CYP1B1 as a therapeutic target in cardio-oncology

Abstract

Cardiovascular complications have been frequently reported in cancer patients and survivors, mainly because of various cardiotoxic cancer treatments. Despite the known cardiovascular toxic effects of these treatments, they are still clinically used because of their effectiveness as anti-cancer agents. In this review, we discuss the growing body of evidence suggesting that inhibition of the cytochrome P450 1B1 enzyme (CYP1B1) can be a promising therapeutic strategy that has the potential to prevent cancer treatment-induced cardiovascular complications without reducing their anti-cancer effects. CYP1B1 is an extrahepatic enzyme that is expressed in cardiovascular tissues and overexpressed in different types of cancers. A growing body of evidence is demonstrating a detrimental role of CYP1B1 in both cardiovascular diseases and cancer, via perturbed metabolism of endogenous compounds, production of carcinogenic metabolites, DNA adduct formation, and generation of reactive oxygen species (ROS). Several chemotherapeutic agents have been shown to induce CYP1B1 in cardiovascular and cancer cells, possibly via activating the Aryl hydrocarbon Receptor (AhR), ROS generation, and inflammatory cytokines. Induction of CYP1B1 is detrimental in many ways. First, it can induce or exacerbate cancer treatment-induced cardiovascular complications. Second, it may lead to significant chemo/radio-resistance, undermining both the safety and effectiveness of cancer treatments. Therefore, numerous preclinical studies demonstrate that inhibition of CYP1B1 protects against chemotherapy-induced cardiotoxicity and prevents chemo- and radio-resistance. Most of these studies have utilized phytochemicals to inhibit CYP1B1. Since phytochemicals have multiple targets, future studies are needed to discern the specific contribution of CYP1B1 to the cardioprotective and chemo/radio-sensitizing effects of these phytochemicals.

New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies

“…Cardiovascular disease is the second cause of mortality in the group of cancer survivors, after secondary malignancies. Inhibition of the CYP1B1 can be a promising therapeutic strategy that has the potential to prevent firstly: chemoand radio-resistance to cancer therapy and secondly, treatment-induced cardiovascular complications without reducing their anti-cancer effects [11]. Most chemotherapeutic agents like doxorubicin, dasatinib, sunitinib, and docetaxel induce CYP1B1 gene expression in cardiac-derived cells in vitro and in animal models in vivo [11], leading to the resistance to cancer chemotherapy.…”

“…Inhibition of the CYP1B1 can be a promising therapeutic strategy that has the potential to prevent firstly: chemoand radio-resistance to cancer therapy and secondly, treatment-induced cardiovascular complications without reducing their anti-cancer effects [11]. Most chemotherapeutic agents like doxorubicin, dasatinib, sunitinib, and docetaxel induce CYP1B1 gene expression in cardiac-derived cells in vitro and in animal models in vivo [11], leading to the resistance to cancer chemotherapy. Increased CYP1B1 expression is associated with cardiac hypertrophy [35][36][37][38], hypertension [39][40][41][42][43], atherosclerosis [44], cardiotoxicity, and vascular dysfunction.…”

“…Efficacy of CYP1B1 inhibition in protection against chemotherapy-induced cardiotoxicity and in the prevention of chemo-and radio-resistance has been demonstrated in numerous preclinical studies. Phytochemicals such as quercetin, apigenin, and other polyphenols exhibit protective activity against cancer chemotherapeutics' side effects [11]. However, the activity of these agents is directed to many other targets and is also responsible for drug interactions.…”

“…On the other hand, the constitutively overexpressed CYP1B1 in cancer cells and the tumor microenvironment may be used to design anti-cancer prodrugs activated by this enzyme. Another pathway of CYP1B1 studies concerns the relation between mutations of the CYP1B1 gene and the occurrence of eye diseases [9,10] and cardiovascular disorders [11] (Figure 1). CYP1s are induced by agonists of the aryl hydrocarbon receptor (AhR), includin polychlorinated dioxins with strong inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD and polycyclic aromatic hydrocarbons [12,13].…”

Remodeling the Epigenetic Landscape of Cancer—Application Potential of Flavonoids in the Prevention and Treatment of Cancer

“…Research on flavonoids is inspired by their biological effects, including, but not limited to, antioxidation, free-radical scavenging, cell cycle regulation, anti-estrogens affects, protein tyrosine kinase inhibition, and epigenetic activity (211)(212)(213)(214). Plant compounds may exert a plethora of effects (215), which may, however, harbor some disadvantages (216,217). Flavonoids produce anticancer effects through various mechanisms, and unspecific action may be problematic for potential drug administration.…”