Metallodrugs: an approach against invasion and metastasis in cancer treatment

Abstract

Cancer is a heterogeneous and multifactorial disease that causes high mortality throughout the world; therefore, finding the most effective therapies is a major research challenge. Currently, most anticancer drugs present a limited number of well-established targets, such as cell proliferation or death; however, it is important to consider that the worse progression of cancer toward pathological stages implies invasion and metastasis processes. Medicinal Inorganic Chemistry (MIC) is a young area that deals with the design, synthesis, characterization, preclinical evaluation, and mechanism of action of new inorganic compounds, called metallodrugs. The properties of metallic ions allow enriching of strategies for the design of new drugs, enabling the adjustment of physicochemical and stereochemical properties. Metallodrugs can adopt geometries, such as tetrahedral, octahedral, square planar, and square planar pyramid, which adjusts their arrangement and facilitates binding with a wide variety of targets. The redox properties of some metal ions can be modulated by the presence of the bound ligands to adjust their interaction, thereby opening a range of mechanisms of action. In this regard, the mechanisms of action that trigger the biological activity of metallodrugs have been generally identified by: (a) coordination of the metal to biomolecules (for instance, cisplatin binds to the N7 in DNA guanine, as Pt-N via coordination of the inhibition of enzymes); (b) redox-active; and (c) ROS production. For this reason, a series of metallodrugs can interact with several specific targets in the anti-invasive processes of cancer and can prevent metastasis. The structural base of several metal compounds shows great anticancer potential by inhibiting the signaling pathways related to cancer progression. In this minireview, we present the advances in the field of antimetastatic effects of metallodrugs.

Keywords: cancer; invasion; metallodrugs; metastasis; transition metals.

Fig. 1

General process of metastasis. During the metastasis process, tumor cells follow a series of steps called the metastatic cascade, which consist of local invasion of nearby tissues, intravasation, survival in the circulation, arrest in distant organs, extravasation, and the establishment of metastasis. In order to carry out these processes, malignant cells lose their epithelial characteristics and acquire mesenchymal properties, this process is known as epithelial‐mesenchymal transition (EMT). At the cellular level, EMT is characterized by the loss of cell adhesion, increased mobility and invasiveness, and the secretion of extracellular matrix metalloproteases (MMPs); these changes are caused by the activation of signaling pathways such as TGF‐β or WNT / β‐catenin, increasing the expression of genes such as Snail1, Snail2, Twist, and Zeb‐1. Another key aspect for tumor development and metastasis is angiogenesis, a complex process that involves a highly regulated interaction of multiple signaling molecules. One of the most relevant pro‐angiogenic signaling molecules is vascular endothelial growth factor (VEGF) and its cognate receptor 2 (VEGFR‐2), because it promotes the formation of new blood vessels through cell migration, proliferation, and mobilization of endothelial progenitor cells; in addition, some interleukins play an important role in inflammation and the progression of metastasis, such as IL‐5, IL‐6, IL‐8, IL‐12, and IL‐17A. (Created with BioRender.com.).

Fig. 2

(A) Mechanism of action of cisplatin. Modern studies have revealed that copper transporter protein CTR1 is responsible for cisplatin uptake. Cisplatin activates both the intrinsic mitochondrial pathway and the extrinsic death receptor pathway of apoptosis. In addition, ER stress may also be induced. Among the three pathways, the intrinsic pathway, involving the mitochondria, is the major one. The administration of cisplatin causes cellular stress and results in the alteration of the mitochondrial membrane, leading to the release of apoptogenic factors such as apoptosis‐inducing factor (AIF), endonuclease G and cytochrome C, from the mitochondria into the cytosol. After being released from the mitochondria, endonuclease G and AIF accumulate in the nucleus, leading to apoptosis in a caspase‐independent manner while the released cytochrome C binds to the adaptor protein Apaf‐1 and induces its conformational changes, activating caspase 9, which, in turn, leads to activation of several downstream caspases for caspase‐dependent apoptosis. The ER‐stress pathway is also involved in apoptosis during cisplatin administration. Caspase 12, which localizes at the cytosolic face of the ER and is activated by ER stress, is the key initiator caspase in the ER pathway and in the extrinsic pathway. Binding of the death receptors by ligands results in the recruitment and activation of caspase 8, which leads to the activation of downstream caspases to trigger apoptosis. Furthermore, cisplatin induces oxidative stress by triggering the formation of reactive oxygen species (ROS), such as hydroxyl radical and, superoxides, which depends on the concentration of cisplatin and time of exposure. ROS are thought to be responsible for peroxidation of lipids, depletion of sulfhydryl groups, and alterations in various signal transduction pathways, which can cause DNA damage and consequently apoptosis of cells. Although cisplatin can bind to various biomolecules, it is generally considered that DNA is the major biological target, forming adducts. Adapted from ‘Apoptosis Extrinsic and Intrinsic Pathways’, by BioRender.com (2020) (Retrieved from https://app.biorender.com/biorender‐templates). (B) Platin drugs in the general process of metastasis. Cisplatin induces the expression of the transcription regulation factor ATF3, which suppresses a variety of genes related to the rearrangement of the cytoskeleton, the extracellular matrix, filopodia, and cell adhesion, including TGFβ/SMAD3 signaling and the β‐catenin signaling pathway (and consequently compromises MET), and cell migration in vitro and cancer metastasis in vivo. Similarly, PIP platinum can increase cell adhesion and block cell migration/invasion by inhibiting the Wnt signaling pathway due to nuclear translocation of β‐catenin (which is necessary for the activation of Wnt signaling) and inducing the translocation of β‐catenin in the cell membrane, which favors cell adhesion through E‐Cadherin. (Created with BioRender.com.).

Fig. 3

Metallodrugs in the general process of the invasion and metastasis. In order to undergo invasion and metastasis, malignant cells require different processes, which allow them to acquire invasive properties (mobility, degradation of the extracellular matrix, etc.); these changes are caused by the activation of signaling pathways such as TGF‐β or Wnt/β‐catenin, increasing the expression of genes such as Snail1, Snail2, Twist, and Zeb‐1. It also needs to mold its microenvironment by means of signaling molecules such as VEGF or EGF (angiogenesis) and interleukins that have an important role in inflammation and the progression of metastasis (such as IL‐5, IL‐6, IL‐8, IL‐12, and IL‐17A). To date, different metallodrugs have been described that can intervene or inhibit these processes. (Created with BioRender.com.).