Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States of America.
Augsburg University, Minnesota, Minneapolis, MN, United States of America.
Clin Sci (Lond). 2020 Nov 13;134(21):2897-2927. doi: 10.1042/CS20200310.
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.
心血管并发症在癌症患者和幸存者中经常被报道，主要是因为各种心脏毒性的癌症治疗。尽管这些治疗方法存在已知的心血管毒性作用，但由于它们作为抗癌药物的有效性，它们仍在临床上使用。在这篇综述中，我们讨论了越来越多的证据表明，抑制细胞色素 P450 1B1 酶（CYP1B1）可能是一种有前途的治疗策略，它有可能预防癌症治疗引起的心血管并发症，而不降低其抗癌效果。CYP1B1 是一种细胞色素 P450 超家族中的细胞色素，在心血管组织中表达，并在不同类型的癌症中过度表达。越来越多的证据表明，CYP1B1 通过内源性化合物代谢紊乱、致癌代谢物的产生、DNA 加合物形成和活性氧（ROS）的产生，在心血管疾病和癌症中都具有有害作用。一些化疗药物已被证明可以在心血管和癌细胞中诱导 CYP1B1，可能通过激活芳香烃受体（AhR）、ROS 生成和炎症细胞因子。CYP1B1 的诱导在许多方面都是有害的。首先，它可以诱导或加重癌症治疗引起的心血管并发症。其次，它可能导致显著的化疗/放疗耐药性，从而破坏癌症治疗的安全性和有效性。因此，许多临床前研究表明，抑制 CYP1B1 可预防化疗引起的心脏毒性，并预防化疗和放疗耐药性。这些研究大多利用植物化学物质来抑制 CYP1B1。由于植物化学物质有多个靶点，因此需要进一步的研究来区分 CYP1B1 对这些植物化学物质的心脏保护和化疗/放疗增敏作用的具体贡献。
