Abstract
The DNA repair enzyme O6-methylguanin-DNA-methltransferase (MGMT) is able to remove products of alkylating agent such as O6-meG and emerges as a central determinant of cancer resistance to temozolomide (TMZ). Temozolomide–perillyl alcohol conjugate (TMZ–POH), a novel TMZ analog developed based on the conjugation of TMZ and POH, displayed strong anticancer potency in multiple cancer types, but seemed not to experience the chemoresistance even in cells with high MGMT expression unlike TMZ and other alkylating agents. In this study, we demonstrated TMZ–POH inhibited MGMT dependent on proteasomal pathway and this inhibition is a significant factor in its toxic effect in the non-small cell lung cancer (NSCLC) cells.
Highlights
Nowadays, chemotherapy has been traditionally considered as one of the standard treatment options for cancer patients, but the chemoresistance dramatically hinders its clinical application, especially for alkylating agents like temozolomide (TMZ)[1]
We demonstrated that Temozolomide–perillyl alcohol conjugate (TMZ–POH), a newly designed TMZ analog, inhibited MGMT significantly in a concentration-dependent and time-dependent manner
Our data show that MGMT downregulation is required for TMZ–POH’s cytotoxicity, as evidence from TMZ–POH’s cytotoxicity enhanced by O6-BG but alleviated by MGMT overexpression, supporting the idea that MGMT is involved in the efficiency of alkylating agents
Summary
Chemotherapy has been traditionally considered as one of the standard treatment options for cancer patients, but the chemoresistance dramatically hinders its clinical application, especially for alkylating agents like temozolomide (TMZ)[1]. Its cytotoxicity is mainly due to its capability to react with DNA to form methyl adducts[3], TMZ chemotherapy may enhance survival of cancer patients, intrinsic or acquired resistance to TMZ is common and accounts for many treatment failures[5], because TMZ-induced DNA alkylation damage can be repaired by O6-methylguanin-DNA-methltransferase (MGMT)[6]. MGMT is able to remove O6-meG which covalently is attached to the protein and inactivates it[9], and emerges as a central determinant of tumor resistance to alkylating agents. Despite the development and application of many MGMT inhibitors including O6-benzylguanine
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