Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases.

ABSTRACT: The DNA repair protein O ⁶-methylguanine-DNA-methyltransferase (MGMT) is a key determinant of cancer resistance. The MGMT inhibitors O ⁶-benzylguanine (O⁶BG) and O ⁶-(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-

SUBMITTER: Tomaszowski KH 

PROVIDER: S-EPMC5655675 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature