A "Clickable" Probe for Active MGMT in Glioblastoma Demonstrates Two Discrete Populations of MGMT
CANCERS(2020)
Abstract
Various pathways can repair DNA alkylation by chemotherapeutic agents such as temozolomide (TMZ). The enzyme O-6-methylguanine methyltransferase (MGMT) removes O-6-methylated DNA adducts, leading to the failure of chemotherapy in resistant glioblastomas. Because of the anti-chemotherapeutic activities of MGMT previously described, estimating the levels of active MGMT in cancer cells can be a significant predictor of response to alkylating agents. Current methods to detect MGMT in cells are indirect, complicated, time-intensive, or utilize molecules that require complex and multistep chemistry synthesis. Our design simulates DNA repair by the transfer of a clickable propargyl group from O-6-propargyl guanine to active MGMT and subsequent attachment of fluorescein-linked PEG linker via "click chemistry." Visualization of active MGMT levels reveals discrete active and inactive MGMT populations with biphasic kinetics for MGMT inactivation in response to TMZ-induced DNA damage.
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Key words
MGMT,glioblastoma,click chemistry,cancers,temozolomide,DNA repair,drug resistance
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