Inhibitors and Prodrugs Targeting CYP1: A Novel Approach in Cancer Prevention and Therapy
Jiahua Cui and Shaoshun Li
Affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
Keywords: CYP1 inhibitors, prodrugs, chemoprevention, bioactivation, natural products, flavonoids, trans-stilbenes, benzothiazoles,
metabolism, anticancer, SARs.
Since Human CYP1 enzymes catalyze the metabolic activation of procarcinogens and deactivation of certain
anticancer drugs, the inhibition of these enzymes has been considered as an effective approach for chemoprevention and
treatment of CYP1-mediated drug resistance. Recent knowledge relating to the enhanced expression of CYP1B1 in tumors
also provided certain advantages in cancer therapy by the activation of prodrugs only in tumor cells. This review concentrates
on the characterized CYP1 inhibitors and CYP1-activatied anticancer prodrugs. The mechanism for enzyme inhibition
and activation of prodrugs, the cancer preventive/therapeutic potential of these chemicals and their related SARs are
highlighted. According to their structural features, CYP1 inhibitors are divided into the following categories: flavonoids,
trans-stilbenes, coumarins, terpenoids, alkaloids, quinones, isothiocyanates and synthetic aromatics. In the same way,
CYP1-activatied prodrugs are categorized into four groups: benzothiazoles, flavonoids, stilbenes and alkylating agents.
Almost all of these inhibitors and prodrugs are planar molecules with one aromatic ring and some have similarity with
identified CYP1 substrates. CYP1 inhibitors could effectively block the procarcinogen-induced tumor initiation in animal
models and benefit us with chemoprevention. The advent of Phortress and aminoflavone as clinical candidates shows
promising perspectives in developing CYP1-mediated prodrugs as chemotherapeutic drugs that are specifically activated
in tumors. All of these preclinical and clinical studies indicate that inhibitors and prodrugs target CYP1 are promising
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