The well understanding of cancer metabolism and signaling pathways, has allowed for development of more effective therapies. For instance, the increase of glucose consumption in many types of cancer cells is regulated by overexpression of type II hexokinase (HKII). Indeed, tumor cells show active glycolysis even under aerobic conditions, which is known as the Warburg effect . This unique pathway endows cancer cells with selective advantages like enhanced proliferation, invasion, and metastasis . The glycolysis furthermore confers selective advantage to cancer cells by supporting uninterrupted growth. For example, a higher glycolytic rate in tumor cells has been shown to promote resistance to chemotherapeutics. In the cervical cancer cell line, HeLa for example, the enzyme pyruvate dehydrogenase kinase (PDK) isoforms PDK1 and PDK3 have been demonstrated to provide resistance to chemotherapeutics . Hexokinase is a key glycolytic enzyme that catalyzes the first step in the glycolytic pathway and helps to exhibit the Warburg effect. This enzyme transfers a phosphate group from ATP to glucose to form glucose-6-phosphate. Moreover, HKII interacts with the outer membrane protein voltage dependent anion channel (VDAC). It blocks mitochondrial inter membrane space proteins release and prevents activation of the apoptotic process . Whereas , HKII prevents association of pro-apoptotic BcL-2 family member proteins (Bad, Bak, Bax) with the mitochondrial permeability transition pore (mtPTP) complex; pro-apoptotic factor association is necessary for mitochondrial permeability transition and cytochrome c release (the apoptotic cascade) . This observation has led to the development of therapeutic strategies such as use of small molecules for inhibition of glycolytic activity in cancer cells . In this case, lonidamine, 3-bromopyruvate (3-BrPA) and 3-BrOP (3-bromo-2-oxopropionate-1 -propyl ester) [7,8], are used as HK-II inhibitors in the early stages of treatment, can effectively inhibit glycolysis. The crucial problem for using them in clinical application is related to their interaction with normal cells, especially erythrocytes . Thus, there is an urgent need to encapsulate them inside smart carriers having efficient strategies from size, shape, and targeted for cancer cells . In our previous report, 3BrPA attached Poly(allylamine) hydrochloride was entrapped inside CaCO3 rods during their fabrication. . However, non-specific, passive, targeting, carriers can result in uptake by healthy cells. This can be minimized by the active targeting of the therapy, In our recent work, targeted hybrid lipid polymer as alternate assembly structure instead of liposomes is fabricated. Their positive attributes make them a promising drug delivery vehicle for further in vivo evaluation. Hybrid polymeric protein carriers (HPPNCs) were assembled by using chitosan, oleic acid and BSA-FA to form core shell structure .
- Kaelin WG Jr, Thompson CB (2010) Q &A: Cancer: clues from cell metabolism. Nature 465: 562-564. [Crossref]
- Gillies RJ, Robey I, Gatenby RA (2008) Causes and consequences of increased glucose metabolism of cancers. J Nucl Med 49: 24S-42S. [Crossref]
- Lu CW, Lin SC, Chen KF, Lai YY, Tsai SJ (2008) Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem 283: 28106-28114. [Crossref]
- Pastorino JG, Hoek JB, Shulga N (2005) Activation of Glycogen Synthase Kinase 3_ Disrupts the Binding of Hexokinase II to Mitochondria by Phosphorylating Voltage-Dependent Anion Channel and Potentiates Chemotherapy-Induced Cytotoxicity. Cancer Res 65: 10545-10554. [Crossref]
- Mathupala SP, Ko YH, Pedersen PL (2006) Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25: 4777-4786. [Crossref]
- Pelicano H, Martin DS, Xu RH, Huang P (2006) Glycolysis inhibition for anticancer treatment. Oncogene 25: 4633-4646. [Crossref]
- 7. Chen Z, Lu W, Garcia-Prieto C, Huang P (2007) The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr 39: 267-274. [Crossref]
- Akers LJ, Fang W, Levy AG, Franklin AR, Huang P, Zweidler-McKay PA (2011) Targeting glycolysis in leukemia: a novel inhibitor 3-BrOP in combination with rapamycin. Leuk Res 5: 814-820. [Crossref]
- Sadowska-Bartosz I, Soszynski M, Ulaszewski S, KoY, Bartosz G (2014) Transport of 3-bromopyurvate across the human erytherocyte membrane. Cell Mol Biol Lett 19: 201-214. [Crossref]
- Hanafy NAN, Quarta A, Di Corato R, Dini L, Nobile C, et al. (2017) Hybrid polymeric-protein nano-carriers (HPPNC) for targeted delivery of TGFβ inhibitors to hepatocellular carcinoma cells. J Mater Sci Mater Med 28: 120 [Crossref]
- Hanafy NAN, De Giorgi ML, Nobile C, Cascione MF, Rinaldi R, et al. (2016) CaCO3 rods as chitosan-polygalacturonic acid carriers for bromopyruvic acid delivery. Sci Adv Mater 8: 514-523.
- Hanafy NA, Dini L, Citti C, Cannazza G, Leporatti S (2018) Inhibition of Glycolysis by Using a Micro/Nano- Lipid Bromopyruvic Chitosan Carrier as a Promising Tool to Improve Treatment of Hepatocellular Carcinoma. Nanomaterials (Basel) 8: [Crossref]
University of Rochester Medical Center
2021 Copyright OAT. All rights reserv
Received date: December 02, 2017
Accepted date: December 22, 2017
Published date: December 26, 2017
© 2017 Hanafy NAN. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Hanafy NAN (2017) Glycolysis is a promising target for encapsulation nano-therapeutic molecules against cancer cells. Integr Cancer Sci Therap. 4: DOI: 10.15761/ICST.1000262
Nemany A.N. Hanafy
Institute of Nanoscience and Nanotechnology, Kafrelsheikh University, Egypt.
E-mail : firstname.lastname@example.org