Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis

Gandham, Srujan; Talekar, Meghna; Singh, Amit; Amiji, Mansoor M.

doi:10.2147/ijn.s82818

Cited by 18 publications

(10 citation statements)

References 29 publications

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“…HK2 is regulated by the transcription factors such as p53, Myc, and HIF-1 [ 168 ]. Besides, the effective anticancer drug 3-bromopyruvate (3BP) is a structural analog of pyruvic acid, which plays the inhibitory effects on HK2 [ 169 – 171 ]. HK2 is characterized as an oncoprotein since its role in tumor onset [ 164 ].…”

Section: Hk2mentioning

confidence: 99%

Chaperone-mediated autophagy substrate proteins in cancer

et al. 2017

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All intracellular proteins undergo continuous synthesis and degradation. Chaperone-mediated autophagy (CMA) is necessary to maintain cellular homeostasis through turnover of cytosolic proteins (substrate proteins). This degradation involves a series of substrate proteins including both cancer promoters and suppressors. Since activating or inhibiting CMA pathway to treat cancer is still debated, targeting to the CMA substrate proteins provides a novel direction. We summarize the cancer-associated substrate proteins which are degraded by CMA. Consequently, CMA substrate proteins catalyze the glycolysis which contributes to the Warburg effect in cancer cells. The fact that the degradation of substrate proteins based on the CMA can be altered by posttranslational modifications such as phosphorylation or acetylation. In conclusion, targeting to CMA substrate proteins develops into a new anticancer therapeutic approach.

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Section: Hk2mentioning

confidence: 99%

Chaperone-mediated autophagy substrate proteins in cancer

et al. 2017

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“…Some commonly used inhibitors include glucose analogs 2-deoxy-D-glucose (2-DG) and 3-bromopyruvate (3-BPA), which have been shown to induce cytotoxic effects on acute lymphoblastic leukemia while enhancing the efficacy of prednisone treatment [73,74]. An epidermal growth factor receptor-targeted liposomal formulation of 3-BPA showed improved permeability, HKII inhibition, and cytotoxicity compared with conventional aqueous 3-BPA formulations [75]. However, a recent study indicated that 3-BPA was still effective in killing HKII knockout cells, thus suggesting that in addition to HKII, the efficacy of 3-BPA may be also dependent on tumour microenvironment and glucose availability [76].…”

Section: Strategies To Target Mitochondriamentioning

confidence: 99%

Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells

Nguyen

Pandey

2019

Cancers

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The transformation of normal cells to the cancerous stage involves multiple genetic changes or mutations leading to hyperproliferation, resistance to apoptosis, and evasion of the host immune system. However, to accomplish hyperproliferation, cancer cells undergo profound metabolic reprogramming including oxidative glycolysis and acidification of the cytoplasm, leading to hyperpolarization of the mitochondrial membrane. The majority of drug development research in the past has focused on targeting DNA replication, repair, and tubulin polymerization to induce apoptosis in cancer cells. Unfortunately, these are not cancer-selective targets. Recently, researchers have started focusing on metabolic, mitochondrial, and oxidative stress vulnerabilities of cancer cells that can be exploited as selective targets for inducing cancer cell death. Indeed, the hyperpolarization of mitochondrial membranes in cancer cells can lead to selective importing of mitocans that can induce apoptotic effects. Herein, we will discuss recent mitochondrial-selective anticancer compounds (mitocans) that have shown selective toxicity against cancer cells. Increased oxidative stress has also been shown to be very effective in selectively inducing cell death in cancer cells. This oxidative stress could lead to mitochondrial dysfunction, which in turn will produce more reactive oxygen species (ROS). This creates a vicious cycle of mitochondrial dysfunction and ROS production, irreversibly leading to cell suicide. We will also explore the possibility of combining these compounds to sensitize cancer cells to the conventional anticancer agents. Mitocans in combination with selective oxidative-stress producing agents could be very effective anticancer treatments with minimal effect on healthy cells.

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“…Nevertheless, the acidic environment of the tumor milieu proves thermodynamically favorable for the uptake of 3-BP by cancer cells because of the pH difference across the plasma membrane (Azevedo-Silva et al, 2015). Another important reason for its selectivity against neoplastic cells is caused by the unmatched ability of 3-BP to alkylate and inactivate metabolic enzymes, which are selectively upregulated in malignant cells (Chen et al, 2009; Ganapathy-Kanniappan et al, 2009; Gandham et al, 2015; Azevedo-Silva et al, 2016; Jardim-Messeder and Moreira-Pacheco, 2016). Being an electrophile, 3-BP covalently and irreversibly modifies its targets’ nucleophilic moieties via S N 2 mechanism of alkylation (Azevedo-Silva et al, 2016; Oronsky et al, 2012) ( Figure 3 ).…”

Section: -Bromopyruvate Is Capable Of Multifaceted Targeting Of Tumomentioning

confidence: 99%

“…The main recommendations for overcoming the limitations regarding the use of 3-BP include strict implementation of only formulated preparations in human applications (El Sayed, 2018; Fan et al, 2019b), use of GSH scavengers accompanying 3-BP administration because GSH can inactivate 3-BP (El Sayed, 2018), and strict monitoring of the dose regimens (El Sayed, 2018). Furthermore, approaches of liposome-encapsulated 3-BP formulations are suggested to improve its adequate concentrations in the tumor milieu (Gandham et al, 2015). Use of 3-BP as an adjunct agent along with other conventional approaches is considered to hold therapeutic potential (Ganapathy-Kanniappan et al, 2013; Zhang et al, 2015; Chong et al, 2017).…”

Section: Limitations and Prospectsmentioning

confidence: 99%

Diverse Stakeholders of Tumor Metabolism: An Appraisal of the Emerging Approach of Multifaceted Metabolic Targeting by 3-Bromopyruvate

et al. 2019

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Malignant cells possess a unique metabolic machinery to endure unobstructed cell survival. It comprises several levels of metabolic networking consisting of 1) upregulated expression of membrane-associated transporter proteins, facilitating unhindered uptake of substrates; 2) upregulated metabolic pathways for efficient substrate utilization; 3) pH and redox homeostasis, conducive for driving metabolism; 4) tumor metabolism-dependent reconstitution of tumor growth promoting the external environment; 5) upregulated expression of receptors and signaling mediators; and 6) distinctive genetic and regulatory makeup to generate and sustain rearranged metabolism. This feat is achieved by a “battery of molecular patrons,” which acts in a highly cohesive and mutually coordinated manner to bestow immortality to neoplastic cells. Consequently, it is necessary to develop a multitargeted therapeutic approach to achieve a formidable inhibition of the diverse arrays of tumor metabolism. Among the emerging agents capable of such multifaceted targeting of tumor metabolism, an alkylating agent designated as 3-bromopyruvate (3-BP) has gained immense research focus because of its broad spectrum and specific antineoplastic action. Inhibitory effects of 3-BP are imparted on a variety of metabolic target molecules, including transporters, metabolic enzymes, and several other crucial stakeholders of tumor metabolism. Moreover, 3-BP ushers a reconstitution of the tumor microenvironment, a reversal of tumor acidosis, and recuperative action on vital organs and systems of the tumor-bearing host. Studies have been conducted to identify targets of 3-BP and its derivatives and characterization of target binding for further optimization. This review presents a brief and comprehensive discussion about the current state of knowledge concerning various aspects of tumor metabolism and explores the prospects of 3-BP as a safe and effective antineoplastic agent.

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Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis

Cited by 18 publications

References 29 publications

Chaperone-mediated autophagy substrate proteins in cancer

Chaperone-mediated autophagy substrate proteins in cancer

Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells

Diverse Stakeholders of Tumor Metabolism: An Appraisal of the Emerging Approach of Multifaceted Metabolic Targeting by 3-Bromopyruvate

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