Abstract
The DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) is a key determinant of cancer resistance. The MGMT inhibitors O6-benzylguanine (O6BG) and O6-(4-bromothenyl)guanine (O6BTG) failed to enhance the therapeutic response due to toxic side effects when applied in combination with alkylating chemotherapeutics, indicating a need of inhibitor targeting. We assessed MGMT targeting that relies on conjugating the inhibitors O6BG and O6BTG to ß-D-glucose, resulting in O6BG-Glu and O6BTG-Glu, respectively. This targeting strategy was selected by taking advantage of high demand of glucose in cancers. Contrary to our expectation, the uptake of O6BG-Glu and O6BTG-Glu was not dependent on glucose transporters. Instead, it seems that after membrane binding the conjugates are taken up via flippases, which normally transport phospholipids. This membrane binding is the consequence of the amphiphilic character of the conjugates, which at higher concentrations lead to the formation of micelle-like particles in aqueous solution. The unusual uptake mechanism of the conjugates highlights the importance of proper linker selection for a successful ligand-based drug delivery strategy. We also demonstrate that proteins of the P4-Type ATPase family are involved in the transport of the glucose conjugates. The findings are not only important for MGMT inhibitor targeting, but also for other amphiphilic drugs.
Highlights
In many countries, cancer is the second most common cause of death after cardiovascular diseases
We show that the uptake of O6BG-Glu and O6-(4-bromothenyl) guanine (O6BTG)-Glu is not dependent on glucose transporters, but relies on an unexpected mechanism of drug flipping
Are glucose transporters involved in the uptake of glucose-conjugated MGMT inhibitors? To demonstrate the ability of the conjugates to inhibit MGMT, T98G glioblastoma cells were treated with the MGMT inhibitors O6BG and O6BTG and with the glucose conjugates derived from them, O6BG-Glu and O6BTG-Glu, We observed a clear time-dependent inhibition of MGMT for the glucose-conjugated MGMT inhibitors
Summary
Cancer is the second most common cause of death after cardiovascular diseases. Despite the development of efficient MGMT inhibitors such as O6-benzylguanine (O6BG) and O6-(4-bromothenyl) guanine (O6BTG, lomeguatrib), the therapeutic outcome in clinical trials conducted so far was not improved This could be due to unselective reaction of MGMT inhibitors throughout the body enhancing systemic side effects, such as hematotoxicity, which in turn requires dose reduction of the alkylating drug. In cancer therapy, which exploits the enhanced glucose uptake in tumors, the pharmacological inhibition of glucose uptake or activity of certain glycolytic enzymes represents a potential target[16]. Another clinical application is the conjugation of anticancer drugs to glucose molecules, taking advantage of high glucose uptake as a drug delivery strategy for targeting cancer cells. Recent studies indicate that P4-ATPases differ in their substrate specificities and mediate unidirectional transport of a multitude of substrates, including lysophospholipids and the anticancer molecules alkylphospholipids[24,25,26]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
