

A Family of Glycosylated Macrolides Selectively Target Energetic Vulnerabilities in Leukemia

Reisman

Guo

et al. 2021

Preprint

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“…Metformin is an old drug widely used for type II diabetes; it is well-known that metformin has the capacity to remodulate metabolic pathways that are altered in cancer, and to inhibit specific chromatin-modifying metabolites. Research studies indicated an impact of metformin also on CSCs and suggested that epigenetic changes may increase the sensitivity of tumor cells to chemotherapy (Jones et al 2021 ). In ovarian cancer patients, metformin inclusion in the treatment strategy significantly reduced the proportion of ALDH + CD133 + CSCs and improved the overall survival (Brown et al 2020 ).…”

Section: Main Textmentioning

confidence: 99%

Macrophages and cancer stem cells: a malevolent alliance

Allavena

Digifico

Belgiovine

2021

Mol Med

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Myeloid cells infiltrating tumors are gaining ever growing attention in the last years because their pro-tumor and immunosuppressive functions are relevant for disease progression and therapeutic responses. The functional ambiguity of tumor-associated macrophages (TAMs), mostly promoting tumor evolution, is a challenging hurdle. This is even more evident in the case of cancer stem cells (CSCs); as active participants in the specialized environment of the cancer stem cell niche, TAMs initiate a reciprocal conversation with CSCs. TAMs contribute to protect CSCs from the hostile environment (exogenous insults, toxic compounds, attacks from the immune cells), and produce several biologically active mediators that modulate crucial developmental pathways that sustain cancer cell stemness. In this review, we have focused our attention on the interaction between TAMs and CSCs; we describe how TAMs impact on CSC biology and, in turn, how CSCs exploit the tissue trophic activity of macrophages to survive and progress. Since CSCs are responsible for therapy resistance and tumor recurrence, they are important therapeutic targets. In view of the recent success in oncology obtained by stimulating the immune system, we discuss some macrophage-targeted therapeutic strategies that may also affect the CSCs and interrupt their malevolent alliance.

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“…The mitochondria of cancer cells can have increased transmembrane potentials in comparison with normal cells [ 32 ]. However, the bioenergetics of resistant and cancer stem cells (CSCs), which are mainly responsible for metastasis, differ from the cancer cells themselves [ 33 , 34 , 35 ]. Ultimately, this may allow cancer cells to be discriminated according to their degree of aggressiveness.…”

Section: Introductionmentioning

confidence: 99%

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

et al. 2021

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In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.

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Targeting Energy Metabolism in Cancer Stem Cells: Progress and Challenges in Leukemia and Solid Tumors

Cited by 89 publications

References 175 publications

A Family of Glycosylated Macrolides Selectively Target Energetic Vulnerabilities in Leukemia

A Family of Glycosylated Macrolides Selectively Target Energetic Vulnerabilities in Leukemia

Macrophages and cancer stem cells: a malevolent alliance

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

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