Isolation of hypoxia-inducible factor 1 (HIF-1) inhibitors from frankincense using a molecularly imprinted polymer

Abstract

Hypoxia-Inducible Factor 1 (HIF-1), a transcriptional activator, is highly involved in the pathology of cancer. Inhibition of HIF-1 retards tumor growth and enhances treatment efficiency when used in combination with chemo- or radiation therapy. The recent validation of HIF-1 as an important drug target in cancer treatment has stimulated efforts to identify and isolate natural or synthetic HIF-1 inhibitors. In the present study, quercetin, a known inhibitor of HIF-1, was imprinted in a polymer matrix in order to prepare a Molecularly Imprinted Polymer (MIP), which was subsequently used for the selective isolation of new inhibitors from frankincense, a gum resin used as anticancer remedy in traditional medicine. The frankincense components isolated by Solid Phase Extraction on MIP (MIP-SPE), efficiently inhibited the transcriptional activity of HIF-1 and decreased the protein levels of HIF-1α, the regulated subunit of HIF-1. The selective retention of acetyl 11-ketoboswellic acid (AKBA, one of the main bioactive components of frankincense) by MIP led to the revealing of its inhibitory activity on the HIF-1 signaling pathway. AKBA was selectively retained by SPE on the quercetin imprinted polymer, with an imprinting effect of 8.1 ± 4.6. Overall, this study demonstrates the potential of MIP application in the screening, recognition and isolation of new bioactive compounds that aim selected molecular targets, a potential that has been poorly appreciated until.

Hypoxia Inducible Factor Pathway Inhibitors as Anticancer Therapeutics

“…Results from high-throughput screenings and natural product discovery [198] have also yielded new hits and lead compounds, but even more new methods need to be identified. Recently, novel HIF inhibitors from frankincense were identified through a new method using a molecularly imprinted polymer [199]. Acriflavine was identified as a HIF-dimerization inhibitor from a screening of drugs that had previously made it to Phase II clinical trials [200].…”

Intelligent recognitive systems in nanomedicine

“…HIF-1 is a protein whose transcriptional activity is increased in the hypoxic environment of tumors. By incubating the MIPs with frankincense, a natural anticancer remedy, they identified and isolated other bioactive compounds that work as HIF-1 inhibitors [52]. …”

Computer simulation based selection of optimal monomer for imprinting of tri-O-acetiladenosine in polymer matrix: vacuum calculations

“…In particular, molecular imprinted polymers with cavities obtained using TOAA molecule as template and imitating ATP binding sites of protein kinases are proposed for recognizing and blocking of the appropriate inhibitors [1]. To fabricate such polymers, the molecular imprinting method based on functional monomer polymerization in the presence of molecule-templates was applied.…”

“…Polymers imprinted with 3-O-acetiladenosine (TOAA), soluble in organic solvents analog of adenosine, can be used for selective recognition and extraction of ATP-competitive inhibitors from various natural and synthetic sources [1]. These compounds are capable of inhibiting the protein kinases, a large family of adenosine triphosphate (ATP)-dependent enzymes ubiquitously involved in cell signaling that controls a diverse set of cellular processes such as cell cycle progression, proliferation, metabolism, apoptosis and differentiation.…”