Targeting emerging cancer hallmarks by transition metal complexes: Epigenetic reprogramming and epitherapies. Part II

Highlights

• The development of many cancer types is associated with global epigenetic changes.

• Metal complexes were shown to interfere with the function of DNMTs, HMDs and HDACs.

• Metal prodrugs can be activated upon intracellular triggers.

• Selective release of epigenetic modulators might translate into lower toxicity.

• Transition metal complexes represent a promising alternative to existing epitherapies.

Abstract

In this last decade, our understanding of the complex factors and processes that drive cancer development and progression has broadened in scope and grown in depth. Today, it is widely held that as a disease, cancer can be characterized in terms of specific hallmarks that normal cells need to acquire to transform into malignant cells. Because it is both logical and intuitive, the hallmarks of cancer concept has been adopted by both the scientific and medical community as an organising principle to understand cancer and to develop new therapeutic approaches. Several new hallmarks have emerged in recent years arising from a better understanding of the crosstalk between cancer cells and their surrounding tumor microenvironment. The current review is based on the collaborative efforts of bioinorganic chemists, molecular biologists and medical doctors. It focuses on the use of transition metals as therapeutic drugs to treat malignancies arising from epigenetic dysregulation and compares the therapeutic approaches of transition metal complexes over existing drugs in clinical use.

Introduction

In 2000, Weinberg and Hanahan organized the evidence of cancer development and summarised the common capabilities shared by most human tumors into six essential alterations that are required by cells to acquire malignant phenotype [1]. These six essential alterations, including self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis and evading apoptosis were termed the “Hallmarks of Cancer” (Fig. 1). In 2011, two new hallmarks – deregulating cellular energetics and avoiding immune destruction, as well as two enabling characteristics – genome instability and tumor-promoting inflammation, were further included into the classification (Fig. 1) [2]. Recently, Hanahan further expanded the existing classification by the addition of four new hallmarks and enabling characteristics, including unlocking phenotypic plasticity, nonmutational epigenetic reprogramming, polymorphic microbiomes and senescent cells (Fig. 1) [3]. The newly added hallmarks and enabling characteristics revealed the emerging role of tumor microenvironment (TME) in cancer pathogenesis. Since TME was characterized by altered metal homeostasis, we hypothesized that rationally-designed transition metal complexes might interfere with the function of various TME components and might represent a promising therapeutic option for treating cancers. In Part I of this review, the therapeutic strategies developed for targeting phenotypic plasticity and cancer microbiome with transition metal were summarised and extensively covered [4]. Herein, we will focus on the use of transition metals as therapeutic drugs to treat malignancies arising from epigenetic dysregulation and compare the therapeutic approaches of transition metal complexes over existing treatment options.

The term “epigenetics” was originally proposed by C. H. Waddington in 1942 from the perspective of embryology [5] and literally means “in addition to or beyond genetics” [6]. Thus, epigenetics encompasses any process that results in a change in genes without altering DNA and can serve as a link between genotype and phenotype [7]. Epigenetic processes influence the implementation of the genetic code throughout the life of the cell and are affected by a wide range of factors, both physiological (e.g. embryological, aging) [8] and pathological (e.g. cancer) [9], [10]. Embryological epigenetic rearrangements have a greater impact on the implementation of the genetic program [11] because they occur in embryonic stem cells and can be transferred to more differentiated cell populations, in contrast to the changes that occur in adult cells [12], [13], [14]. However, pathological factors, such as the process of cancer development, were also shown to significantly influence epigenetic regulation of cells [15], [16], [17].

The analysis of differential epigenetic mechanisms in healthy and cancer patients revealed the potential role of epigenetics as a therapeutic target for cancer. Therapeutic modulation of epigenetic mechanisms governing cancer cells might be used to enhance the cytotoxicity of chemotherapeutic and targeted treatment regimens. On the other hand, regulation of epigenetic mechanisms in healthy cells might be useful for enhancing their defense activity. According to the current classification of major epigenetic mechanisms, they can be divided into three groups: 1) writers, which are responsible for modifications of DNA and histones; 2) readers, which recognize and elucidate these modifications, and 3) erasers, which are the proteins that can remove these modifications [18], [19]. This review will summarize the role of each group of epigenetic modulators in cancer development and describe the existing epitherapies, which are either approved by the FDA (Table 1) or currently investigated in clinical trials (Table 2). Subsequently, we will summarize transition metal complexes that have been developed to interfere with different epigenetic modulators involved in the nonmutational epigenetic reprogramming.