Temozolomide–perillyl alcohol conjugate downregulates O(6)-methylguanin DNA methltransferase via inducing ubiquitination-dependent proteolysis in non-small cell lung cancer

The DNA repair enzyme O(6)-methylguanin-DNA-methltransferase (MGMT) is able to remove products of alkylating agent such as O(6)-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.