Molecular Pathways: A Novel Approach to Targeting Hypoxia and Improving Radiotherapy Efficacy via Reduction in Oxygen Demand

Lin, Alexander P.; Maity, Amit

doi:10.1158/1078-0432.ccr-14-0858

Cited by 43 publications

(37 citation statements)

References 47 publications

(59 reference statements)

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“…However, we cannot completely rule out possible effects of tamoxifen on upstream processes, such as the TCA cycle, that contribute electron donors to the respiratory chain. Another implication of our findings with translational potential is the fact that inhibition of oxygen consumption is a validated strategy to increase tumor pO2 and decrease hypoxia, a major cause of cancer resistance to genotoxic therapy, including radiation (35). Therefore, tamoxifen has the potential to function as a radiation and chemotherapeutic sensitizer.…”

Section: Discussionmentioning

confidence: 91%

AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor–Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment

et al. 2016

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Tamoxifen is the most widely used adjuvant chemotherapeutic for the treatment of estrogen receptor (ER) positive breast cancer, yet a large body of clinical and preclinical data indicates that tamoxifen can modulate multiple cellular processes independently of ER status. Here, we describe the ER-independent effects of tamoxifen on tumor metabolism. Using combined pharmacological and genetic knockout approaches, we demonstrate that tamoxifen inhibits oxygen consumption via inhibition of mitochondrial complex I, resulting in an increase in the AMP/ATP ratio and activation of the AMPK signaling pathway in vitro and in vivo. AMPK in turn promotes glycolysis, and alters fatty acid metabolism. We also show that tamoxifen-induced cytotoxicity is modulated by isoform-specific effects of AMPK signaling, in which AMPKα1 promotes cell death through inhibition of the mTOR pathway and translation. By using agents which concurrently target distinct adaptive responses to tamoxifen-mediated metabolic reprogramming, we demonstrate increased cytotoxicity through synergistic therapeutic approaches. Our results demonstrate novel metabolic perturbations by tamoxifen in tumor cells which can be exploited to expand the therapeutic potential of tamoxifen treatment beyond ER+ breast cancer.

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Section: Discussionmentioning

confidence: 91%

AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor–Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment

et al. 2016

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“…517–520 Published reports suggest that decreasing oxygen consumption by inhibiting respiration with pharmacologic agents is an effective way to increase tumor oxygenation (i.e., decreased hypoxia) and radiosensitivity. 588,589 Several inhibitors of mitochondrial respiration, including metformin, enhanced tumor radiosensitivity by improving tumor oxygenation. 590–595 …”

Section: Mitochondria-targeted Therapeutics In the Pre-clinical Momentioning

confidence: 99%

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Zielonka¹,

Joseph²,

et al. 2017

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Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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“…Similarly, in the case of myeloma, NFV was able to enhance bortezomib to overcome both bortezomib and carfilzomib resistance, again, attributed to ER stress leading to increased unfolded protein response (UPR) pathway-induced apoptosis 46. Additionally, owing to its influence on cellular stress, NFV has also been considered in combination with radiation therapy 33,39,47,48. To consider NFV’s application in the treatment of pediatric leukemia, we examined a panel of mechanistically diverse chemotherapeutic drugs in combination with NFV.…”

Section: Discussionmentioning

confidence: 99%

The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia

Meier-Stephenson¹,

Riemer²,

Narendran³

2017

OTT

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PurposeRefractory pediatric leukemia remains one of the leading causes of death in children. Intensification of current chemotherapy regimens to improve the outcome in these children is often limited by the effects of drug resistance and cumulative toxicity. Hence, the search for newer agents and novel therapeutic approaches are urgently needed to formulate the next-generation early-phase clinical trials for these patients.Materials and methodsA comprehensive library of antimicrobials, including eight HIV protease inhibitors (nelfinavir [NFV], saquinavir, indinavir, ritonavir, amprenavir, atazanavir, lopinavir, and darunavir), was tested against a panel of pediatric leukemia cells by in vitro growth inhibition studies. Detailed target modulation studies were carried out by Western blot analyses. In addition, drug synergy experiments with conventional and novel antitumor agents were completed to identify effective treatment regimens for future clinical trials.ResultsSeveral of the HIV protease inhibitors showed cytotoxicity at physiologically relevant concentrations (half-maximal inhibitory concentration values ranging from 1–24 µM). In particular, NFV was found to exhibit the most potent antileukemic properties across all cell lines tested. Mechanistic studies show that NFV leads to the induction of autophagy and apoptosis possibly through the induction of endoplasmic reticulum stress. Furthermore, interference with cell signaling pathways, including Akt and mTOR, was also noted. Finally, drug combination studies have identified agents with potential for synergy with NFV in its antileukemic activity. These include JQ1 (BET inhibitor), AT101 (Bcl-2 family inhibitor), and sunitinib (TK inhibitor).ConclusionHere, we show data demonstrating the potential of a previously unexplored group of drugs to address an unmet therapeutic need in pediatric oncology. The data presented provide preclinical supportive evidence and rationale for future studies of these agents for refractory leukemia in children.

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Molecular Pathways: A Novel Approach to Targeting Hypoxia and Improving Radiotherapy Efficacy via Reduction in Oxygen Demand

Cited by 43 publications

References 47 publications

AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor–Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment

AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor–Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia

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