Strategies for the Improvement of Metal-Based Chemotherapeutic Treatments

Abstract

This article provides an overview of the various research approaches we have explored in recent years to improve metal-based agents for cancer or infection treatments. Although cisplatin, carboplatin, and oxaliplatin remain the cornerstones in tumor chemotherapy, the discovery and approval of novel inorganic anticancer drugs is a very slow process. Analogously, although a few promising inorganic drugs have found clinical application against parasitic or bacterial infections, their use remains relatively limited. Moreover, the discovery process is often affected by small therapeutic enhancements that are not attractive for the pharmaceutical industry. However, the availability of increasing mechanistic information for the modes of action of established inorganic drugs is fueling the exploration of various approaches for developing effective inorganic chemotherapy agents. Through a series of examples, some from our own research experience, we focus our attention on a number of promising strategies, including (1) drug repurposing, (2) the simple modification of the chemical structures of approved metal-based drugs, (3) testing novel drug combinations, and (4) newly synthesized complexes coupling different anticancer drugs. Accordingly, we aim to suggest and summarize a series of reliable approaches that are exploitable for the development of improved and innovative treatments.

Keywords: antibacterial agents; bioinorganic chemistry; cancer; drug development; drug repurposing; inorganic chemistry; metal-based drugs.

Figure 1

Chemical structure of auranofin [2,3,4,6-tetra-o-acetyl-L-thio-β-D-glycol-pyranoses-S-(triethyl-phosphine)-gold(I)].

Figure 2

Chemical structures of (from the left) cisplatin, carboplatin, and oxaliplatin.

Figure 3

Chemical structure of cis-PtI₂(NH₃)₂.

Figure 4

Chemical structure of Au(PEt₃)I.

Figure 5

The orthotopic model was established by injection of 1 × 10⁶ A2780-luc cells in the ovary bursa of nude mice. Left Panel (upper corner): Levels of ROI after 1 week of treatment; data are reported as the mean of each group (n = 10 animals/group) ± SD (** p < 0.01); (bottom) volume of tumor masses (mean ± SD) at sacrifice after 3 weeks from injection of A2780-luc cells (control group, n = 8; AF, n = 5; Au(PEt₃)I, n = 5). * p < 0.05, ** p < 0.01. Adapted from ref. [61]. Right panel Representative pseudocolor BLI images tracking A2780-luc cell emission in mice at increasing time intervals after A2780-luc injection. Color from blue (lower) to red (higher). The light intensity levels are reported as counts per minute (cpm). Adapted from ref. [61].

Scheme 1

Radicals’ production from the reaction of cisplatin with an electron donor (left) and chemical structure of Rhodamine-B (BV10) (right) [74].

Figure 6

Left panel: Time course of tumor growth in control, cisplatin-, cisplatin + riluzole-, and cisplatin + riluzole + E4031-treated mice. Cisplatin was administered at 0.35 mg kg⁻¹ for the first week and then lowered to 0.35 mg kg⁻¹ for the following 2 weeks to mimic resistance (see the scheme of treatment at the bottom). The slopes of the curves were: cisplatin = 0.056; cisplatin + riluzole = 0.036; cisplatin + riluzole + E4031 = 0.033. Right panel: The volume of tumor masses was measured at killing and calculated by applying the ellipsoid equation. Data are reported as the mean ± s.e.m. of the number of masses shown in the figure. The onset of chemoresistance was reproduced by treating the xenografted animals with full cisplatin doses first and then with very low doses. Statistical analysis was performed by one-way ANOVA (adapted from reference [79], Attribution-Non-Commercial-(CC BY-NC-SA 4.0)).

Figure 7

Synthetic strategy and mode of action of Pt(IV) prodrugs proposed by Gibson and coworkers. The axial position can be easily functionalized with two different biologically active molecules. Adapted from ref. [89].

Figure 8

Some representative metal-based complexes are coupled with bioactive molecules (1,2) and heterobimetallic cytotoxic compounds (3–8).

Figure 9

Chemical structure of arsenoplatin-1 (AP-1).

Figure 10

Summary of the NCI-60 human tumor cell line screen. AP-1 shows superior activity compared to arsenic trioxide in all nine indications tested; it also shows higher potency than cisplatin in breast, leukemia, colon, and CNS. Numbers in parentheses represent the number of cell lines tested for each indication, and the one-dose data are reported as a mean graph of the percentage growth of treated cells, according to the NCI-60 form. The cell growth in the one-dose assay is relative to the no-drug control and relative to the time zero number of cells, allowing the detection of both cellular growth inhibition (values between 0 and 100) and cellular lethality (values less than 0). (Reprinted with permission from reference [115]. Copyright 2019, American Chemical Society).