Platinum F6-wh

[Nicol Allphin]

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Lung cancer is the most common cause of cancer-related deaths worldwide. More efficient treatments are desperately needed. For decades, the success of platinum-based anticancer drugs has promoted the exploration of metal-based agents. Four ruthenium-based complexes have also entered clinical trials as candidates of anticancer metallodrugs. However, systemic toxicity, severe side effects and drug-resistance impeded their applications and efficacy. Stimuli-responsiveness of Pt- and Ru-based complexes provide a great chance to weaken the side effects and strengthen the clinical efficacy in drug design. This review provides an overview on the stimuli-responsive Pt- and Ru-based metallic anticancer drugs for lung cancer. They are categorized as endo-stimuli-responsive, exo-stimuli-responsive, and dual-stimuli-responsive prodrugs based on the nature of stimuli. We describe various representative examples of structure, response mechanism, and potential medical applications in lung cancer. In the end, we discuss the future opportunities and challenges in this field.

Lung cancer (LC) is the most common malignancy and the top leading cause of cancer-related death worldwide (Govindan et al., 2006; Sung et al., 2021). Due to the lack of early clinical symptoms, most patients with LC are diagnosed at an advanced stage, resulting in the loss of opportunity for surgical treatment (Wang et al., 2015a). Platinum(II)-based chemotherapy is one of the pillars of clinical treatment for advanced LC (Chang, 2011; Pirker, 2020). The success of platinum-based anticancer drugs sparks interest in other metal-based anticancer drugs. Despite the dominance of small organic molecules and bio-derived compounds in the pharmaceutical market, metallic drugs continue to attract attention for their unique properties. In addition, four ruthenium complexes by far have successfully entered clinical trials and exhibited inspiring therapeutic effect on lung cancer metastasis.

Despite the great success of cisplatin in clinical usages, it still has some drawbacks, including significant side effects due to systemic toxicity, primary and acquired resistance, and low bioavailability for various reasons (Lippard, 1982; Wang and Lippard, 2005; Wang, 2010; Wang and Guo, 2013). Therefore, the development of metallic drugs urgently requires new strategies that can address these issues in a targeted manner. Prodrugs may be a potential strategy that can address the current metallic drugs dilemma. Prodrugs are inactive derivatives of a drug that are biotransformed in vivo to produce an active form for targeted drug delivery and therapy (Rautio et al., 2008; Bildstein et al., 2011; Redasani and Bari, 2015). To date, prodrugs have been at the forefront of improving the targeting and bioavailability of drugs and improving their physiochemical, pharmaceutical, and pharmacokinetic properties (Kratz et al., 2008; Mazzaferro et al., 2013; Walther et al., 2017).

One of the most important aspects of prodrug activation is the appropriate trigger (Zhang et al., 2017; Gu et al., 2018), which can be divided into two main categories: endogenous and exogenous stimuli (Chen et al., 2016a; Liu et al., 2016; Yang et al., 2016; Brun et al., 2017; Hu et al., 2017). Endogenous stimuli include redox gradients, pH values, enzyme concentrations, hormone levels, glucose concentrations, etc., usually related to pathological characteristics. Exogenous stimuli, such as light, temperature, magnetic fields, high-energy radiation, and ultrasound, remotely control prodrug activation by means outside the organism. In addition to the single triggers mentioned above, different triggers can act synergistically with each other to accomplish the activation of the drug. Therefore, the structural characteristics of the parent drug and its function in response to stimuli are prerequisites for the action of the prodrug. For metal drugs, the versatility of molecular structure and function makes them more likely to be qualified stimulus-responsive prodrugs (Van Rijt and Sadler, 2009; Schatzschneider, 2010; Graf and Lippard, 2012). Some recent studies have also shown the potential of some stimulus-responsive metal drugs to enhance pharmacological effects and reduce side effects, for example, some inactive complexes of metal ions in the oxidized state can be reductively activated in the reducing environment of the pathological state and transformed into the active form to exert their pharmacological effects (Van Rijt and Sadler, 2009; Romero-Canelon and Sadler, 2013).

Due to the great success of Pt- and Ru-based metallodrugs in clinical usages or in clinic trials, in this review we aim to summarize and analyze the representative stimulant-responsive Pt- and Ru-based agents in lung cancer therapy. These metallic anticancer agents are classified into three categories: endo-stimuli-responsive drugs, exo-stimuli-responsive drugs, and multi-stimuli-responsive drugs. The different stimulatory modalities are described in terms of design strategies, molecular structures, mechanisms of action and corresponding clinical applications. Finally, we discuss the future opportunities and challenges in this field.

Tumor development is a dynamic process involving a continuous interaction between tumor cells and the tumor microenvironment (Jin and Jin, 2020). Compared with normal tissues, tumor tissues have unique pathophysiological hallmarks, such as hypoxia, reducing environment, low pH, elevated reactive oxygen species (ROS) levels, elevated intracellular glutathione (GSH) levels, and abnormal expression of specific enzymes (Jin and Jin, 2020). These unique factors can act as endogenous triggers of the prodrug, specifically triggering the conversion of the prodrug and exerting its pharmacological effects (Mura et al., 2013; Gulzar et al., 2015). A large number of endo-stimuli-responsive metallic drugs triggered by redox, pH, and specific enzymes have been developed for these abnormal factors (Van Rijt and Sadler, 2009; Schatzschneider, 2010; Scaffidi-Domianello et al., 2011; Graf and Lippard, 2012; Ding et al., 2014). In this section, these metallic drugs are outlined according to different microenvironmental factors.

Metal ions such as Pt, Ru, Co and Fe have multiple oxidation states that can be regulated by ligands so that they can be activated in the reducing environment in the pathological state and thus release the active form of the drug. Thus, the redox reactivity of metal complexes has become one of the most successful classes of stimuli-responsive metal drugs designed.

Bioactive ligands are introduced to Pt(IV) prodrugs for seeking high anticancer efficacy in lung cancer (Figure 2). Overexpression of glutathione-S-transferase (GST) leads to cisplatin resistance (Nakajima et al., 2003). Etanercept (EA), a broad-spectrum GST inhibitor, can reverse GST-mediated cisplatin resistance (Takamatsu and Inaba, 1992). An EA-Pt (IV) complex 6 was developed based on this (Ang et al., 2005). Complex 6 inhibited GST activity in lung cancer A549 cells more strongly than EA and cisplatin alone. Complex 6 exhibited inhibitory effects on cisplatin-resistant A549 cells. Given that the long-term efficacy of EA is limited by toxicity due to diuresis and fluid imbalance (Ploemen et al., 1994), and that EA is readily transported out of the cell by specific pumps (Townsend and Tew, 2003), NBDHEX, a new GST inhibitor with stronger GST inhibition than EA and not transported by transport pumps (Ricci et al., 2005; Federici et al., 2009), was conjugated to oxoplatin via a succinic anhydride reaction to yield a new Pt(IV) complex 7 (Chen et al., 2019). Complex 7 showed stronger tumor suppression efficacy and less biotoxicity than cisplatin in animal studies.

Redox-responsive Pt(IV) prodrugs undergo reduction to form active Pt(II) drugs accompanied by the release bioactive molecules. Complexes 6 and 7 bear glutathione-S-transferase inhibitors; Complex 8 bears dichloroacetate as pyruvate dehydrogenase kinase inhibitor; complex 9 bears α-TOS as inhibitor for Bcl-xL-Bax protein-protein interaction; complexes 10-12 bear histone deacetylase inhibitors (HDACi); Complexes 13a,b bear perillic acid as anti-metastatic molecule; and complex 14 bears dual bioactive ligands: phenylbutyrate as HDACi and CA4 as tubulin polymerization inhibitor, respectively.

Based on the same strategy, a new Pt(IV) complex, named mitaplatin (8) with two dichloroacetate (DCA) axial ligands was developed (Dhar and Lippard, 2009). DCA is an inhibitor of pyruvate dehydrogenase kinase (Stacpoole et al., 2003). DCA promotes the release of cytochrome c (cyt c) and nuclear translocation of apoptosis-inducing factor (AIF) by altering the mitochondrial metabolism of tumor cells, ultimately leading to apoptosis without affecting normal cells (Bonnet et al., 2007). Thus, Complex 8 shows a dual-killing mode which targets the nuclear DNA with released cisplatin and mitochondria with released DCA. Complex 8 exhibited comparable cytotoxicity to cisplatin in lung cancer cells and did not induce normal cell death at the same concentration.

The combination of histone deacetylase inhibitors (HDACi) with platinum-based anticancer drugs has received much attention (Bots and Johnstone, 2009; Hrebackova et al., 2010). HDACi increases the acetylation level of histones, hinders the interaction of histones with DNA, and exposes nuclear DNA to DNA-damaging chemotherapeutic drugs (Bolden et al., 2006; Buchwald et al., 2009). The Pt(IV) complex is well suited for this combination therapy, reducing the side effects of traditional Pt(II) drugs while exert the chemosensitizing effect of HDACi. Based on the above idea, various Pt(IV) complexes with HDACi as axial ligand were developed. Valproic acid (VA)-Pt(IV) complexes (10) (Figure 2) are the first complexes of this type (Yang et al., 2012). Complex 10 showed enhanced antitumor activity in vitro and in vivo, and animal experiments confirmed the lower nephrotoxicity of complex 10 in vivo.

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