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Maxwell, P.H., Wiesener, M.S., Chang, G.W., Clifford, S.C., Vaux, E.C., Cockman, M.E., Wykoff, C.C., Pugh, C.W., Maher, E.R. and Ratcliffe, P.J. (1999) The Tumor Suppressor Protein VHL Targets Hypoxia Inducible Factors for Oxygen-Dependent Proteolysis. Nature, 399, 271-275.
https://doi.org/10.1038/20459

has been cited by the following article:

• TITLE: Effect of Modified HIF-1α Linked to Carbonic Anhydrase IX Inhibitor and Glycosylated Cisplatin on Solid Tumors: Short Review

  AUTHORS: Waleed O. Atta, Ahmed Z. Abdel Azeiz

  KEYWORDS: Hypoxia, Carbonic Anhydrase, Cancer, Cisplatin, Nitric Oxide Donor, Glycosylation

  JOURNAL NAME: Journal of Biosciences and Medicines, Vol.9 No.8, August 16, 2021

  ABSTRACT: Many cancer cells in solid tumors are hypoxic or pseudohypoxic and create acidic environment for malignancy progression. Under low oxygen conditions (hypoxia), hypoxia-inducible factors (HIFs) play pathological roles in cancer cell survival and spreading. HIF regulates several genes such as genes of glucose transporters that enhance anaerobic glycolysis, angiogenesis, erythropoiesis and carbonic anhydrase IX (CA-IX). CA-IX is a cell-surface glycoprotein that catalyzes the hydration of CO2 to protons and bicarbonate ions (respiratory acidification). This process is involved in adaptation to acidosis and implicated in cancer progression. Therefore, CA-IX inhibitors (such as sulfonamide-based compounds) showed hoping results in reduction malignancy progression. The article aims to reversal the malignant hypoxic environment in solid tumors to create a condition of weakness within the cancer for further focused cisplatin potency. This article suggests the use of modified synthesized HIF as a drug delivery molecule for both carbonic anhydrase IX inhibitor and glycosylated cisplatin that damages the DNA of malignant cell. HIF molecule has high affinity to bind with CA IX-expressing malignant cells, which is followed by cell entrance via endocytosis. Once the HIF-Cisplatin-CA-inhibitor complex enters the cell, the carbonic anhydrase inhibitor will improve the cellular pH that makes the environment unsuitable for HIF 1α function and it may be ubiquitinated. So, the raise in target genes transcription will be arrested. On the other hand, once the synthetized HIF is degraded, the cisplatin molecules will be released inside the malignant cell and start to damage its DNA. This approach may be a good solution for many solid tumors.